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Objective: To discuss the influence of Sailuotong (, SLT) on the Neurovascular Unit (NVUs) of amyloid precursor protein (APP)/presenilin-1(PS1) mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease (AD)., Methods: The mice were allocated into the following nine groups: (a) the C57 Black (C57BL) sham-operated group (control group), (b) ischaemic treatment in C57BL mice (the C57 ischaemic group), (c) the APP/PS1 sham surgery group (APP/PS1 model group), (d) ischaemic treatment in APP/PS1 mice (APP/PS1 ischaemic group), (e) C57BL mice treated with aspirin following ischaemic treatment (C57BL ischaemic + aspirin group), (f) C57BL mice treated with SLT following ischaemic treatment (C57BL ischaemic + SLT group), (g) APP/PS1 mice treated with SLT (APP/PS1 + SLT group), (h) APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment (APP/PS1 ischaemic + donepezil hydrochloride group) and (i) APP/PS1 mice treated with SLT following ischaemic treatment (APP/PS1 ischaemic + SLT group). The ischaemic model was established by operating on the bilateral common carotid arteries and creating a microembolism. The Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of mice. The hippocampus of each mouse was observed by haematoxylin and eosin (HE) and Congo red staining. The ultrastructure of NVUs in each group was observed by electron microscopy, and various biochemical indicators were detected by enzyme-linked immunosorbent assay (ELISA). The protein expression level was detected by Western blot. The mRNA expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR)., Results: The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice, which were restored by SLT. The results of HE staining showed that SLT restored the pathological changes of the NVUs. The Congo red staining results revealed that SLT also improved the scattered orange-red sediments in the upper cortex and hippocampus of the APP/PS1 and APP/PS1 ischaemic mice. Furthermore, SLT significantly reduced the content of Aβ, improved the vascular endothelium and repaired the mitochondrial structures. The ELISA detection, western blot detection and qRT-PCR showed that SLT significantly increased the vascular endothelial growth factor (VEGF), angiopoietin and basic fibroblast growth factor, as well as the levels of gene and protein expression of low-density lipoprotein receptor-related protein-1 (LRP-1) and VEGF in brain tissue., Conclusions: By increasing the expression of VEGF, SLT can promote vascular proliferation, up-regulate the expression of LRP-1, promote the clearance of Aβ and improve the cognitive impairment of APP/PS1 mice. These results confirm that SLT can improve AD by promoting vascular proliferation and Aβ clearance to protect the function of NVUs.

Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages., Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition., Results: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating ® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures., Discussion: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials., Highlights: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction., (© 2023 Wiley Periodicals LLC.)

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein ( APP ) or the presenilin ( PSEN1/2 ) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.

Introduction: Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin-1 (PSEN1) E280A mutation for autosomal dominant AD., Methods: A total of 27 PSEN1 mutation carriers and 26 non-carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15-item Geriatric Depression Scale., Results: Carriers and non-carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition. This relationship was not significant in non-carriers., Discussion: Hippocampal neurodegeneration may underlie depressive symptoms in preclinical autosomal dominant AD. These findings provide support for the utility of targeting depressive symptoms in AD prevention., Highlights: We compared unimpaired autosomal dominant Alzheimer's disease (AD) mutation carriers and non-carriers. Carriers and non-carriers did not differ in severity of depressive symptoms. In carriers, hippocampal volume was inversely associated with depressive symptoms. Depressive symptoms may be a useful target in AD prevention., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species., Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model., Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction., Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases., Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease.

γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid-β. The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin-1 (PS1) and Presenilin-2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1- and PS2-γ-secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK-293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc-PS1-NTF is 5.5-times higher than Myc-PS2-NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1-γ-secretase, PS2-γ-secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1- and PS2-specific contributions to substrate processing, and their potential influence in AD pathogenesis., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Although there are indications of a trend towards less severe acute respiratory symptoms and a decline in overall lethality from the novel Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), more and more attention has been paid to the long COVID, including the increased risk of Alzheimer's disease (AD) in COVID-19 patients. In this study, we aim to investigate the involvement of N-terminal amyloid precursor protein (APP) in SARS-CoV-2-induced amyloid-β (Aβ) pathology. Utilizing both in vitro and in vivo methodologies, we first investigated the interaction between the spike protein of SARS-CoV-2 and N-terminal APP via LSPR and CoIP assays. The in vitro impacts of APP overexpression on virus infection were further evaluated in HEK293T/ACE2 cells, SH-SY5Y cells, and Vero cells. We also analyzed the pseudovirus infection in vivo in a mouse model overexpressing human wild-type APP. Finally, we evaluated the impact of APP on pseudovirus infection within human brain organoids and assessed the chronic effects of pseudovirus infection on Aβ levels. We reported here for the first time that APP, the precursor of the Aβ of AD, interacts with the Spike protein of SARS-CoV-2. Moreover, both in vivo and in vitro data further indicated that APP promotes the cellular entry of the virus, and exacerbates Aβ-associated pathology in the APP/PS1 mouse model of AD, which can be ameliorated by N-terminal APP blockage. Our findings provide experimental evidence to interpret APP-related mechanisms underlying AD-like neuropathology in COVID-19 patients and may pave the way to help inform risk management and therapeutic strategies against diseases accordingly., (© 2023. The Author(s).)

Alzheimer's disease (AD) is a progressive neurological disorder that affects the central nervous system (CNS), leading to memory and cognitive decline. In AD, the brain experiences three main structural changes: a significant decrease in the quantity of neurons, the development of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, and the formation of amyloid beta (Aβ) or senile plaques, which are protein deposits found outside cells and surrounded by dystrophic neurites. Genetic studies have identified four genes associated with autosomal dominant or familial early-onset AD (FAD): amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2), and apolipoprotein E (ApoE). The formation of plaques primarily involves the accumulation of Aβ, which can be influenced by mutations in APP, PS1, PS2, or ApoE genes. Mutations in the APP and presenilin (PS) proteins can cause an increased amyloid β peptides production, especially the further form of amyloidogenic known as Aβ42. Apart from genetic factors, environmental factors such as cytokines and neurotoxins may also have a significant impact on the development and progression of AD by influencing the formation of amyloid plaques and intracellular tangles. Exploring the causes and implications of protein aggregation in the brain could lead to innovative therapeutic approaches. Some promising therapy strategies that have reached the clinical stage include using acetylcholinesterase inhibitors, estrogen, nonsteroidal anti-inflammatory drugs (NSAIDs), antioxidants, and antiapoptotic agents. The most hopeful therapeutic strategies involve inhibiting activity of secretase and preventing the β-amyloid oligomers and fibrils formation, which are associated with the β-amyloid fibrils accumulation in AD. Additionally, immunotherapy development holds promise as a progressive therapeutic approach for treatment of AD. Recently, the two primary categories of brain stimulation techniques that have been studied for the treatment of AD are invasive brain stimulation (IBS) and non-invasive brain stimulation (NIBS). In this article, the amyloid proteins that play a significant role in the AD formation, the mechanism of disease formation as well as new drugs utilized to treat of AD will be reviewed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype complexes. A set of known PSEN-1 selective γ-Secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency. Using these insights, a series of brain-penetrant 2-azabicyclo[2,2,2]octane sulfonamides was devised and synthesized as a new class of PSEN-1 selective inhibitors. Compounds 13c and 13k displayed high potency towards PSEN1-APH1B complex but moderate selectivity towards PSEN2 complexes. However, compound (+)-13b displayed low nanomolar potency towards the PSEN1-APH1B complex, little (∼4-fold) selectivity towards PSEN1-APH1A, and high selectivity (>350-fold) versus PSEN2 complexes. Excellent brain penetration, no significant CYP inhibition, or cardiotoxicity, good solubility, and permeability make (+)-13b an excellent candidate for further lead optimization., Competing Interests: Declaration of competing interest Rajeshwar Narlawar, Lutgarde Serneels, Celia Gaffric, François Bischoff, Harrie J. M. Gijsen declare no competing interest. Bart De Strooper is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. B.D.S is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL‑LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 ( SESN2 ; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an SCL‑LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.

Aims: Memory impairment is a major clinical manifestation in Alzheimer's disease (AD) patients, while regular exercise may prevent and delay degenerative changes in memory functions, and our aim is to explore the influence and molecular mechanisms of aerobic exercise on the early stages of Alzheimer's disease., Main Methods: 3-month-old male APP/PS1 transgenic AD mice and C57BL/6J wild-type mice were randomly divided into four groups: wild-type and APP/PS1 mice with sedentary (WT-SED, AD-SED), and running (WT-RUN, AD-RUN) for 12-weeks. The spatial learning and memory function, RNA-sequencing, spine density, synaptic associated protein, mRNA and protein expression involved in G protein-coupled receptor 81 (GPR81) signaling pathway, and complement factors in brain were measured., Key Findings: Aerobic exercise improved spatial learning and memory in APP/PS1 mice, potentially attributed to increased dendritic spine density. Subsequently, potential underlying mechanisms were identified through RNA sequencing: regular aerobic exercise could activate the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) cAMP/PKA signaling pathway and upregulate synaptic function-related proteins to promote synaptic growth, possibly by modulating GPR81. Notably, regular aerobic exercise inhibited microglial activation, reversed the microglial phenotype, reduced the production of initiation factor C1q and central factor C3 in the complement cascade in the brain, prevented the colocalization of microglia and PSD-95, and thus prevented synaptic loss., Significance: Physical exercise could play a critical role in improving cognitive function in AD by promoting synaptic growth and preventing synaptic loss, which may be related to the regulation of the GPR81/cAMP/PKA signaling pathway and inhibition of complement-mediated microglial phagocytosis of synapses., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD) are growing public health concerns in aged populations of all ethnic and racial groups. AD and ADRD are caused by multiple factors, such as genetic mutations, modifiable and non-modifiable risk factors, and lifestyle. Studies of postmortem brains have revealed multiple cellular changes implicated in AD and ADRD, including the accumulation of amyloid beta and phosphorylated tau, synaptic damage, inflammatory responses, hormonal imbalance, mitochondrial abnormalities, and neuronal loss. These changes occur in both early-onset familial and late-onset sporadic forms. Two-thirds of women and one-third of men are at life time risk for AD. A small proportion of total AD cases are caused by genetic mutations in amyloid precursor protein, presenilin 1, and presenilin 1 genes, and the APOE4 allele is a risk factor. Tremendous research on AD/ADRD, and other comorbidities such as diabetes, obesity, hypertension, and cancer has been done on almost all ethnic groups, however, very little biomedical research done on US Native Americans. AD/ADRD prevalence is high among all ethnic groups. In addition, US Native Americans have poorer access to healthcare and medical services and are less likely to receive a diagnosis once they begin to exhibit symptoms, which presents difficulties in treating Alzheimer's and other dementias. One in five US Native American people who are 45 years of age or older report having memory issues. Further, the impact of caregivers and other healthcare aspects on US Native Americans is not yet. In the current article, we discuss the history of Native Americans of United States (US) and health disparities, occurrence, and prevalence of AD/ADRD, and shedding light on the culturally sensitive caregiving practices in US Native Americans. This article is the first to discuss biomedical research and healthcare disparities in US Native Americans with a focus on AD and ADRD, we also discuss why US Native Americans are reluctant to participate in biomedical research., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation., Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds., Results: Eight compounds (AZ1 - AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation., Conclusions: AZ1 - AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease., Competing Interests: The authors declare no conflicts of interest.

Introduction: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD., Methods: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members., Results: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function., Discussion: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials., Highlights: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance., (© 2022 the Alzheimer's Association.)

Presenilin 1 (PSEN1) is a part of the gamma secretase complex with several interacting substrates, including amyloid precursor protein (APP), Notch, adhesion proteins and beta catenin. PSEN1 has been extensively studied in neurodegeneration, and more than 300 PSEN1 mutations have been discovered to date. In addition to the classical early onset Alzheimer's disease (EOAD) phenotypes, PSEN1 mutations were discovered in several atypical AD or non-AD phenotypes, such as frontotemporal dementia (FTD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) or spastic paraparesis (SP). For example, Leu113Pro, Leu226Phe, Met233Leu and an Arg352 duplication were discovered in patients with FTD, while Pro436Gln, Arg278Gln and Pro284Leu mutations were also reported in patients with motor dysfunctions. Interestingly, PSEN1 mutations may also impact non-neurodegenerative phenotypes, including PSEN1 Pro242fs, which could cause acne inversa, while Asp333Gly was reported in a family with dilated cardiomyopathy. The phenotypic diversity suggests that PSEN1 may be responsible for atypical disease phenotypes or types of disease other than AD. Taken together, neurodegenerative diseases such as AD, PD, DLB and FTD may share several common hallmarks (cognitive and motor impairment, associated with abnormal protein aggregates). These findings suggested that PSEN1 may interact with risk modifiers, which may result in alternative disease phenotypes such as DLB or FTD phenotypes, or through less-dominant amyloid pathways. Next-generation sequencing and/or biomarker analysis may be essential in clearly differentiating the possible disease phenotypes and pathways associated with non-AD phenotypes.

Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (Aβ). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether Aβ, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and Aβ deposits displayed a region-specific pattern in the 13-month-old APP/PS1 transgenic mouse brains. Aβ plaques cause focal demyelination, but only about 15% Aβ plaques are closely associated with newly formed myelin in the APP/PS1 brains. Further, the Aβ plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that Aβ plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble Aβ in regulating myelinogenesis, we chose to observe the visual system, wherein soluble Aβ is detectable but without the presence of Aβ plaques in the APP/PS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APP/PS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble Aβ probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble Aβ (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFRα positive OPCs in vitro. Consistently, injection of soluble Aβ into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt; Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to Aβ, but rather probably a synergic result in adapting to AD pathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Lipopolysaccharide (LPS) produced by the gut during systemic infections and inflammation is thought to contribute to Alzheimer's disease (AD) progression. Since thymosin beta 4 (Tβ4) effectively reduces LPS-induced inflammation in sepsis, we tested its potential to alleviate the impact of LPS in the brain of the APPswePS1dE9 mouse model of AD (APP/PS1) and wildtype (WT) mice. 12.5-month-old male APP/PS1 mice (n = 30) and their WT littermates (n = 29) were tested for baseline food burrowing performance, spatial working memory and exploratory drive in the spontaneous alternation and open-field tests, prior to being challenged with LPS (100ug/kg, i.v.) or its vehicle phosphate buffered saline (PBS). Tβ4 (5 mg/kg, i.v.) or PBS, was administered immediately following and at 2 and 4 h after the PBS or LPS challenge, and then once daily for 6 days (n = 7-8). LPS-induced sickness was assessed though monitoring of changes in body weight and behaviour over a 7-day period. Brains were collected for the determination of amyloid plaque load and reactive gliosis in the hippocampus and cortex. Treatment with Tβ4 alleviated sickness symptoms to a greater extent in APP/PS1 than in WT mice by limiting LPS-induced weight loss and inhibition of food burrowing behaviour. It prevented LPS-induced amyloid burden in APP/PS1 mice but increased astrocytic and microglial proliferation in the hippocampus of LPS-treated WT mice. These data show that Tβ4 can alleviate the adverse effects of systemic LPS in the brain by preventing exacerbation of amyloid deposition in AD mice and by inducing reactive microgliosis in aging WT mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2022. Published by Elsevier Inc.)

Patients with early-onset Alzheimer's disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p < 0.02; females: p < 0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p = 0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p = 0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner., Competing Interests: Declaration of Competing Interest None, the authors declare no competing financial interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with the total amount Aβ present in human plasma, CSF, or supernatants from cultured neurons. The involvement of EVs has largely been inferred by pharmacological inhibition or whole body deletion of the sphingomyelin hydrolase neutral sphingomyelinase-2 (nSMase2) that is a key regulator for the biogenesis of at-least one population of EVs. Here we used a Cre-Lox system to selectively delete nSMase2 from pyramidal neurons in APP/PS1 mice (APP/PS1-SMPD3-Nex1) and found a ∼ 70% reduction in Aβ deposition at 6 months of age and ∼ 35% reduction at 12 months of age in both cortex and hippocampus. Brain ceramides were increased in APP/PS1 compared with Wt mice, but were similar to Wt in APP/PS1-SMPD3-Nex1 mice suggesting that elevated brain ceramides in this model involves neuronally expressed nSMase2. Reduced levels of PSD95 and deficits of long-term potentiation in APP/PS1 mice were normalized in APP/PS1-SMPD3-Nex1 mice. In contrast, elevated levels of IL-1β, IL-8 and TNFα in APP/PS1 mice were not normalized in APP/PS1-SMPD3-Nex1 mice compared with APP/PS1 mice. Mechanistic studies showed that the size of liquid ordered membrane microdomains was increased in APP/PS1 mice, as were the amounts of APP and BACE1 localized to these microdomains. Pharmacological inhibition of nSMase2 activity with PDDC reduced the size of the liquid ordered membrane microdomains, reduced the localization of APP with BACE1 and reduced the production of Aβ 1 - 40 and Aβ 1 - 42 . Although inhibition of nSMase2 reduced the release and increased the size of EVs, very little Aβ was associated with EVs in all conditions tested. We also found that nSMase2 directly protected neurons from the toxic effects of oligomerized Aβ and preserved neural network connectivity despite considerable Aβ deposition. These data demonstrate that nSMase2 plays a role in the production of Aβ by stabilizing the interaction of APP with BACE1 in liquid ordered membrane microdomains, and directly protects neurons from the toxic effects of Aβ. The effects of inhibiting nSMase2 on EV biogenesis may be independent from effects on Aβ production and neuronal protection., (Copyright © 2023. Published by Elsevier Inc.)

Background: Current treatment options for Alzheimer's disease (AD) are limited, inefficient, and often have serious side effects. Oxytocin is a neuropeptide implicated in a variety of central processes, such as social and reproductive behaviors. Among others, it has garnered attention in various domains of psychiatric research, while its role in the development and course of neurodegenerative disorders like AD is rather unknown., Objective: This study aimed to investigate the role of exogenous oxytocin administration on memory, specifically in view of AD, as a potential novel treatment option., Methods: We describe a novel treatment approach by using a relatively low dose of long-term intranasal oxytocin treatment, to restore memory deficits in female APPswePS1dE9 mice., Results: Female APPswePS1dE9 mice treated with oxytocin showed increased spatial memory performance in the object location task and improved working memory in the Y-Maze, while indicating decreased sociability., Conclusions: These results indicate that oxytocin is able to reverse acquired cognitive deficits in female APPswePS1dE9 mice.

Gut microbiota alterations might affect the development of Alzheimer's disease (AD) through microbiota-derived metabolites. For example, microbiota-derived Indoles via tryptophan metabolism prevented Aβ accumulation and Tau hyperphosphorylation, restored synaptic plasticity, and then promoted the cognitive and behavioral ability of APP/PS1 mice. The imbalanced compositions of Indoles-producing bacteria with tryptophan deficiency were found in male APP/PS1 mice, but the molecular mechanisms remained unclear. Our current study revealed that Indoles (including indole, indole-3-acetic acid and indole-3-propionic acid) upregulated the production of aryl hydrocarbon receptor (AhR), inhibited the activation of the NF-κB signal pathway as well as the formation of the NLRP3 inflammasome, reduced the release of inflammatory cytokines, including TNF-α, IL-6, IL-1β and IL-18, alleviating the inflammatory response of APP/PS1 mice. These findings demonstrated the roles of Indoles-producing bacteria in activating the AhR pathway to regulate neuroinflammation of AD through gut microbiota-derived Indoles, which implied a novel way for AD treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer's disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein.

Clinical evidence shows that postmenpausal women are almost twice as likely to develop Alzheimer's disease (AD) as men of the same age, and estrogen is closely related to the occurrence of AD. Estrogen receptor (ER) α is mainly expressed in the mammary gland and other reproductive organs like uterus while ERβ is largely distributed in the hippocampus and cardiovascular system, suggesting that ERβ selective agonist is a valuable drug against neurodegenerative diseases with low tendency in inducing cancers of breast and other reproductive organs. In this study we identified a natural product patchouli alcohol (PTA) as a selective ERβ agonist which improved the cognitive defects in female APP/PS1 mice, and explore the underlying mechanisms. Six-month-old female APP/PS1 mice were administered PTA (20, 40 mg · kg -1  · d -1 , i.g.) for 90 days. We first demonstrated that PTA bound to ERβ with a dissociation constant (K D ) of 288.9 ± 35.14 nM in microscale thermophoresis. Then we showed that PTA administration dose-dependently ameliorated cognitive defects evaluated in Morris water maze and Y-maze testes. Furthermore, PTA administration reduced amyloid plaque deposition in the hippocampus by promoting microglial phagocytosis; PTA administration improved synaptic integrity through enhancing BDNF/TrkB/CREB signaling, ameliorated oxidative stress by Catalase level, and regulated Bcl-2 family proteins in the hippocampus. The therapeutic effects of PTA were also observed in vitro: PTA (5, 10, 20 μM) dose-dependently increased phagocytosis of o-FAM-Aβ 42 in primary microglia and BV2 cells through enhancing ERβ/TLR4 signaling; PTA treatment ameliorated o-Aβ 25-35 -induced reduction of synapse-related proteins VAMP2 and PSD95 in primary neurons through enhancing ERβ/BDNF/TrkB/CREB pathways; PTA treatment alleviated o-Aβ 25-35 -induced oxidative stress in primary neurons through targeting ERβ and increasing Catalase expression. Together, this study has addressed the efficacy of selective ERβ agonist in the amelioration of AD and highlighted the potential of PTA as a drug lead compound against the disease., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Objective: To observe the effect of moxibustion (Moxi) at acupoints of Governor Vessel on autophagy lysosomal function and lncRNA H19 in amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic Alzheimer's disease (AD) mice, so as to explore its underlying mechanisms in relieving AD., Methods: Fifty two male APP/PS1 double transgenic AD mice were randomly divided into model, Moxi, Moxi+inhibitor and medication (rapamycin) groups, with 13 mice in each group. Other 13 male C57BL/6J mice of the same age were selected as the control group. The mice of the Moxi group received aconite cake-separated Moxi stimulation at "Baihui" (GV20), "Dazhui"(GV14) and "Fengfu" (GV16), for 15 min, those of the Moxi+inhibitor group received intraperitoneal injection of 3-methyladenine (an inhibitor of PI3K for suppressing autophagy) 1.5 mg· kg -1 · d -1 on the basis of Moxi, and those of the medication group received intraperitoneal injection of rapamycin 2 mg· kg -1 · d -1 . The treatment was conducted once daily for 2 weeks. The mouse's learning-memory ability was detected by Morris water maze tests. The hippocampus tissue was sampled for observing the formation of autophagy by using transmission electron microscope, detecting the expression of Aβ&#95;(1-42) protein with immunohistochemical staining, and for detecting the expression levels of long noncoding RNA H19 (lncRNA H19), mammalian target of rapamycin kinase (mTOR), nuclear transcription factor EB (TFEB), Cathepsin D and lysosome associated membrane protein-1 (LAMP1) genes and proteins as well as microtubule associated protein 1 light chain 3B (LC3B)-Ⅱ/LC3B-Ⅰand autophagy protein p62 protein by quantitative real-time PCR and Western blot, respectively., Results: In contrast to the control group, the model group had an evident increase in the escape latency of Morris water maze test, and in the expression levels of Aβ&#95;(1-42) protein, lncRNA H19 mRNA, mTOR mRNA and protein, and p62 protein ( P <0.05), and a significant decrease in the expression levels of TFEB, Cathepsin D, LAMP1 mRNAs and proteins and LC3B-Ⅱ/LC3B-Ⅰ ( P <0.05). After the treatment and relevant to the model and Moxi+inhibitor groups, both the Moxi and medication groups had an obvious down-regulation in the levels of latency of Morris water maze, expression levels of Aβ&#95;(1-42) protein, lncRNA H19 mRNA, mTOR mRNA and protein, and p62 protein ( P <0.05), and a significant up-regulation in the levels of TFEB, Cathepsin D, LAMP1 mRNAs and proteins and LC3B-Ⅱ/LC3B-Ⅰ ( P <0.05)., Conclusion: Moxi at acupoints of Governor Vessel can improve cognitive function of AD mice, which may be associated with its functions in inhibiting mTOR/TFEB pathway by down-regulating the expression of lncRNA H19, improving autophagy lysosomal function, promoting autophagy and clearing away Aβ1-42 in the hippocampus.

Background: The mammalian target of rapamycin (mTOR) plays a critical role in controlling cellular homeostasis, and its dysregulation has been implicated in Alzheimer's disease (AD). Presenilin-1 (PS1) mutations account for the most common causes of familial Alzheimer's disease (FAD); however, whether PS1 mutation causes mTOR dysregulation in human neurons remains a key unresolved issue., Methods: We generated heterozygotes and homozygotes of PS1 F105C knock-in mutation in human induced pluripotent stem cells (iPSCs) via CRISPR/Cas9/piggyback-based gene editing and differentiated them into human neurons. Secreted Aβ and tau accumulation were determined by ELISA assay, immunofluorescence staining, and western blotting analysis. mTOR signaling was evaluated by western blotting analysis, immunofluorescence staining, and co-immunoprecipitation. Autophagy/lysosome activities were determined by LC3-based assay, LysoTracker Red staining, and DQ-Red BSA staining., Results: Through comparison among these isogenic neurons, PS1 F105C mutant neurons exhibited elevated Aβ and tau accumulation. In addition, we found that the response of mTORC1 to starvation decreases in PS1 F105C mutant neurons. The Akt/mTORC1/p70S6K signaling pathway remained active upon EBSS starvation, leading to the co-localization of the vast majority of mTOR with lysosomes. Consistently, PS1 F105C neurons displayed a significant decline in starvation-induced autophagy. Notably, Torin1, a mTOR inhibitor, could efficiently reduce prominent tau pathology that occurred in PS1 F105C neurons., Conclusion: We demonstrate that Chinese PS1 F105C mutation causes dysregulation of mTORC1 signaling, contributing to tau accumulation in human neurons. This study on inherited FAD PS1 mutation provides unprecedented insights into our understanding of the molecular mechanisms of AD. It supports that pharmaceutical blocking of mTOR is a promising therapeutic strategy for the treatment of AD., (© 2022. The Author(s).)

Objective: Subjective Cognitive Decline (SCD) may be an early indicator of risk for Alzheimer's disease (AD). Findings regarding sex differences in SCD are inconsistent. Studying sex differences in SCD within cognitively unimpaired individuals with autosomal-dominant AD (ADAD), who will develop dementia, may inform sex-related SCD variations in preclinical AD. We examined sex differences in SCD within cognitively unimpaired mutation carriers from the world's largest ADAD kindred and sex differences in the relationship between SCD and memory performance., Methods: We included 310 cognitively unimpaired Presenilin-1 (PSEN-1) E280A mutation carriers (51% females) and 1998 noncarrier family members (56% females) in the study. Subjects and their study partners completed SCD questionnaires and the CERAD word list delayed recall test. ANCOVAs were conducted to examine group differences in SCD, sex, and memory performance. In carriers, partial correlations were used to examine associations between SCD and memory performance covarying for education., Results: Females in both groups had greater self-reported and study partner-reported SCD than males (all p < 0.001). In female mutation carriers, greater self-reported ( p = 0.02) and study partner-reported SCD ( p < 0.001) were associated with worse verbal memory. In male mutation carriers, greater self-reported ( p = 0.03), but not study partner-reported SCD ( p = 0.11) was associated with worse verbal memory., Conclusions: Study partner-reported SCD may be a stronger indicator of memory decline in females versus males in individuals at risk for developing dementia. Future studies with independent samples and preclinical trials should consider sex differences when recruiting based on SCD criteria.

Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced.

THC has been used as a promising treatment approach for neurological disorders, but the highly psychoactive effects have largely warned off many scientists from pursuing it further. We conducted an intranasal treatment using low-dose THC on 12-month-old APP/PS1 mice daily for 3 months to overcome any potential psychoactive response induced by the systemic delivery. Our results demonstrate that the THC nasal treatment at 0.002 and 0.02 mg/kg significantly slowed the memory decline compared to that in the vehicle-treated transgenic mouse control group. An enzyme-linked immunosorbent assay showed that the Aβ1-40 and 1-42 peptides decreased in the THC-treated groups. The Western blot data indicate that long-term low-dose THC intranasal administration promoted p-tau level reduction and mitochondrial function marker redistribution. The blood biochemical parameter data demonstrate some insignificant changes in cytokine, immunoglobulin, and immune cell profiles during intranasal THC treatment. Intranasal delivery is a non-invasive and convenient method that rapidly targets therapeutics to the brain, minimizing systemic exposure to avoid unwanted adverse effects. Our study provides new insights into the role of low-dose THC intranasal treatment as a pharmacological strategy to counteract alterations in Alzheimer's disease-related cognitive performance.

Neuroinflammation occurs early in Alzheimer's disease (AD). The initial stage of AD is related to glial dysfunction, which contributes to impairment of Aβ clearance and disruption of synaptic connection. CEBPβ, a member of the CCAAT-enhancer-binding protein (CEBP) family, modulates the expression of inflammation-associated genes, and its expression is elevated in brains undergoing degeneration and injured brains. However, the mechanism underlying CEBPβ-mediated chronic inflammation in AD is unclear. In this study, we observed that increases in the levels of nuclear CEBPβ facilitated the interaction of CEBPβ with the NFκB p65 subunit, increasing the transcription of proinflammatory cytokines in the APP/PS1 mouse brain. Oral administration of nanocarrier-packaged carnosic acid (CA) reduced the aberrant activation of microglia and astrocytes and diminished mature IL-1β, TNFα and IL-6 production in the APP/PS1 mouse brain. CA administration reduced β-amyloid (Aβ) deposition and ameliorated cognitive impairment in APP/PS1 mice. We observed that CA blocked the interaction of CEBPβ with NFκB p65, and chromatin immunoprecipitation revealed that CA reduced the transcription of the NFκB target genes TNFα and IL-6. We confirmed that CA alleviated inflammatory mediator-induced neuronal degeneration and reduced Aβ secretion by inhibiting the CEBPβ-NFκB signalling pathway in vitro. Sulfobutyl ether-beta-cyclodextrin (SBEβCD) was used as the encapsulation agent for the CA-loaded nanocarrier to overcome the poor water solubility and enhance the brain bioavailability of CA. The CA nanoparticles (NPs) had no obvious toxicity. We demonstrated a feasible SBEβCD-based nanodelivery system targeting the brain. Our data provide experimental evidence that CA-loaded NPs are potential therapeutic agents for AD treatment., (© 2022. The Author(s).)

Mutations in the PSEN1 gene encoding presenilin-1 (PS1) protein are the most common cause of familial Alzheimer's disease. One of these, deletion of exon 9, results in the production of shortened PS1 protein (PS1ΔE9). Neuronal hyperexcitability and hyperactivation of L-type calcium channels were observed in cellular and animal models of familial Alzheimer's disease. However, the effect of PS1ΔE9 on L-type calcium channels has not been studied before. We demonstrate enhanced calcium entry through L-type calcium channels in hippocampal mouse neurons with exogenous expression of PS1ΔE9. Additionally, we show that the same effect of the exogenous PS1ΔE9 can be observed in cells with predominant expression of L-type calcium channels subunit Cav1.2. Further research is required to unravel molecular mechanisms underlying hyperactivation L-type calcium channels caused by PS1ΔE9 expression., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Abbreviations: Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A 1 ; CFC: contextual/cued fear conditioning assay; CHX: Ca 2+ /H + exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long-term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H + -ATPase.

Myocyte enhancer factor 2C (MEF2C) is highly expressed in the nervous system, and regulates neuro-development, synaptic plasticity, and inflammation. However, its mechanism in Alzheimer's disease (AD) is underestimated. In this study, the role and mechanism of MEF2C were investigated in the brain tissue specimens from patients with AD, APPswe/PSEN1dE9 double transgenic (APP/PS1&#95;DT) mice, and SH-SY5Y cells treated with β-amyloid peptide (Aβ). The results indicated that the expression of MEF2C is significantly reduced, and the expression of MEF2C/Aβ in different parts of brain is negatively correlated in patients with AD. Knockdown of MEF2C promotes cell apoptosis and the level of β-amyloid precursor protein cleaving enzyme 1 (BACE) but reduces BACE2 expression. In addition, knockdown of enhances the generation and aggregation of Aβ in the cortex of APP/PS1&#95;DT mice, reduces the expression of synaptic proteins, exacerbates the ability of learning and memory of APP/PS1&#95;DT mice, damages the structure of mitochondria, increases the oxidative stress (OS) level, and inhibits the expression levels of members of the Nrf2-ARE signal pathway. In summary, inhibition of MEF2C exacerbates the toxic effect of Aβ and , damages synaptic plasticity, reduces the ability of learning and memory of APP/PS1 mice, and increases the level of OS via the Nrf2-ARE signal pathway.

Background: There is growing evidence of strong associations between the pathogenesis of Alzheimer's disease (AD) and dysbiotic oral and gut microbiota. Recent studies demonstrated that isoorientin (ISO) is anti-inflammatory and alleviates markers of AD, which were hypothesized to be mediated by the oral and gut microbiota., Objectives: We studied the effects of oral administration of ISO on AD-related markers and the oral and gut microbiota in mice., Methods: Eight-month-old amyloid precursor protein/presenilin-1 (AP) transgenic male mice were randomly allocated to 3 groups of 15 mice each: vehicle (AP) alone or with a low dose of ISO (AP + ISO-L; 25 mg/kg) or a high dose of ISO (AP + ISO-H; 50 mg/kg). Age-matched wild-type (WT) C57BL/6 male littermates were used as controls. The 4 groups were treated intragastrically with ISO or sterilized ultrapure water for 2 months. AD-related markers in the brain, serum, colon, and liver were analyzed with immunohistochemical and histochemical staining, Western blotting, and ELISA. Oral and gut microbiotas were analyzed using 16S ribosomal RNA gene sequencing., Results: The high-dose ISO treatment significantly decreased amyloid beta 42-positive deposition by 38.1% and 45.2% in the cortex and hippocampus, respectively, of AP mice (P < 0.05). Compared with the AP group, both ISO treatments reduced brain phospho-Tau, phosphor-p65, phosphor-inhibitor of NF-κB, and brain and serum LPS and TNF-α by 17.9%-72.5% and increased brain and serum IL-4 and IL-10 by 130%-210% in the AP + ISO-L and AP + ISO-H groups (P < 0.05). Abundances of 26, 25, and 23 microbial taxa in oral, fecal and cecal samples, respectively, were increased in both the AP + ISO-L and AP + ISO-H groups relative to the AP group [linear discriminant analysis (LDA) >3.0; P < 0.05]. Gram-negative bacteria, Alteromonas, Campylobacterales, and uncultured Bacteroidales bacterium were positively correlated (rho = 0.28-0.59; P < 0.05) with the LPS levels and responses of inflammatory cytokines., Conclusions: The microbiota-gut-brain axis is a potential mechanism by which ISO reduces AD-related markers in AP mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Alzheimer's disease (AD) is the most common neurodegenerative disease. SUMOylation, a post-translational modification, has been found to be dysregulated in the AD brain and to exacerbate learning and memory disabilities and increase amyloid beta (Aβ) expression further. To investigate whether exercise-induced alleviation of AD was associated with SUMOylation, which still remains unknown, 3-month-old C57BL/6 mice and APP/PS1 transgenic mice were randomly divided into the wild-type control (WC), wild-type exercise (WE), APP/PS1 control (AC), and APP/PS1 exercise (AE) groups. Mice in the exercise groups underwent a 3-month treadmill exercise regimen. We observed impaired learning and memory abilities in APP/PS1 mice, but the 3-month treadmill exercise regimen improved spatial learning and memory abilities in wild-type and APP/PS1 mice. In addition, senile plaques, SUMO1 mRNA, and SENP1 mRNA levels increased in the hippocampi of APP/PS1 mice. However, 3-month treadmill exercise decreased the levels of senile plaques, SUMO1 mRNA and SENP1 mRNA as well as may reduce SUMO1 modification in 6-month-old APP/PS1 mice, but SUMO2 mRNA expression, SUMO2/3 modification, and overall SUMOylation levels did not significantly change. Our results suggest that the impaired learning and memory abilities and aggregations of Aβ may relate to increased hippocampal SUMO1 transcription levels; the beneficial effects of treadmill exercise on learning and memory performances and AD pathogenesis may associated with the abatement of SUMO1 modification, but may not with SUMO2/3 modification., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) pathology is characterized by amyloid-β (Aβ) deposition and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating Aβ pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified non-erythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on AD-like pathology in an early-onset model, represented by young APP/PS1 mice. Our findings indicate that ARA 290 early treatment decelerated Aβ pathology progression in APP/PS1 mice while improving cognitive functions. ARA 290 potently increased the levels of total monocytes by specifically stimulating the generation of Ly6C Low patrolling subset, which are implicated in clearing Aβ from the cerebral vasculature, and subsequently reducing overall Aβ burden in the brain. Moreover, ARA 290 increased the levels of monocyte progenitors in the bone marrow. Using chimeric APP/PS1 mice in which Ly6C Low patrolling subset are selectively depleted, ARA 290 was inefficient in attenuating Aβ pathology and ameliorating cognitive functions in young animals. Interestingly, ARA 290 effects were compromised when delivered in a late-onset model, represented by aged APP1/PS1. In aged APP/PS1 mice in which AD-like pathology is at advanced stages, ARA 290 failed to reverse Aβ pathology and to increase the levels of circulating monocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Cerebral Methyl-CpG binding Protein 2 (MeCP2) is involved in several psychiatric disorders that are concomitant with cognitive dysfunction. However, the regulatory function of striatal MeCP2 and its association with Alzheimer's disease (AD) has been largely neglected due to the absence of amyloid plaque accumulation in the striatal region until the later stages of AD progression. Considerable evidence indicates that neuropsychiatric symptoms related to cognitive decline are involved with striatal dysfunction. To this respect, we investigated the epigenetic function of striatal MeCP2 paralleling the pathogenesis of AD. Methods: We investigated the brain from amyloid precursor protein (APP)/presenilin1 (PS1) transgenic mice and postmortem brain samples from normal subjects and AD patients. The molecular changes in the brain, particularly in the striatal regions, were analyzed with thioflavin S staining, immunohistochemistry, immunoblotting, and MeCP2 chromatin immunoprecipitation sequencing (ChIP-seq). The cognitive function of APP/PS1 mice was assessed via three behavioral tests: 3-chamber test (3CT), Y-maze test (YMT), and passive avoidance test (PA). A multi-electrode array (MEA) was performed to analyze the neuronal activity of the striatum in APP/PS1 mice. Results: Striatal MeCP2 expression was increased in the younger (6 months) and older (10 months) ages of APP/PS1 mice, and the genome-wide occupancy of MeCP2 in the younger APP/PS1 showed dysregulated binding patterns in the striatum. Additionally, we confirmed that APP/PS1 mice showed behavioral deficits in multiple cognitive behaviors. Notably, defective cognitive phenotypes and abnormal neuronal activity in old APP/PS1 mice were rescued through the knock-down of striatal MeCP2. Conclusion: We found that the MeCP2-mediated dysregulation of the epigenome in the striatum is linked to the defects in cognitive behavior and neuronal activity in the AD animal model, and that this alteration is initiated even in the very early stages of AD pathogenesis. Together, our data indicates that MeCP2 may be a potential target for the diagnosis and treatment of AD at asymptomatic and symptomatic stages., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer's disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients., Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD., Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma., Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%., Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD.

Methylglyoxal (MG), a potent glycotoxin that can be found in the diet, is one of the main precursors of Advanced glycation end products (AGEs). It is well known that modifications in lifestyle such as nutritional interventions can be of great value for preventing brain deterioration. This study aimed to evaluate in vivo how an oral MG treatment, that mimics a high MG dietary intake, could affect brain health. From our results, we demonstrated that MG administration affected working memory, and induced neuroinflammation and oxidative stress by modulating the Receptor for Advanced glycation end products (RAGE). The gene and protein expressions of RAGE were increased in the hippocampus of MG mice, an area where the activity of glyoxalase 1, one of the main enzymes involved in MG detoxification, was found reduced. Furthermore, at hippocampus level, MG mice showed increased expression of proinflammatory cytokines and increased activities of NADPH oxidase and catalase. MG administration also increased the gene and protein expressions of Presenilin-1, a subunit of the gamma-secretase protein complex linked to Alzheimer's disease. These findings suggest that high MG oral intake induces alteration directly in the brain and might establish an environment predisposing to AD-like pathological conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 Aβ 40 and Aβ 42 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 CB 2 receptor and a weak partial agonist of CB 1 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 CB 2 receptor, and weakly mediated by the CB 1 receptor., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is the major cause of dementia worldwide. Early-onset familial AD accounts for about 0.5% of all AD and is caused by single major gene mutations and autosomal dominant inheritance. An N141I missense mutation is associated with a significant increase in basal cell death and apoptosis. In this work we generated hiPSC from skin fibroblasts obtained from an AD patient carrying a N141I missense mutation in PSEN2. The generated iPSC colonies grew and were characterized by pluripotency marker staining; the N141I missense mutation was corrected using genome editing technology., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Autosomal-dominant Alzheimer's disease (ADAD) may be associated with atypical amyloid beta deposits in the brain. In vivo amyloid imaging using 11 C-Pittsburgh compound B (PiB) tracer has shown differences in binding between brains from ADAD and sporadic Alzheimer's disease (sAD) patients. To gain further insight into the various pathological characteristics of these genetic variants, we performed large frozen hemisphere autoradiography and brain homogenate binding assays with 3 H-PiB, 3 H-MK6240- 3 H-THK5117, and 3 H-deprenyl for detection of amyloid fibrils, tau depositions, and activated astrocytes, respectively, in two AβPParc mutation carriers, one PSEN1ΔE9 mutation carrier, and three sAD cases. The results were compared with Abeta 40, Abeta 42, AT8, and GFAP immunostaining, respectively, as well as with Congo red and Bielschowsky. PiB showed a very low binding in AβPParc. A high binding was observed in PSEN1ΔE9 and in sAD tissues but with different binding patterns. Comparable 3 H-THK5117 and 3 H-deprenyl brain homogenate binding was observed for AβPParc, PSEN1ΔE9, and sAD, respectively. Some differences were observed between 3 H-MK6240 and 3 H-THK5117 in ADAD. A positive correlation between 3 H-deprenyl and 3 H-THK5117 binding was observed in AβPParc, while no such correlation was found in PSEN1ΔE9 and sAD. Our study demonstrates differences in the properties of the amyloid plaques between two genetic variants of AD and sAD. Despite the lack of measurable amyloid fibrils by PiB in the AβPParc cases, high regional tau and astrocyte binding was observed. The lack of correlation between 3 H-deprenyl and 3 H-THK5117 binding in PSEN1ΔE9 and sAD in contrast of the positive correlation observed in the AβPParc cases suggest differences in the pathological cascade between variants of AD that warrant further exploration in vivo., (© 2020. The Author(s).)

Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the catalytic subunit of γ-secretase whose mutation is linked to familial AD (FAD), localizes to the mitochondrial membrane and regulates its homeostasis. Thus, we investigated how five PS1 mutations (A431E, E280A, H163R, M146V, and Δexon9) observed in FAD affect mitochondrial functions. Methods: We used H4 glioblastoma cell lines genetically engineered to inducibly express either the wild-type PS1 or one of the five PS1 mutants in order to examine mitochondrial morphology, dynamics, membrane potential, ATP production, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), oxidative stress, and bioenergetics. Furthermore, we used brains of PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients in order to investigate the role of PS1 in regulating MAMs formation. Results: Each PS1 mutant exhibited slightly different mitochondrial dysfunction. Δexon9 mutant induced mitochondrial fragmentation while A431E, E280A, H163R, and M146V mutants increased MAMs formation. A431E, E280A, M146V, and Δexon9 mutants also induced mitochondrial ROS production. A431E mutant impaired both complex I and peroxidase activity while M146V mutant only impaired peroxidase activity. All PS1 mutants compromised mitochondrial membrane potential and cellular ATP levels were reduced by A431E, M146V, and Δexon9 mutants. Through comparative profiling of hippocampal gene expression in PS1M146V knock-in mice, we found that PS1M146V upregulates Atlastin 2 (ATL2) expression level, which increases ER-mitochondria contacts. Down-regulation of ATL2 after PS1 mutant induction rescued abnormally elevated ER-mitochondria interactions back to the normal level. Moreover, ATL2 expression levels were significantly elevated in the brains of 3xTg-AD mice and AD patients. Conclusions: Overall, our findings suggest that each of the five FAD-linked PS1 mutations has a deleterious effect on mitochondrial functions in a variety of ways. The adverse effects of PS1 mutations on mitochondria may contribute to MAMs formation and oxidative stress resulting in an accelerated age of disease onset in people harboring mutant PS1., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)