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The neuroprotective potential of blueberry (BB) extracts against Alzheimer's disease (AD) has been previously hinted at, while its exact mechanism has remained largely enigmatic. Our study endeavored to unravel the impacts and mechanisms by which BB extracts ameliorated the learning and memory prowess of AD-afflicted mice, with a specific focus on the MEK-ERK pathway. We employed 3-month-old APP/PS1 transgenic mice and stratified them into three distinct groups: AD+BB, AD, and control (CT). The Morris Water Maze Test (MWMT) was then administered to gauge their learning and memory faculties. In vitro experiments were executed on Aβ25-35-afflicted rat hippocampal neurons, which were subsequently treated with varying concentrations of BB extracts. We then assessed the expression levels of genes and proteins integral to the MEK-ERKBDNF/UCH-L1 pathway. The data showed that the AD mice demonstrated compromised learning and memory faculties in MWMT. However, the AD+BB cohort showcased marked improvements in performance. Furthermore, in the AD subset, significant elevations in the expressions of MEK2 and ERK1/2 were observed, both at the mRNA and protein levels. Conversely, UCH-L1 mRNA expressions exhibited a decline, while BDNF expressions surged significantly. However, post BB extract treatment, the expressions of MEK2 and ERK1/2 were subdued, with UCH-L1 and BDNF mRNA expressions reverting to control levels. Our findings propounded that BB extracts could offer therapeutic promise for AD by bolstering learning and memory capacities. The unwarranted activation of the MEK-ERK pathway, coupled with the aberrant expressions of BDNF and UCH-L1, might underpin AD's pathogenesis. [ABSTRACT FROM AUTHOR]

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer's disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management. [ABSTRACT FROM AUTHOR]

Despite decades of rigorous research and numerous clinical trials, Alzheimer's disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer’s treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and ¹H-magnetic resonance spectroscopy (¹HMRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, ¹HMRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD. [ABSTRACT FROM AUTHOR]

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management.

Despite decades of rigorous research and numerous clinical trials, Alzheimer’s disease (AD) stands as a notable healthcare challenge of this century, with effective therapeutic solutions remaining elusive. Recently, the endocannabinoid system (ECS) has emerged as an essential therapeutic target due to its regulatory role in different physiological processes, such as neuroprotection, modulation of inflammation, and synaptic plasticity. This aligns with previous research showing that cannabinoid receptor ligands have the potential to trigger the functional structure of neuronal and brain networks, potentially impacting memory processing. Therefore, our study aims to assess the effects of prolonged, intermittent exposure (over 90 days) to JWH-133 (0.2 mg/kg) and an EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos, 2.5 mg/kg) on recognition memory, as well as their influence on brain metabolism and modulation of the expanded endocannabinoid system in APP/PS1 mice. Chronic therapy with cannabinoid receptor ligands resulted in reduced anxiety-like behavior and partially reversed the cognitive deficits. Additionally, a reduction was observed in both the number and size of Aβ plaque deposits, along with decreased cerebral glucose metabolism, as well as a decline in the expression of mTOR and CB2 receptors. Furthermore, the study revealed enlarged astrocytes and enhanced expression of M1 mAChR in mice subjected to cannabinoid treatment. Our findings highlight the pivotal involvement of the extended endocannabinoid system in cognitive decline and pathological aspects associated with AD, presenting essential preclinical evidence to support the continued exploration and assessment of cannabinoid receptor ligands for AD treatment.

This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients.

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Objective To study the effects of 50 Hz magnetic field exposure on metabolism of cerebral cortex in APP/PS1 transgenic mice. Methods Twelve 12-week-old male APP/PS1 double transgenic mice were randomly divided into the control group (C group) and the 50 Hz magnetic field exposure group (MF group) (n=6). The mice in the MF group were exposed to 1.0 mT 50 Hz magnetic field 2 h/d for 3 weeks (21 d). The mice in the sham exposure group had the same conditions as those in the MF group, except for no magnetic field exposure. After exposure, the cerebral cortex tissues of mice were taken according to the standard method for high-resolution untargeted metabonomics tests, including sample metabolite extraction, sample LC-MS/MS mass spectrometry analysis, metabolite qualitative and quantitative analysis and data analysis. Results The growth of APP/PS1 double transgenic mice were not affected after 50 Hz magnetic field exposure. The high-resolution untargeted metabonomics showed 1 068 metabolites were identified. Based on fold change analysis (FC>1.5 or FC < 0.67, P < 0.05), 22 significant changed metabolites were identified in cerebral cortex of mice after 50 Hz magnetic field exposure, and 11-keto-beta-boswellic acid was the most increased metabolite (FC=80.68), and 5-aminolevulinic acid was the most decreased metabolite (FC=0.34). Based on the variable importance in the projection (VIP) value of each variable in the orthogonal partial least-squares discriminant analysis (OPLS-DA) model (VIP>1, P < 0.05), 30 identified significant changed metabolites were screened in cerebral cortex of mice after 50 Hz magnetic field exposure. And the top 3 significant changed metabolites in VIP value were 2-oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine (VIP=19.76, FC=0.52), dehydroascorbic acid (VIP=12.71, FC=0.72) and inosine (VIP=10.64, FC=1.05). The analyses of hierarchical clustering, correlation and Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the 30 VIP significant changed metabolites may be involved in 16 KEGG pathways. L-aspartic acid, L-alanine and acetylcholine may be involved in 13, 7 and 3 pathways of the 16 KEGG pathways respectively. Conclusion The amino acid metabolism, ATP-binding cassette transporters, CoA and aminoacyl-tRNA biosynthesis, regulation of actin cytoskeleton and neuroactive ligand-receptor interaction may be impacted in cerebral cortex of APP/PS1 transgenic mice by 50 Hz magnetic field exposure.

Objective To compare and explore the histopathological and ultrastructural characteristics of the olfactory bulb in 6- and 12-month-old APP/PS1 double-transgenic mice and their spatial learning and memory ability, as well as the effects of memantine intervention.Methods Three-month-old SPF male APP/PS1 mice were randomly divided into 6- and 12-month-old model groups (named 6-APP/PS1 group and 12-APP/PS1 group, respectively) and memantine (MEM) groups (named 6-MEM group and 12-MEM group, respectively, the dose of MEM was 2.60 mg/kg/d), with 10 mice in each group. Age-matched C57BL/6 mice were used as the blank controls. The mice in the MEM groups were continuously administered MEM (from 3 months and 9 months, respectively) by gavage for 3 months, and the mice in the non-MEM group received equal volume of pure water for 3 months. The Morris water maze test was used to assess spatial learning and memory ability of those mice at 6 months and 12 months of age. After hematoxylin-eosin staining, the pathological morphology of the olfactory bulb was observed under an optical microscope, and the ultrastructure of the olfactory bulb was observed under a transmission electron microscope.Results The results of the water maze test revealed that the crossing numbers and the time spent in the target quadrant were significantly decreased in the 6-APP/PS1 and 12-APP/PS1 groups compared with the blank control group of the same age (all P < 0.05), whereas the 12-APP/PS1 group showed a more significant decrease than the 6-APP/PS1 group (both P < 0.05). Compared with the non-MEM group, the two parameters of the MEM treatment groups increased significantly (all P < 0.05). Histopathological observation showed that, compared with the age-matched blank group, the nerve cells in the olfactory bulb had no obvious atrophy and deformation, and the number of mitral cells was significantly reduced in the 6-APP/PS1 group (P < 0.05), while the nerve cells in the olfactory bulb were atrophic and deformed, and the number of periglomerular cells and mitral cells were significantly reduced in the 12-APP/PS1 group (all P < 0.05). Compared with the non-MEM group, the number of mitral cells were significantly increased in the 6-APP/PS1 group (P < 0.05), but there was no significant difference in the number of periglomerular cells and mitral cells in the 12-MEM group (all P > 0.05). Ultrastructural observation showed that, compared with the blank control group, the synaptic structure was swollen in the 6-APP/PS1 and 12-APP/PS1 groups, the thickness of the postsynaptic density was reduced and the number of asymmetric synapses decreased in the 6-APP/PS1 group, while the thickness of the postsynaptic density and the number of asymmetric synapses could not be observed clearly in the 12-APP/PS1 group. Compared with the non-MEM group, the synaptic swelling in the 6-MEM group was significantly improved, the thickness of the postsynaptic density and the number of asymmetric synapses increased, but the synaptic swelling in the 12-MEM group was not significantly improved, and the thickness of the postsynaptic density and the number of asymmetric synapses could not be observed.Conclusion Changes in the pathology and synaptic ultrastructural morphology of the olfactory bulbs in the APP/PS1 mice correlated with age, accompanied by behavioral alterations. MEM intervention not only improved spatial memory ability in the APP/PS1 mice, but also increased the number of mitral cells and alleviated the damage to the synaptic structure in the 6-APP/PS1 group, with significant improvement in early intervention.

PM 2.5 aggravated brain pathological injury and inflammatory responses in of AD mice. PM 2.5 increased Aβ−42 expression and induced neurotransmitter imbalance in AD mice. Selected miRNAs and genes have potential regulatory roles in brain of PM 2.5 -AD mice. Predicted signal pathways are significant in clarifying mechanism of PM 2.5 -caused AD. Fine particulate matter (PM 2.5) is associated with increased risks of Alzheimer's disease (AD), yet the toxicological mechanisms of PM 2.5 promoting AD remain unclear. In this study, wild-type and APP/PS1 transgenic mice (AD mice) were exposed to either filtered air (FA) or PM 2.5 for eight weeks with a real-world exposure system in Taiyuan, China (mean PM 2.5 concentration in the cage was 61 µg/m3). We found that PM 2.5 exposure could remarkably aggravate AD mice's ethological and brain ultrastructural damage, along with the elevation of the pro-inflammatory cytokines (IL-6 and TNF-α), Aβ-42 and AChE levels and the decline of ChAT levels in the brains. Based on high-throughput sequencing results, some differentially expressed (DE) mRNAs and DE miRNAs in the brains of AD mice after PM 2.5 exposure were screened. Using RT-qPCR, seven DE miRNAs (mmu-miR-193b-5p, 122b-5p, 466h-3p, 10b-5p, 1895, 384–5p, and 6412) and six genes (Pcdhgb8, Unc13b, Robo3, Prph, Pter, and Tbata) were evidenced the and verified. Two miRNA-target gene pairs (miR-125b-Pcdhgb8 pair and miR-466h-3p-IL-17Rα/TGF-βR2/Aβ-42/AChE pairs) were demonstrated that they were more related to PM 2.5 -induced brain injury. Results of Gene Ontology (GO) pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways predicted that synaptic and postsynaptic regulation, axon guidance, Wnt, MAPK, and mTOR pathways might be the possible regulatory mechanisms associated with pathological response. These revealed that PM 2.5 -elevated pro-inflammatory cytokine levels and PM 2.5 -altered neurotransmitter levels in AD mice could be the important causes of brain damage and proposed the promising miRNA and mRNA biomarkers and potential miRNA-mRNA interaction networks of PM 2.5 -promoted AD. [Display omitted]. [ABSTRACT FROM AUTHOR]

IntroductionAlzheimer’s disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown.MethodsWe used 11-month-old APP/PS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results.ResultsHere we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP/ PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APP/PS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APP/PS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2_Glycos_transf_2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6.ConclusionOur results indicated that the effects of Qi-Fu-Yin anti-aging of APP/PS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.

Anandamide (AEA) analogs show fair effects in counteracting the deterioration of Alzheimer's disease (AD). Our previous studies demonstrated that AEA analog-N-linoleyltyrosine (NITyr) exerted significant activities. In our current research, the role and mechanisms of NITyr were assessed in APP/PS1 mice mimicking the AD model. NITyr improved motor coordination in the rotarod test (RRT) and ameliorated spatial memory in the Morris water maze (MWM) but did not increase spontaneous locomotor activity in the open field test (OFT). In addition, NITyr protected neurons against β-amyloid (Aβ) injury via hematoxylin-eosin (HE) and Nissl staining. Moreover, the related biochemical indexes showed that NITyr reduced the levels of Aβ40 and Aβ42 in the hippocampus but did not affect the expression of p-APP and β-secretase 1 (BACE1). Furthermore, the autophagy inhibitor 3-methyladenine (3 MA) attenuated the effect of NITyr on animal behaviors and neurons. Meanwhile, NITyr upregulated the expression levels of LC3-II and Beclin-1, which were weakened by AM630 (an antagonist of CB2 receptor and a weak partial agonist of CB1 receptors). AM630 also weakened the role of NITyr in animal behaviors. Thus, NITyr improved behavioral impairment and neural loss by inducing autophagy mainly mediated by the CB2 receptor, and weakly mediated by the CB1 receptor.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Growing evidence suggests an important role for gut dysbiosis and gut microbiota-host interactions in aging and neurodegeneration. Our previous works have demonstrated that supplementation with the nicotinamide adenine dinucleotide (NAD+) precursor, nicotinamide riboside (NR), reduced the brain features of AD, including neuroinflammation, deoxyribonucleic acid (DNA) damage, synaptic dysfunction, and cognitive impairment. However, the impact of NR administration on the intestinal microbiota of AD remains unknown. In this study, we investigated the relationship between gut microbiota and NR treatment in APP/PS1 transgenic (AD) mice. Compared with wild type (WT) mice, the gut microbiota diversity in AD mice was lower and the microbiota composition and enterotype were significantly different. Moreover, there were gender differences in gut microbiome between female and male AD mice. After supplementation with NR for 8 weeks, the decreased diversity and perturbated microbial compositions were normalized in AD mice. This included the species Oscillospira, Butyricicoccus, Desulfovibrio, Bifidobacterium, Olsenella, Adlercreutzia, Bacteroides, Akkermansia, and Lactobacillus. Our results indicate an interplay between NR and host-microbiota in APP/PS1 mice, suggesting that the effect of NR on gut dysbiosis may be an important component in its therapeutic functions in AD. [ABSTRACT FROM AUTHOR]

Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model. Methods In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb–KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses. Results The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system. Conclusions These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. Graphical Abstract

Background: Synaptic abnormalities in synaptic proteins are the initial hallmarks of Alzheimer's disease (AD). The higher level of palmitoylation of synaptic proteins was closely associated with amyloid-β (Aβ) in AD. Cattle encephalon glycoside and ignotin (CEGI) have been shown to act as multitarget neurotrophic agents in APPswe/PS1dE9 (APP/PS1) transgenic AD mice. However, it is not clear whether CEGI can influence Aβ deposition or whether it does so by the regulation of protein palmitoylation and expression of synaptic proteins in transgenic AD mice.Objective: In this study, we investigated the roles of CEGI in modulating postsynaptic density protein 95 (PSD-95) palmitoylation, Aβ pathologies, and expression of synaptic-associated proteins in APP/PS1 mice.Methods: Five-month-old APP/PS1 mice were treated intraperitoneally with 6.6 mL/kg of CEGI for 6 weeks. At the end of the treatment period, APP/PS1 mice were subjected to Morris water maze to test their cognitive functions. Acyl-biotinyl exchange (ABE) for PSD-95 palmitoylation, immunofluorescent staining for expression of PSD-95, N-methyl-D-aspartic acid receptor subunit 2B (NR2B), and synaptotagmin 1 (SYT1) were assessed in mouse brain sections.Results: CEGI treatment in APP/PS1 mice significantly reduced Aβ deposition, relieved memory deficits, and decreased PSD-95 palmitoylation while markedly increasing the expression of PSD-95, NR2B, and SYT1 in the frontal cortex. There was a significant correlation between Aβ expression and PSD-95 palmitoylation in APP/PS1 mice.Conclusion: Our findings demonstrate that CEGI improved AD-like neuropathology, possibly by inhibiting PSD-95 palmitoylation, improving learning memory, and enhancing expression of synaptic-associated proteins, representing a potential therapy for AD treatment. [ABSTRACT FROM AUTHOR]

Abstract Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer’s Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice. Using local injections of the AAV virus containing LIMK1 under the control of the CaMKIIα promoter, we show that expression of LIMK1 in hippocampal excitatory neurons increases cofilin phosphorylation (i.e., decreases cofilin activity), rescues impairments in long-term potentiation, and improves social memory in APP/PS1 mice. Our results suggest that deficits in LIMK1/cofilin signaling in the hippocampal excitatory neurons contribute to AD pathology and that manipulations of LIMK1/cofilin activity provide a potential therapeutic strategy to treat AD.

Abstract Background Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD’s improvement in cognitive function remain unclear. In this study, we examined SZRD’s effect on APP/PS1 transgenic mice and mechanisms associated with SZRD’s action in alleviating neuroinflammation and improving synaptic plasticity. Methods The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P

Background: The neuroprotective potential of blueberry (BB) extracts against Alzheimer's disease (AD) has been previously hinted at, while its exact mechanism has remained largely enigmatic., Objective: Our study endeavored to unravel the impacts and mechanisms by which BB extracts ameliorated the learning and memory prowess of AD-afflicted mice, with a specific focus on the MEK-ERK pathway., Methods: We employed 3-month-old APP/PS1 transgenic mice and stratified them into three distinct groups: AD+BB, AD, and control (CT). The Morris Water Maze Test (MWMT) was then administered to gauge their learning and memory faculties. In vitro experiments were executed on Aβ25-35-afflicted rat hippocampal neurons, which were subsequently treated with varying concentrations of BB extracts. We then assessed the expression levels of genes and proteins integral to the MEK-ERKBDNF/UCH-L1 pathway., Results: The data showed that the AD mice demonstrated compromised learning and memory faculties in MWMT. However, the AD+BB cohort showcased marked improvements in performance. Furthermore, in the AD subset, significant elevations in the expressions of MEK2 and ERK1/2 were observed, both at the mRNA and protein levels. Conversely, UCH-L1 mRNA expressions exhibited a decline, while BDNF expressions surged significantly. However, post BB extract treatment, the expressions of MEK2 and ERK1/2 were subdued, with UCH-L1 and BDNF mRNA expressions reverting to control levels., Conclusions: Our findings propounded that BB extracts could offer therapeutic promise for AD by bolstering learning and memory capacities. The unwarranted activation of the MEK-ERK pathway, coupled with the aberrant expressions of BDNF and UCH-L1, might underpin AD's pathogenesis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by pathological deposition of misfolded self-protein amyloid beta (Aβ) which in kind facilitates tau aggregation and neurodegeneration. Neuroinflammation is accepted as a key disease driver caused by innate microglia activation. Recently, adaptive immune alterations have been uncovered that begin early and persist throughout the disease. How these occur and whether they can be harnessed to halt disease progress is unclear. We propose that self-antigens would induct autoreactive effector T cells (Teffs) that drive pro-inflammatory and neurodestructive immunity leading to cognitive impairments. Here, we investigated the role of effector immunity and how it could affect cellular-level disease pathobiology in an AD animal model.Methods: In this report, we developed and characterized cloned lines of amyloid beta (Aβ) reactive type 1 T helper (Th1) and type 17 Th (Th17) cells to study their role in AD pathogenesis. The cellular phenotype and antigen-specificity of Aβ-specific Th1 and Th17 clones were confirmed using flow cytometry, immunoblot staining and Aβ T cell epitope loaded haplotype-matched major histocompatibility complex II IAb (MHCII-IAb-KLVFFAEDVGSNKGA) tetramer binding. Aβ-Th1 and Aβ-Th17 clones were adoptively transferred into APP/PS1 double-transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1, and the mice were assessed for memory impairments. Finally, blood, spleen, lymph nodes and brain were harvested for immunological, biochemical, and histological analyses.Results: The propagated Aβ-Th1 and Aβ-Th17 clones were confirmed stable and long-lived. Treatment of APP/PS1 mice with Aβ reactive Teffs accelerated memory impairment and systemic inflammation, increased amyloid burden, elevated microglia activation, and exacerbated neuroinflammation. Both Th1 and Th17 Aβ-reactive Teffs progressed AD pathology by downregulating anti-inflammatory and immunosuppressive regulatory T cells (Tregs) as recorded in the periphery and within the central nervous system.Conclusions: These results underscore an important pathological role for CD4+ Teffs in AD progression. We posit that aberrant disease-associated effector T cell immune responses can be controlled. One solution is by Aβ reactive Tregs. [ABSTRACT FROM AUTHOR]

Vitamin A deficiency (VAD) plays an essential role in the pathogenesis of Alzheimer's disease (AD). However, the specific mechanism by which VAD aggravates cognitive impairment is still unknown. At the intersection of microbiology and neuroscience, the gut-brain axis is undoubtedly contributing to the formation and function of neurological systems, but most of the previous studies have ignored the influence of gut microbiota on the cognitive function in VAD. Therefore, we assessed the effect of VAD on AD pathology and the decline of cognitive function in AD model mice and determined the role played by the intestinal microbiota in the process. Twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were randomly assigned to either a vitamin A normal (VAN) or VAD diet for 45 weeks. Our results show that VAD aggravated the behavioral learning and memory deficits, reduced the retinol concentration in the liver and the serum, decreased the transcription of vitamin A (VA)-related receptors and VA-related enzymes in the cortex, increased amyloid-β peptides (Aβ40 and Aβ42) in the brain and gut, upregulate the translation of beta-site APP-cleaving enzyme 1 (BACE1) and phosphorylated Tau in the cortex, and downregulate the expression of brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) receptors in the cortex. In addition, VAD altered the composition and functionality of the fecal microbiota as exemplified by a decreased abundance of Lactobacillus and significantly different α- and β-diversity. Of note, the functional metagenomic prediction (PICRUSt analysis) indicated that GABAergic synapse and retinol metabolism decreased remarkably after VAD intervention, which was in line with the decreased expression of GABA receptors and the decreased liver and serum retinol. In summary, the present study provided valuable facts that VAD exacerbated the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice, and the intestinal microbiota may play a key mediator role in this mechanism. [ABSTRACT FROM AUTHOR]

Vitamin A deficiency (VAD) plays an essential role in the pathogenesis of Alzheimer’s disease (AD). However, the specific mechanism by which VAD aggravates cognitive impairment is still unknown. At the intersection of microbiology and neuroscience, the gut-brain axis is undoubtedly contributing to the formation and function of neurological systems, but most of the previous studies have ignored the influence of gut microbiota on the cognitive function in VAD. Therefore, we assessed the effect of VAD on AD pathology and the decline of cognitive function in AD model mice and determined the role played by the intestinal microbiota in the process. Twenty 8-week-old male C57BL/6J amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were randomly assigned to either a vitamin A normal (VAN) or VAD diet for 45 weeks. Our results show that VAD aggravated the behavioral learning and memory deficits, reduced the retinol concentration in the liver and the serum, decreased the transcription of vitamin A (VA)-related receptors and VA-related enzymes in the cortex, increased amyloid-β peptides (Aβ40 and Aβ42) in the brain and gut, upregulate the translation of beta-site APP-cleaving enzyme 1 (BACE1) and phosphorylated Tau in the cortex, and downregulate the expression of brain-derived neurotrophic factor (BDNF) and γ-aminobutyric acid (GABA) receptors in the cortex. In addition, VAD altered the composition and functionality of the fecal microbiota as exemplified by a decreased abundance of Lactobacillus and significantly different α- and β-diversity. Of note, the functional metagenomic prediction (PICRUSt analysis) indicated that GABAergic synapse and retinol metabolism decreased remarkably after VAD intervention, which was in line with the decreased expression of GABA receptors and the decreased liver and serum retinol. In summary, the present study provided valuable facts that VAD exacerbated the morphological, histopathological, molecular biological, microbiological, and behavioral impairment in the APP/PS1 transgenic mice, and the intestinal microbiota may play a key mediator role in this mechanism.

Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer's Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice. Using local injections of the AAV virus containing LIMK1 under the control of the CaMKIIα promoter, we show that expression of LIMK1 in hippocampal excitatory neurons increases cofilin phosphorylation (i.e., decreases cofilin activity), rescues impairments in long-term potentiation, and improves social memory in APP/PS1 mice. Our results suggest that deficits in LIMK1/cofilin signaling in the hippocampal excitatory neurons contribute to AD pathology and that manipulations of LIMK1/cofilin activity provide a potential therapeutic strategy to treat AD. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of running exercise on the number of dendritic spines in the medial prefrontal cortex in an APP/PS1 double transgenic mouse model of Alzheimer's disease (AD). Methods Twelve-month-old male APP/PS1 transgenic mice were randomly divided into control group and running exercise group (n=10), and 10 wild-type littermates of the transgenic mice served as the wild-type control group. The mice in the running exercise group were subjected to forced running exercise for 4 months. The spatial learning and memory abilities of the mice were tested using Morris water maze test, and the total number of the dendritic spines in the medial prefrontal cortex was accurately determined using a unbiased stereological method. Results In the hidden platform task, the escape latency was significantly longer in the control group than in the wild-type control group and the running exercise group (F=15.738, P < 0.001). In the probe task, the frequency of platform location crosses, the time spending in the target quadrant and the percentage distance in the target quadrant all differed significantly among the 3 groups (P < 0.001). The total number of dendritic spines in the medial prefrontal cortex was significantly smaller in the control group than in the running exercise group (P=0.029) and the wild-type control group (P=0.005). Conclusion Running exercise can reduce dendritic spine loss in the medial prefrontal cortex of APP/PS1 transgenic mouse models of AD.

Although lots of new drugs are developed to treat Alzheimer’s disease (AD), many clinical trials of monotherapy have failed to affect disease progression or symptoms compared with placebo. Recently, scientists believe that combination treatment is more promising than monotherapy. Previous studies found that microRNA-195 (miR-195) was down-regulated in the hippocampi and cortices of chronic brain hypoperfusion (CBH) rats and ApoE4(+/+) mice, and up-regulation of miR-195 can improve the declined cognitive function of ApoE4(+/+) mice and CBH rats by targeting multi-genes that are related to AD pathology, including amyloid precursor protein (APP) and β-site APP cleaving enzyme 1 (BACE1) genes. However, whether the gain-of-function of miR-195 could improve the impaired learning and memory ability of APP/PS1 transgenic mouse has not been reported. In this study, we stereotaxically injected lentiviral-carried miR-195 into the bilateral hippocampus of 4-month-old (4M) APP/PS1 mice. Morris water maze (MWM) was performed to detect the effect of miR-195 on the cognitive function of APP/PS1 mice after 1M, 2M, and 3M treatment. Western blot was used to detect the expression of APP, BACE1, and AT8. Aβ plagues were quantitatively assessed by immunofluorescence technique. We found that the declined cognitive phenotype of APP/PS1 mice occurred at the age of 6M, not at the age of 5M. And treatment of Lv-pre-miR-195 to APP/PS1 mice for 1M did not achieve any changes. Although Lv-pre-miR-195 treatment for 2M improved the declined learning ability of APP/PS1 mice, it did not affect the memory functions. However, Lv-pre-miR-195 treatment in APP/PS1 mice for 3M can effectively improve both the learning and memory ability of APP/PS1 mice at the age of 7M. Further studies demonstrated that gain-of-function of miR-195 by Lv-pre-miR-195 injection could inhibit the increased APP and AT8 expression of APP/PS1 mice but did not affect BACE1 level that was not changed in both hippocampus and cortex. By counting the number of Aβ plaques of different sizes, we found that Lv-pre-miR-195 treatment mainly reduced the number of Aβ plaques of less than 20 μm, but did not affect the number of Aβ plaques of greater than 50 μm. Taken together, the gain-of -function of miR-195 in the hippocampus can improve the cognition of APP/PS1 mice, probably by blocking the formation of Aβ plagues rather than clearing those that have already formed Aβ plagues.

• Alpha-asarone improves the cognitive function of APP/PS1 transgenic mice. • Alpha-asarone reduced Aβ 42 and p-tau protein levels in the hippocampus. • Alpha-asarone reduced the brain GFAP expression and alleviated neuroinflammation. • Alpha-asarone decreased autophagosomes and promoted hippocampal neuron survival. • Alpha-asarone might be a promising drug candidate for the treatment of AD. Alzheimer's disease (AD) is a progressive neurodegenerative disease most often characterized by memory impairment and cognitive decline. Alpha-asarone has been reported to have the potential to treat AD. Our previous studies have found that alpha-asarone improves aged rats' cognitive function by alleviating neuronal excitotoxicity via type A gamma-aminobutyric acid (GABA) receptors. GABA level's change, neuroinflammation, and dysfunctional autophagy are found to be associated with AD. However, the effect of alpha-asarone on cognitive function of APP/PS1 transgenic mice and its underlying mechanism in terms of aggregation of amyloid-β42 (Aβ 42) and phosphorylated tau (p-tau), glutamic acid decarboxylase (GAD) level, neuroinflammation, and autophagy are unclear. Accordingly, we attempted to explore whether alpha-asarone improves AD mice's cognitive function and alleviates pathological symptoms by regulating GAD level, inhibiting neuroinflammation, or restore autophagy. We found that alpha-asarone enhanced spatial learning memory and decreased Aβ 42 and p-tau levels without influencing the GAD level in APP/PS1 transgenic mice. Also, it decreased the GFAP expression and reduced pro-inflammatory cytokines levels, thus alleviating neuroinflammation. Furthermore, alpha-asarone decreased the excess number of autophagosomes and promoted hippocampal neurons' survival. In conclusion, the results confirmed the therapeutic effect of alpha-asarone on AD-related astrogliosis, dysfunctional autophagy, and neuronal damage, which indicates its great potential to treat AD. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Evidence suggests that people can benefit from consumption of diets rich in plant phenolics because they can attenuate AD symptoms. The phenolic glucoside gastrodin is the main bioactive compound of Rhizoma Gastrodiae and is widely used for treating various neurological disorders. In this study, we assess whether long term oral administration of gastrodin can improve cognitive impairment and AD-like pathology. Our results showed that chronic gastrodin administration inhibits aggregation and disaggregate oligomeric and fibrillar species of Aβ42, prevents Aβ42 induced neurotoxicity in cell SH-SY5Y, decreases the levels of Aβ plaques and hyperphosphorylated tau, alleviates activation of glial cells and proinflammatory cytokines, attenuates oxidative stress in the APP/PS1 transgenic mice. The mechanisms underlying can be attributed to the inhibition levels of enzymes of Aβ and prevention GSK3β activity. Our results suggest that gastrodin might be a potential agent for thetreatment of AD.

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model.

Studies on the effective and safe therapeutic dosage of delta-9-tetrahydrocannabinol (THC) for the treatment of Alzheimer’s disease (AD) have been sparse due to the concern about THC’s psychotropic activity. The present study focused on demonstrating the beneficial effect of low-dose THC treatment in preclinical AD models. The effect of THC on amyloid-β (Aβ) production was examined in N2a/AβPPswe cells. An in vivo study was conducted in aged APP/PS1 transgenic mice that received an intraperitoneal injection of THC at 0.02 and 0.2 mg/kg every other day for three months. The in vitro study showed that THC inhibited Aβ aggregation within a safe dose range. Results of the radial arm water maze (RAWM) test demonstrated that treatment with 0.02 and 0.2 mg/kg of THC for three months significantly improved the spatial learning performance of aged APP/PS1 mice in a dose-dependent manner. Results of protein analyses revealed that low-dose THC treatment significantly decreased the expression of Aβ oligomers, phospho-tau and total tau, and increased the expression of Aβ monomers and phospho-GSK-3β (Ser9) in the THC-treated brain tissues. In conclusion, treatment with THC at 0.2 and 0.02 mg/kg improved the spatial learning of aged APP/PS1 mice, suggesting low-dose THC is a safe and effective treatment for AD.

Background: Suan-Zao-Ren Decoction (SZRD) has been widely used to treat neurological illnesses, including dementia, insomnia and depression. However, the mechanisms underlying SZRD's improvement in cognitive function remain unclear. In this study, we examined SZRD's effect on APP/PS1 transgenic mice and mechanisms associated with SZRD's action in alleviating neuroinflammation and improving synaptic plasticity. Methods: The APP/PS1 mice were treated with different dosages of SZRD (12.96 and 25.92 g/kg/day, in L-SZRD and H-SZRD groups, respectively) for 4 weeks. Morris water maze was conducted to determine changes in behaviors of the mice after the treatment. Meanwhile, in the samples of the hippocampus, Nissl staining and Golgi-Cox staining were used to detect synaptic plasticity. ELISA was applied to assess the expression levels of Aβ1−40 and Aβ1−42 in the hippocampus of mice. Western blot (WB) was employed to test the protein expression level of Aβ1−42, APP, ADAM10, BACE1, PS1, IDE, IBA1, GFAP, PSD95 and SYN, as well as the expressions of JAK2, STAT3 and their phosphorylation patterns to detect the involvement of JAK2/STAT3 pathway. Besides, we examined the serum and hippocampal contents of IL-1β, IL-6 and TNF-α through ELISA. Results: Compared to the APP/PS1 mice without any treatment, SZRD, especially the L-SZRD, significantly ameliorated cognitive impairment of the APP/PS1 mice with decreases in the loss of neurons and Aβ plaque deposition as well as improvement of synaptic plasticity in the hippocampus (P < 0.05 or 0.01). Also, SZRD, in particular, the L-SZRD markedly inhibited the serum and hippocampal concentrations of IL-6, IL-1β and TNF-α, while reducing the expression of p-JAK2-Tyr1007 and p-STAT3-Tyr705 in the hippocampus of the APP/PS1 mice (P < 0.05 or 0.01). Conclusions: The SZRD, especially the L-SZRD, may improve the cognitive impairment and ameliorate the neural degeneration in APP/PS1 transgenic mice through inhibiting Aβ accumulation and neuroinflammation via the JAK2/STAT3 pathway. [ABSTRACT FROM AUTHOR]

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2′3′cyclic nucleotide 3′-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3β (GSK3β) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3β through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3β on oligodendrocyte maturation in the hippocampus of an AD mouse model. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common neurodegenerative disease that is always accompanied by synaptic loss in the brain. Safflower yellow (SY) is the extract of safflower, a traditional Chinese medicine, which has shown neuroprotective effects in recent studies. However, the mechanism of SY in protecting synapses remains unclear. In this study, we are going to study the mechanism of how SY treats AD in terms of synaptic plasticity. We found, via behavioral experiments, that SY treatment could improve the abilities of learning and memory in APP/PS1 mice. In addition, using Golgi staining and HE staining, we found that SY treatment could reduce the loss of dendritic spines in the pathological condition and could maintain the normal physiological state of the cells in cortex and in hippocampus. In addition, the results of immunofluorescence staining and western blotting showed that SY treatment could significantly increase the expression of synapse-related proteins. Moreover, after being treated with SY, the expression of iNOS (marker of M1 microglia) declined remarkably, and the level of Arginase-1 (marker of M2 microglia) increased significantly. Finally, we found BDNF/TrkB/ERK signaling cascade was activated. These results indicate that SY enhances synaptic plasticity in APP/PS1 mice by regulating microglia activation phenotypes and BDNF/TrkB/ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Sirtuin 2 (SIRT2) is an NAD+ dependent deacetylase that is the most abundant sirtuin protein in the brain. Accumulating evidence revealed the role of SIRT2 in a wide range of biological processes and age‐related diseases. However, the pivotal mechanism of SIRT2 played in Alzheimer's disease (AD) remains unknown. Here, we report that pharmacological inactivation of SIRT2 has a beneficial effect in AD. The deacetylase inhibitor of SIRT2 rescued the cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mouse (APP/PS1 mouse), and the BACE1 cleavage was weakened to reduce the β‐amyloid (Aβ) production in the hippocampus. Moreover, we firstly identified that Reticulon 4B (RTN4B) played a crucial role between SIRT2/BACE1 regulation in AD. RTN4B, as a deacetylation substrate for SIRT2, the deacetylation by SIRT2 drived the ubiquitination and degradation of RTN4B and then the disturbed RTN4B interacted with and influenced the expression of BACE1. When we overexpressed RTN4B in neurons of the hippocampus in the AD mouse model, the abnormal Aβ accumulation and cognitive impairment were ameliorated, consistent with the results of SIRT2 inhibition in vivo. Moreover, we showed that the regulatory effect of SIRT2 on BACE1 is dependent on RTN4B. When RTN4B was knocked down, the effects of SIRT2 inhibition on the BACE1 level, Aβ pathology, and AD‐liked behaviors were also blocked. Collectively, we provide evidence that SIRT2 may be a potential target for AD; the new found SIRT2/RTN4B/BACE1 pathological pathway is one of the critical mechanisms for the improvement of SIRT2 on AD. [ABSTRACT FROM AUTHOR]

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-β protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-β plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD. • Suvorexant treatment ameliorates the cognitive impairments in APP/PS1 mice. • Suvorexant treatment alleviates in vivo hippocampal LTP suppression in APP/PS1 mice. • Suvorexant treatment restores the circadian rhythm of pCREB expression in the hippocampus in APP/PS1 mice. • Suvorexant treatment reduces Aβ deposition in the hippocampus and cortex in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD. [ABSTRACT FROM AUTHOR]

Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer's disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity. [ABSTRACT FROM AUTHOR]

Cognitive decline, memory impairment and circadian rhythm disturbance are iconic manifestations of Alzheimer's disease (AD). APPswe/PS1dE9 (APP/PS1) mice, a model of AD, show deficits in multiple learning and memory abilities, synaptic plasticity, and behavioral circadian rhythm, but whether circadian differences in cognitive performance and synaptic plasticity could be affected in AD remain unclear. Here, the cognitive behaviors of 6-month-old APP/PS1 mice were assessed by multiple behavior tests in the rest phase (light period) or active phase (dark period) of the day. The possible electrophysiological mechanism was subsequently investigated by in vivo hippocampal long-term potentiation (LTP) recording, and the locomotor activity rhythm of the mice was detected using wheel-running activities. Compared to wild-type (WT) mice, APP/PS1 mice exhibited long-term spatial memory impairment and in vivo hippocampal LTP suppression. In addition, in APP/PS1 mice, circadian differences in new object recognition memory and LTP were lost, and the circadian difference in long-term spatial memory was decreased, accompanied by a less robust locomotor activity rhythm. These results indicate that the loss of circadian differences in new object recognition memory and the decrease in the circadian difference in long-term spatial memory in APP/PS1 mice, which are closely associated with the loss of the circadian difference in LTP and less robust locomotor activity, might occur early in the course of AD. [ABSTRACT FROM AUTHOR]

Aggregated β‐amyloid (Aβ) is widely considered as a key factor in triggering progressive loss of neuronal function in Alzheimer's disease (AD), so targeting and inhibiting Aβ aggregation has been broadly recognized as an efficient therapeutic strategy for curing AD. Herein, we designed and prepared an organic platinum‐substituted polyoxometalate, (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2] (abbreviated as PtII‐PW11) for inhibiting Aβ42 aggregation. The mechanism of inhibition on Aβ42 aggregation by PtII‐PW11 was attributed to the multiple interactions of PtII‐PW11 with Aβ42 including coordination interaction of Pt2+ in PtII‐PW11 with amino group in Aβ42, electrostatic attraction, hydrogen bonding and van der Waals force. In cell‐based assay, PtII‐PW11 displayed remarkable neuroprotective effect for Aβ42 aggregation‐induced cytotoxicity, leading to increase of cell viability from 49 % to 67 % at a dosage of 8 μm. More importantly, the PtII‐PW11 greatly reduced Aβ deposition and rescued memory loss in APP/PS1 transgenic AD model mice without noticeable cytotoxicity, demonstrating its potential as drugs for AD treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1 H-magnetic resonance spectroscopy ( 1 H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1 H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD., Competing Interests: YS was employed by Shenzhen Cell Valley Biopharmaceuticals Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Liu, Liu, Gong, Li, Zhang, Shi and Shi.)

Alzheimer's disease (AD) is a chronic neurodegenerative disease and mitochondrial impairment is a key feature of AD. The mitochondrial DNA (mtDNA) epigenetic mechanism is a relatively new field compared to nuclear DNA. The relationship between mtDNA epigenetic mechanism and AD hasn't been established. So we analyzed the mtDNA methylation in D-loop region and 12 S rRNA gene in the hippocampi in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice by bisulfite pyrosequencing. Mitochondrial DNA copy number and gene expression were studied by quantitative real-time PCR (qRT-PCR). We observed a decrease in the displacement loop (D-loop) methylation and an increase in 12 S rRNA gene methylation, while both the mtDNA copy number and the mitochondrial gene expression were reduced in APP/PS1 transgenic mice. In summary, the present finding suggest that mtDNA methylation may play a role in AD pathology, which warrants larger future investigations. • We analyzed the mtDNA methylation in D-loop region and 12 S rRNA gene in the hippocampi in APP/PS1 transgenic mice by bisulfite pyrosequencing. • There were only two studies performed so far to investigate mtDNA D-loop methylation in AD. • And this is the first study to demonstrate a link between the hypermethylation of 12 S rRNA gene and AD. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. [ABSTRACT FROM AUTHOR]

With aging, there are progressive functional declines in multiple organ systems. One of the major physiological problems observed in aged people is skeletal muscle loss. This age-related muscle loss causes muscle weakness and disability, which in turn might reduce the quality of life in older adults and lead to the progression of several diseases, particularly Alzheimer's disease (AD). Some researchers have hypothesized that loss of muscle mass and strength is linked to the risk of developing AD. In addition, unintended weight loss often occurs in AD patients and might reflect dementia severity. However, the causal relationship between muscle atrophy and cognitive deficits in AD is unclear. We found that double transgenic amyloid precursor protein and presenilin 1 (APP/PS1) mice that co-express APP and PS1 at older ages exhibited lower body weight and lean tissue mass than sex- and age-matched wild-type (WT) mice. In addition, muscle atrophy and the extent of memory decline were strongly correlated in APP/PS1 mice. Myostatin levels in the gastrocnemius (GAS) muscle of 12-month-old APP/PS1 mice were elevated. We determined that the cellular and molecular mechanism of muscle atrophy was through the ubiquitin-proteasome pathway. Furthermore, myostatin knockdown in the GAS muscles increased grip strength and muscle mass, leading to memory improvement in myostatin short-hairpin RNA-treated APP/PS1 mice. We conclude that high-level myostatin expression might mediate or trigger muscle atrophy and cognitive deficits. [ABSTRACT FROM AUTHOR]

Abstract Background Alzheimer's disease (AD) is the most common type of dementia and mainly treated by drugs, while the therapeutic outcomes are very limited. This study aimed to determine the optimized parameters of deep brain stimulation (DBS) which was applied to the treatment of AD and propose the involved mechanisms. Methods Amyloid-β precursor protein/Presenilin1 (APP/PS1) transgenic mice were used and received DBS at nucleus basalis of Meynert (NBM). The optimized parameters of DBS were determined by using different stimulation frequencies, durations and ages of mice under Morris water maze test. The involved mechanisms and the possible signal pathways were also investigated. Results The optimized parameters for DBS were high frequency (100 Hz) for 21 days starting from early age (4 months old). Under the above parameters, the soluble Aβ40 and Aβ42 in the hippocampus and cortex were down-regulated significantly. DBS increased survival neurons and reduced apoptotic cells in the hippocampus and cortex. Meanwhile, the apoptosis-related proteins caspase-3, caspase-8 and Bid were down-regulated. Moreover, DBS caused a significant increase of superoxide dismutase, glutathione peroxidase and choline acetyltransferase activity as well as a decrease of methane dicarboxylic aldehyde content and acetylcholine esterase activity. Phosphorylation of Akt (p -Akt)/total Akt (t-Akt) was up-regulated while p-extracellular signal-regulated kinase 1/2 (ERK1/2)/t-ERK1/2 was down-regulated. The neuroprotective effect of DBS was attenuated by their inhibitors. Conclusions NBM-DBS starting from 4 months of age for 21 days at a high frequency (100 Hz) has therapeutic effects on AD through activating phosphatidylinositol 3′-kinase (PI3K)/Akt pathway and inhibiting ERK1/2 pathway. Highlights • DBS to NBM elicits neuroprotective effects in animal model of Alzheimer's disease. • DBS at 100 Hz for 21 d starting from 4 months of age exhibits optimized effects. • The effects result from activating PI3K/Akt pathway and inhibiting ERK1/2 pathway. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients. [Display omitted] • Gomisin B significantly improved cognitive dysfunction in APP/PS1 mice. • The combination of Gomisin B and Osthole (OST) had enhanced therapeutic effects. • Gomisin B inhibited β-site APP-Cleaving Enzyme 1 (BACE1), reduced oxidative stress, and had anti-apoptotic properties. • Gomisin B had superior inhibitory effects on BACE1 compared to OST, suggesting its potential as an indirect inhibitor of Aβ 1–42. [ABSTRACT FROM AUTHOR]

Background: The deposition of β-sheet rich amyloid in senile plaques is a pathological hallmark of Alzheimer’s disease (AD), which is thought to cause neuronal dysfunction. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated β-amyloid (Aβ) is able to induce cerebral amyloidosis thus causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption.Methods: We investigated whether cerebral transmission of Aβ was possible via oral administration of Aβ-rich brain extract in non-susceptible and susceptible host mice by immunohistochemistry, western blotting and behavior tests. Also brain extracts were supplied to AD transgenic Caenorhabditis elegans, and paralysis curve were conducted, following detection of Aβ amyloid. RNA sequencing of nematodes was applied then inhibitors for relevant dysregulated genes were used in the paralysis induction.Results: The oral treatment of AD brain extract or normal brain extract neither aggravated nor mitigated the Aβ load, glial activation or the abnormal behaviors in recipient Amyloid precursor protein/presenilin 1 (APP/PS1) mice. Whereas, a significant improvement of AD pathology was detected in worms treated with Aβ-rich or normal brain extracts, which was attributable to the heat-sensitive components of brain extracts. Transcriptome sequencing of CL4176 nematodes suggested that brain extracts could delay worm paralysis through multiple pathways, including ubiquitin mediated proteolysis and Transforming growth factor β (TGF-β) signaling pathway. Inhibitors of the ubiquitin proteasome system and the TGF-β signaling pathway significantly blocked the suppressive effects of brain extracts on worm paralysis.Conclusions: Our results suggest that systemic transmissible mechanisms of prion proteopathy may not apply to β amyloid, at least in terms of oral administration. However, brain extracts strongly ameliorated AD pathology in AD transgenic nematodes partially through TGF-β signaling pathway and ubiquitin mediated proteolysis, which indicated that some natural endogenous components in the mammalian tissues could resist Aβ toxicity.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, lacks preclinical diagnostic biomarkers and therapeutic drugs. Thus, earlier intervention in AD is a top priority. Studies have shown that the gut microbiota influences central nervous system disorders and that prebiotics can improve the cognition of hosts with AD, but these effects are not well understood. Preliminary research has shown that oligosaccharides from Morinda officinalis (OMO) are a useful prebiotic and cause substantial memory improvements in animal models of AD; however, the mechanism is still unclear. Therefore, this study was conducted to investigate whether OMO are clinically effective in alleviating AD by improving gut microbiota. OMO were administered to APP/PS1 transgenic mice, and potential clinical biomarkers of AD were identified with metabolomics and bioinformatics. Behavioral experiments demonstrated that OMO significantly ameliorated the memory of the AD animal model. Histological changes indicated that OMO ameliorated brain tissue swelling and neuronal apoptosis and downregulated the expression of the intracellular AD marker Aβ1−42. 16S rRNA sequencing analyses indicated that OMO maintained the diversity and stability of the microbial community. The data also indicated that OMO are an efficacious prebiotic in an animal model of AD, regulating the composition and metabolism of the gut microbiota. A serum metabolomics assay was performed using UHPLC-LTQ Orbitrap mass spectrometry to delineate the metabolic changes and potential early biomarkers in APP/PS1 transgenic mice. Multivariate statistical analysis showed that 14 metabolites were significantly upregulated, and 8 metabolites were downregulated in the model animals compared to the normal controls. Thus, key metabolites represent early indicators of the development of AD. Overall, we report a drug and signaling pathway with therapeutic potential, including proteins associated with cognitive deficits in normal mice or gene mutations that cause AD.

We have recently demonstrated that short term bexarotene treatment of APP/PS1 mice significantly improves their cognitive performance. While there were no changes in plaque load, or insoluble Aβ levels in brain, biochemical analysis strongly suggested improved clearance of soluble Aβ, including Aβ oligomers. To get further insight into molecular mechanisms underlying this therapeutic effect, we explored genome-wide differential gene expression in brain of bexarotene and control treated APP/PS1 mice.We performed high throughput massively parallel sequencing on mRNA libraries generated from cortices of bexarotene or vehicle treated APP/PS1 mice and compared the expression profiles for differential gene expression. Gene Ontology (GO) Biological Process categories with the highest fold enrichment and lowest False Discovery Rate (FDR) are clustered in GO terms immune response, inflammatory response, oxidation–reduction and immunoglobulin mediated immune response. Chromatin immunoprecipitation (ChIP) followed by ChIP-QPCR, and RT-QPCR expression assays were used to validate select genes, including Trem2, Tyrobp, Apoe and Ttr, differentially expressed in response to Retinoid X Receptor (RXR) activation. We found that bexarotene significantly increased the phagocytosis of soluble and insoluble Aβ in BV2 cells.The results of our study demonstrate that in AD model mice expressing human APP, gene networks up-regulated in response to RXR activation by the specific, small molecule, ligand bexarotene may influence diverse regulatory pathways that are considered critical for cognitive performance, inflammatory response and Aβ clearance, and may provide an explanation of the bexarotene therapeutic effect at the molecular level. This study also confirms that unbiased massive parallel sequencing approaches are useful and highly informative for revealing brain molecular and cellular mechanisms underlying responses to activated nuclear hormone receptors in AD animal models.