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Various modifications of proteins and the resulting proteoforms of a protein can associate with many diseases and are also significantly involved in the rapid regulation of hemostasis and thrombosis. For example, the release of prostacyclin from the intact endothelium and the consequent following phosphorylation of VASP in platelets is a post-translational regulation to keep them in a quiescent state. In Alzheimer's disease, proteoforms arise from the altered cleavage of the amyloid precursor protein, which finally causes amyloid plaques in the brain. This changed processing of the amyloid precursor protein can also be detected in platelets, making them an attractive source of biomarkers for this neurodegenerative disease. Age-related or prothrombotic disorders can have multiple origins, including genomic, transcriptional, and translational factors, which together can be mapped at the proteome level. Hence, recording these dynamic protein changes under physiological and pathophysiological conditions is paramount in platelet proteomics. To effectively study diseases through platelet proteomics, it is crucial to consider platelets' primary regulatory mechanism and thoroughly evaluate the disparities between the two leading proteomics technologies, top-down and bottom-up approaches. This commentary provides insights into the differences between these two technologies, which are particularly noticeable in detecting the different proteoforms of a protein. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia, characterized by the abnormal accumulation of protein aggregates in the brain, known as neurofibrillary tangles and amyloid-β (Aβ) plaques. It is believed that an imbalance between cerebral and peripheral pools of Aβ may play a relevant role in the deposition of Aβ aggregates. Therefore, in this study, we aimed to evaluate the effect of the removal of Aβ from blood plasma on the accumulation of amyloid plaques in the brain. We performed monthly plasma exchange with a 5% mouse albumin solution in the APP/PS1 mouse model from 3 to 7 months old. At the endpoint, total Aβ levels were measured in the plasma, and soluble and insoluble brain fractions were analyzed using ELISA. Brains were also analyzed histologically for amyloid plaque burden, plaque size distributions, and gliosis. Our results showed a reduction in the levels of Aβ in the plasma and insoluble brain fractions. Interestingly, histological analysis showed a reduction in thioflavin-S (ThS) and amyloid immunoreactivity in the cortex and hippocampus, accompanied by a change in the size distribution of amyloid plaques, and a reduction in Iba1-positive cells. Our results provide preclinical evidence supporting the relevance of targeting Aβ in the periphery and reinforcing the potential use of plasma exchange as an alternative non-pharmacological strategy for slowing down AD pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by the presence of senile plaques composed of β-amyloid peptide (Aβ) aggregates with toxic effects that are still not fully understood. Recently, it was discovered that Aβ(1–42) fibrils possess catalytic activity on acetylcholine hydrolysis. Catalytic amyloids are an emerging and exciting field of research. In this study, we examined the catalytic activity of the fibrils formed by Aβ(1–40), the most abundant Aβ variant, on acetylcholine hydrolysis. Our findings reveal that Aβ(1–40) fibrils exhibit moderate enzymatic activity, indicating that natural peptide aggregates could serve as biocatalysts and provide new insights into the potential role of Aβ in neurological disorders. [ABSTRACT FROM AUTHOR]

Background: Transthyretin (ATTR) amyloidosis is often diagnosed in an advanced stage, when irreversible cardiac damage has occurred. Lumbar spinal stenosis (LSS) may precede cardiac ATTR amyloidosis by many years, offering the opportunity to detect ATTR already at the time of LSS surgery. We prospectively assessed the prevalence of ATTR in the ligamentum flavum by tissue biopsy in patients aged >50 years undergoing surgery for LSS. Methods: Ligamentum flavum thickness was assessed pre-operatively on axial T2 magnetic resonance imaging (MRI) slices. Tissue samples from ligamentum flavum were screened centrally by Congo red staining and immunohistochemistry (IHC). Results: Amyloid in the ligamentum flavum was detected in 74/94 patients (78.7%). IHC revealed ATTR in 61 (64.9%), whereas amyloid subtyping was inconclusive in 13 (13.8%). Mean thickness of ligamentum flavum was significantly higher at all levels in patients with amyloid (p < .05). Patients with amyloid deposits were older (73.1 ± 9.2 vs. 64.6 ± 10.1 years, p = .01). No differences in sex, comorbidities, previous surgery for carpal tunnel syndrome or LSS were observed. Conclusions: Amyloid, mostly of the ATTR subtype, was found in four out of five patients with LSS and is associated with age and ligamentum flavum thickness. Histopathological work-up of ligamentum flavum might inform future decision making. [ABSTRACT FROM AUTHOR]

Background: Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs. Objective: To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action. Materials and Methods: We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods. Results: We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 mM, while the binding site on SAA is formed by segments of positively charged amino acids. Conclusion: Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions. [ABSTRACT FROM AUTHOR]

Introduction: Histological examination of tissue specimens obtained during surgical treatment of trigger finger frequently encountered unclassifiable amyloid deposits in the annular ligament. We systematically explored this unknown type by a comprehensive analysis using histology, immunohistochemistry, and quantitative mass spectrometry-based proteomics. Methods: 205 tissue specimens of annular ligaments were obtained from 172 patients. Each specimen was studied by histology and immunohistochemistry. Tissue specimens obtained from ten patients with histology proven amyloid in annular ligament were analysed by label-free quantitative proteomics. Histological and immunohistochemical findings were correlated with patient demographics. Results: Amyloid was present as band like deposits along the surface of annular ligament, dot like or patchy deposits within the matrix. Immunohistochemistry identified ATTR amyloid in 92 specimens (mostly patchy in the matrix), while the band like deposits of 100 specimens remained unclassifiable. Proteomic profiles identified the unknown amyloid as most likely of fibrinogen origin. The complete cohort was re-examined by immunohistochemistry using a custom-made antibody and confirmed the presence of fibrinogen alpha-chain (FGA) in a hitherto unclassifiable type of amyloid in annular ligament. Conclusion: Our study shows that two different types of amyloid affect the annular ligament, ATTR amyloid and AFib amyloid, with distinct demographic patient characteristics and histomorphological deposition patterns. [ABSTRACT FROM AUTHOR]

Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and death. Recent studies suggest that hematologic response may be an important prognostic indicator of overall survival (OS) in AL amyloidosis. The aim of this study was to evaluate the trial-level association between hematologic complete response (CR) or very good partial response or better (≥ VGPR) and OS in newly diagnosed patients. Studies were identified via systematic literature review. Pooled effect estimates were generated by a random-effects model. Nine observational studies reporting hematologic CR or ≥VGPR and OS hazard ratios (HRs) were included in the meta-analysis. Achieving hematologic CR was associated with improved OS (HR, 0.21; 95% confidence interval [CI] 0.13–0.34). Achieving ≥ VGPR was also associated with improved OS (HR 0.21; 95% CI 0.17–0.26). Results of a sensitivity analysis excluding one outlier study revealed no heterogeneity and a better overall HR estimate. Potential limitations of this meta-analysis include the small number of eligible studies (consistent with the rarity of the disease) and inconsistencies in reporting of results. Overall, our findings support the use of deep hematologic response (CR or ≥VGPR) as a clinical trial endpoint in newly diagnosed AL amyloidosis. This study provides evidence that early hematologic response is a strong patient-level surrogate for long-term OS in patients with AL amyloidosis receiving frontline therapy. Structured data collection of depth of response in future trials will further strengthen these observations. [ABSTRACT FROM AUTHOR]

Rationale: Extracellular proteolytic activity plays an important role in memory formation and the preservation of cognitive function. Previous studies have shown increased levels of plasminogen activator inhibitor-1 (PAI-1) in the brain of mouse models of Alzheimer's disease (AD) and plasma of AD patients, associated with memory and cognitive decline; however, the exact function of PAI-1 in AD onset and progression is largely unclear. Objective: In this study, we evaluated a novel PAI-1 inhibitor, TM5A15, on its ability to prevent or reverse memory deficits and decrease Aβ levels and plaque deposition in APP/PS1 mice. Methods: We administered TM5A15 mixed in a chow diet to 3-month and 9-month-old APP/PS1 mice before and after neuropathological changes were distinguishable. We then evaluated the effects of TM5A15 on memory function and neuropathology at 9 months and 18 months of age. Results: In the younger mice, 6 months of TM5A15 treatment protected against recognition and short-term working memory impairment. TM5A15 also decreased oligomer levels and amyloid plaques, and increased mBDNF expression in APP/PS1 mice at 9 months of age. In aged mice, 9 months of TM5A15 treatment did not significantly improve memory function nor decrease amyloid plaques. However, TM5A15 treatment showed a trend in decreasing oligomer levels in APP/PS1 mice at 18 months of age. Conclusion: Our results suggest that PAI-1 inhibition could improve memory function and reduce the accumulation of amyloid levels in APP/PS1 mice. Such effects are more prominent when TM5A15 is administered before advanced AD pathology and memory deficits occur. [ABSTRACT FROM AUTHOR]

AA-amyloidosis in Siamese and Oriental shorthair cats is a lethal condition in which amyloid deposits accumulate systemically, especially in the liver and the thyroid gland. The age at death of affected cats varies between one and seven years. A previous study indicated a complex mode of inheritance involving a major locus. In the present study, we performed a multi-locus genome-wide association study (GWAS) using five methods (mrMLM, FASTmrMLM, FASTmrEMMA, pLARmEB and ISIS EM-BLASSO) to identify variants associated with AA-amyloidosis in Siamese/Oriental cats. We genotyped 20 affected mixed Siamese/Oriental cats from a cattery and 48 healthy controls from the same breeds using the Illumina Infinium Feline 63 K iSelect DNA array. The multi-locus GWAS revealed eight significantly associated single nucleotide polymorphisms (SNPs) on FCA A1, D1, D2 and D3. The genomic regions harboring these SNPs contain 55 genes, of which 3 are associated with amyloidosis in humans or mice. One of these genes is SAA1, which encodes for a member of the Serum Amyloid A family, the precursor protein of Amyloid A, and a mutation in the promotor of this gene causes hereditary AA-amyloidosis in humans. These results provide novel knowledge regarding the complex genetic background of hereditary AA-amyloidosis in Siamese/Oriental cats and, therefore, contribute to future genomic studies of this disease in cats. [ABSTRACT FROM AUTHOR]

Background: This study aimed to establish an in vitro model of Alzheimer's Disease (AD) to investigate the neuroprotective activities of allyl isothiocyanate (AITC) and sulforaphane (SFN). Materials and Methods: Human neuroblastoma cell lines (SKNAS) were used for the in vitro model of AD after amyloid-β25−35 (Aβ25–35) treatment. Cytotoxicity analysis was performed using the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Indirect immunocytochemical methods were used to assess the tau protein, alpha-synuclein (α-synuclein), and β-amyloid distribution in the in vitro model of AD and SKNAS cells. Results: An in vitro AD model was induced by treatment of SKNAS cells with 1 µM of Aβ25–35 for 48 h. AITC and SFN were applied for 48 h, and the optimal concentrations were determined as 50 µM AITC and 15 µM SFN. Reduced tau immunoreactivity was shown after AITC and SFN administration in SKNAS cells and in vitro models, demonstrating that AITC and SFN prevented amyloid plaque production in the in vitro AD model control group by reducing the β-amyloid level, α-synuclein levels were similar in control and in vitro AD model cells. Reduced α-synuclein levels were observed after SFN treatment in the AD model cells and AITC treatment in the control cells. Conclusion: It could be concluded that AITC and SFN are potential components as neuroprotective agents against AD. [ABSTRACT FROM AUTHOR]

The brain of a rhesus monkey that died at 43 years of age with symptoms of suspected cognitive dysfunction was analyzed. pathological analyses revealed characteristic Alzheimer’s disease-related lesions: the aggregation of amyloid β (Aβ) in the form of senile plaques and phosphorylated tau proteins. We also revealed that Aβ43, which is prone to aggregation and toxicity in humans, is involved in senile plaques in the brain of the rhesus monkey, as well as several other Aβ species. Comparative studies of neuropathology using aged nonhuman primates lack behavioral descriptions compared to human medicine. This case report showed behavioral abnormalities and the detailed pathological changes that may have caused it in a super-aged rhesus monkey [ABSTRACT FROM AUTHOR]

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials. HIGHLIGHTS: Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers.Prevalence of non‐carriers in trial populations could impact outcomes. [ABSTRACT FROM AUTHOR]

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The pathological features of Alzheimer's disease are the formation of amyloid plaques and entanglement of nerve fibers. Studies have shown that Cu may be involved in the formation of amyloid plaques. However, their role has been controversial. The aim of this study was to explore the role of Cu in AD. We applied the "R" software for our differential analysis. Differentially expressed genes were screened using the limma package. Copper metabolism-related genes and the intersection set of differential genes with GSE5281 were searched; functional annotation was performed. The protein–protein interaction network was constructed using several modules to analyse the most significant hub genes. The hub genes were then qualified, and a database was used to screen for small-molecule AD drugs. We identified 87 DEGs. gene ontology analysis focused on homeostatic processes, response to toxic substances, positive regulation of transport, and secretion. The enriched molecular functions are mainly related to copper ion binding, molecular function regulators, protein-containing complex binding, identical protein binding and signalling receptor binding. The KEGG database is mainly involved in central carbon metabolism in various cancers, Parkinson's disease and melanoma. We identified five hub genes, FGF2, B2M, PTPRC, CD44 and SPP1, and identified the corresponding small molecule drugs. Our study identified key genes possibly related to energy metabolism in the pathological mechanism of AD and explored potential targets for AD treatment by establishing interaction networks. [ABSTRACT FROM AUTHOR]

In the central nervous system, microglia are responsible for removing infectious agents, damaged/dead cells, and amyloid plaques by phagocytosis. Other cell types, such as astrocytes, are also recently recognized to show phagocytotic activity under some conditions. Oligodendrocyte precursor cells (OPCs), which belong to the same glial cell family as microglia and astrocytes, may have similar functions. However, it remains largely unknown whether OPCs exhibit phagocytic activity against foreign materials like microglia. To answer this question, we examined the phagocytosis activity of OPCs using primary rat OPC cultures. Since innate phagocytosis activity could trigger cell death pathways, we also investigated whether participating in phagocytosis activity may lead to OPC cell death. Our data shows that cultured OPCs phagocytosed myelin‐debris‐rich lysates prepared from rat corpus callosum, without progressing to cell death. In contrast to OPCs, mature oligodendrocytes did not show phagocytotic activity against the bait. OPCs also exhibited phagocytosis towards lysates of rat brain cortex and cell membrane debris from cultured astrocytes, but the percentage of OPCs that phagocytosed beta‐amyloid was much lower than the myelin debris. We then conducted RNA‐seq experiments to examine the transcriptome profile of OPC cultures and found that myelination‐ and migration‐associated genes were downregulated 24 h after phagocytosis. On the other hand, there were a few upregulated genes in OPCs 24 h after phagocytosis. These data confirm that OPCs play a role in debris removal and suggest that OPCs may remain in a quiescent state after phagocytosis. [ABSTRACT FROM AUTHOR]

A central event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-β (Aβ) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that Aβ augmented AChE activity in vitro, maximum activation of 548 ± 5% was achieved following 48 h of incubation with 10 μM of Aβ1–40, leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by Aβ1–40 was associated with increased Vmax and unchanged Km. Although BChE activity also increased following incubation with Aβ1–40, this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 μM of Aβ1–40 significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters. [ABSTRACT FROM AUTHOR]

A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains β‐amyloid peptides (Aβ). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aβ processing is rarely known. Aβ levels are detected by using Immunohistochemistry (IHC) and enzyme‐linked immune‐sorbent assay (ELISA). Cryo‐electron microscopy (Cryo‐EM) is used to determine the structure of γ‐secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ‐secretase structure and specifically accelerates γ‐secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N‐terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aβ generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ‐secretase activity and the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has brought a heavy burden to society as a representative neurodegenerative disease. The etiology of AD combines multiple factors, concluding family, gender, head trauma, diseases and social psychology. There are multiple hypotheses explaining the pathogenesis of AD such as β-amyloid (Aβ) deposition and tau hyperphosphorylation, which lead to extracellular amyloid plaques and neurofibrillary tangles in neurons. The existing therapeutic drugs have several disadvantages including single target, poor curative effect, and obvious side effects. Tea contains many bioactive components, such as tea polyphenols (TPP), L-theanine (L-TH), tea pigment, tea polysaccharides and caffeine. The epidemiological investigations have shown that drinking tea can reduce the risk of AD. The mechanisms of tea active ingredients in the prevention and regulation of AD includes reducing the generation and aggregation of Aβ; inhibiting tau aggregation and hyperphosphorylation; inhibiting neuronal apoptosis and regulate neurotransmitters; relieving oxidative stress and neuroinflammation as well as the regulation of intestinal flora. This review summarizes the different signaling pathways that tea active ingredients regulate AD. Furthermore, we propose the main limitations of current research and future research directions, hoping to contribute to the development of natural functional foods based on tea active ingredients in the prevention and treatment of AD. Natural AD-modulating active ingredients in tea have been summarized. Influences of drinking tea or tea active ingredients on AD are reviewed. Main regulating mechanisms of tea active ingredients on AD are explained. The main limitations of current research and future directions are proposed. [ABSTRACT FROM AUTHOR]

BACKGROUND Monoclonal antibodies that target amyloid-beta CAB) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully hunlan, anti-Aβ IgGl monocional antibody with highest affinity for aggregated AB that has been tested for the treatment of Alzheimer's disease. METHODS We conducted two phase 3 trials (GRADUATE I and ID involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alz- heimer' s disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS A total of985 and 980 participants were enrolled in the GRADUATE I and H trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval ICI], -0.66 to 0.05; P=O.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95° CI, -0.55 to 0.17; P=O.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the tWO trialS. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of A/342 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS Among persons with early Alzheimer's disease, the use of gantenerumab led to lower amyloid plague burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.) [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a form of dementia marked by the accumulation of neuritic plaques and neurofibrillary tangles through the action of GSK-3β with both significant epidemiological and clinical impact. Current pharmacological treatment approaches are focused on symptomatic relief and aims to suppress AD's progression rather than disease modification. This issue has triggered further investigations about tau pathology as an important component in AD's pathophysiology, one of them being the Akt signaling pathway. Based on the problem served by AD, combined with the non-existence of conclusive therapy for this disease; hence, this study strives to further investigate the potential therapeutical benefit of Akt signaling towards AD. A total of 82 studies are included, consisting of both national and international articles creating a narrative review based on the PRISMA checklist. Variables searched on this study, include Alzheimer's disease (AD), Akt signaling, serine-9 phosphorylation, and GSK-3β. Tau protein accumulation has been a mainstay in the physiopathology of AD, which are largely influenced by the GSK-3β expression. Akt signaling has been shown to inactivate GSK-3β through serine-9 phosphorylation. Thus, modulating and optimizing the Akt signaling pathway present encouraging prospects for the development of innovative and efficacious therapeutic strategies in addressing AD. Several studies have tried to estimate the harm and benefit as well as dose-effect relationship between Akt signaling and AD, concluding a promising beneficial effect for AD therapy. Here, we show the beneficial therapeutic effects of Akt signaling towards AD through both theoretical and empirical standpoints. [ABSTRACT FROM AUTHOR]

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5–6% of all AD cases (Mendez et al. in Continuum 25:34–51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674–88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674–88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1–30, 2022; Caldwell et al. in Sci Adv 6:1–16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD. [ABSTRACT FROM AUTHOR]

Engulfment of cellular material and proteins is a key function for microglia, a resident macrophage of the central nervous system (CNS). Among the techniques used to measure microglial engulfment, confocal light microscopy has been used the most extensively. Here, we show that autofluorescence (AF) likely due to lipofuscin (lipo-AF) and typically associated with aging, can also be detected within microglial lysosomes in the young mouse brain by light microscopy. This lipo-AF signal accumulates first within microglia and it occurs earliest in white versus gray matter. Importantly, in gray matter, lipo-AF signal can confound the interpretation of antibody-labeled synaptic material within microglia in young adult mice. We further show that there is an age-dependent accumulation of lipo-AF inside and outside of microglia, which is not affected by amyloid plaques. We finally implement a robust and cost-effective strategy to quench AF in mouse, marmoset, and human brain tissue. Microglia are brain macrophages that engulf and clear cellular material and protein aggregates. Here, the authors show that lipofuscin-like autofluorescence can confound microglial engulfment analyses, which they can resolve with a photobleaching protocol. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the well-documented pathophysiology of Alzheimer's Disease (AD), treatment options are limited in diversity and efficacy. Thus, the development of new treatments requires an extensive understanding of molecular pathways altered by drugs in development. In this review, we survey the literature regarding common herbal phytochemicals, kaempferol and quercetin, with a specific focus on their multiple mechanisms that alleviate the pathological underpinnings of AD. Here, we utilize the well-documented mechanisms of quercetin to propose a novel multimodal mechanism of kaempferol, and we discuss common herbal sources and the limitations of these potential treatments. Alzheimer's Disease (AD) is a progressive neurodegenerative disorder impairing cognition and memory in the elderly. This disorder has a complex etiology, including senile plaque and neurofibrillary tangle formation, neuroinflammation, oxidative stress, and damaged neuroplasticity. Current treatment options are limited, so alternative treatments such as herbal medicine could suppress symptoms while slowing cognitive decline. We followed PRISMA guidelines to identify potential herbal treatments, their associated medicinal phytochemicals, and the potential mechanisms of these treatments. Common herbs, including Ginkgo biloba, Camellia sinensis, Glycyrrhiza uralensis, Cyperus rotundus, and Buplerum falcatum, produced promising pre-clinical results. These herbs are rich in kaempferol and quercetin, flavonoids with a polyphenolic structure that facilitate multiple mechanisms of action. These mechanisms include the inhibition of Aβ plaque formation, a reduction in tau hyperphosphorylation, the suppression of oxidative stress, and the modulation of BDNF and PI3K/AKT pathways. Using pre-clinical findings from quercetin research and the comparatively limited data on kaempferol, we proposed that kaempferol ameliorates the neuroinflammatory state, maintains proper cellular function, and restores pro-neuroplastic signaling. In this review, we discuss the anti-AD mechanisms of quercetin and kaempferol and their limitations, and we suggest a potential alternative treatment for AD. Our findings lead us to conclude that a polyherbal kaempferol- and quercetin-rich cocktail could treat AD-related brain damage. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the primary cause of dementia and is characterized by the death of brain cells due to the accumulation of insoluble amyloid plaques, hyperphosphorylation of tau protein, and the formation of neurofibrillary tangles within the cells. AD is also associated with other pathologies such as neuroinflammation, dysfunction of synaptic connections and circuits, disorders in mitochondrial function and energy production, epigenetic changes, and abnormalities in the vascular system. Despite extensive research conducted over the last hundred years, little is established about what causes AD or how to effectively treat it. Given the severity of the disease and the increasing number of affected individuals, there is a critical need to discover effective medications for AD. The US Food and Drug Administration (FDA) has approved several new drug molecules for AD management since 2003, but these drugs only provide temporary relief of symptoms and do not address the underlying causes of the disease. Currently, available medications focus on correcting the neurotransmitter disruption observed in AD, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate (NMDA) receptor, which temporarily alleviates the signs of dementia but does not prevent or reverse the course of AD. Research towards disease-modifying AD treatments is currently underway, including gene therapy, lipid nanoparticles, and dendrimer-based therapy. These innovative approaches aim to target the underlying pathological processes of AD rather than just managing the symptoms. This review discusses the novel aspects of pathogenesis involved in the causation of AD of AD and in recent developments in the therapeutic armamentarium for the treatment of AD such as gene therapy, lipid nanoparticles, and dendrimer-based therapy, and many more. [ABSTRACT FROM AUTHOR]

Background: Renal amyloidosis (RA) has a worldwide incidence of 5–13 cases per million person‐years and is expected to rise in upcoming years due to growing awareness, plus improvement of diagnostic modalities. Diagnosing RA remains challenging, especially when encountering very small, focal, or early amyloid deposits. Since delays in diagnosis portends poor prognosis, high morbidity, and mortality, it is crucial to evaluate the performance of commonly used diagnostic modalities. This is the first study that presents a full picture of the diagnostic performance of fluorescence microscopy (FM) with a tetramethylrhodamine isothiocyanate (TRITC) filter to diagnose RA in general and stratified by compartments. Materials and methods: A retrospective double‐blind diagnostic accuracy study of FM‐TRITC filter was performed. The presence or absence of amyloid in the vascular, interstitial, and glomerular compartments was established in 316 representative Congo red‐stained core biopsies with an FM‐TRITC filter. This was contrasted with polarized microscopy (PM) showing apple‐green birefringence as the gold standard. Sensitivity, specificity, positive and negative predictive values, likelihood ratios, and the receiver operating characteristic (ROC) curve were obtained using STATA13. Results: The prevalence of RA was 6.01%, comparable with that reported in the literature. Reciprocity with regard to the location and pattern of fluorescence and birefringence between the two diagnostic modalities was seen. The FM‐TRITC filter has a sensitivity of 100%, specificity of 97.64%, and a positive and negative predictive value of 73.08% and 100%, respectively. The positive likelihood ratio was 42.37, and the negative was 0.00. Overall accuracy was 97.78%. The area under the ROC curve was 0.98. The Diagnostic performance of the FM‐TRITC filter stratified by compartments is shown in Table 1. The area under the ROC curve was 0.99, 0.98, and 0.99 for the vascular, interstitial, and glomerular compartment, respectively. All patients with RA (n = 19) were correctly identified; this included one new case, one case with small and focal amyloid, and two early cases with less dense amyloid where birefringence was ambiguous by PM. Discussion: The FM‐TRITC filter is a highly accurate, sensitive, specific, with excellent predictive values, time‐efficient, easy to perform, and suitable to reproduce diagnostic modality for RA. It can accurately rule out RA in all compartments, and in most cases concomitant use of PM should not be indispensable. The diagnosis of vascular, interstitial, and glomerular amyloid deposits can be done using only the FM‐TRITC filter with Congo red‐stained slides. Exceptionally, a few cases of interstitial amyloidosis could be overdiagnosed due to interferences (e.g. artefacts), these cases could be further assessed with a second diagnostic modality if positive fluorescence is seen. Routine use of the FM‐TRITC filter can aid in the diagnosis of early RA, even when the deposits are inconspicuous by PM. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a disabling neurodegenerative disease. The prognosis is poor, and currently there are no proven effective therapies. Most likely, the etiology is related to cerebral inflammatory processes that cause neuronal damage, resulting in dysfunction and apoptosis of nerve cells. Pathogens that evoke a neuroinflammatory response, collectively activate astrocytes and microglia, which contributes to the secretion of pro-inflammatory cytokines. This leads to the deposit of clustered fragments of beta-amyloid and misfolded tau proteins which do not elicit an adequate immune reaction. Apart from the function of astrocytes and microglia, molecular entities such as TREM2, SYK, C22, and C33 play a role in the physiopathology of AD. Furthermore, bacteria and viruses may trigger an overactive inflammatory response in the brain. Pathogens like Helicobacter pylori, Chlamydia pneumonia, and Porphyromonas gingivalis (known for low-grade infection in the oral cavity) can release gingipains, which are enzymes that can damage and destroy neurons. Chronic infection with Borrelia burgdorferi (the causative agent of Lyme disease) can co-localize with tau tangles and amyloid deposits. As for viral infections, herpes simplex virus 1, cytomegalovirus, and Epstein-Barr virus can play a role in the pathogenesis of AD. Present investigations have resulted in the development of antibodies that can clear the brain of beta-amyloid plaques. Trials with humanized aducanumab, lecanemab, and donanemab revealed limited success in AD patients. However, AD should be considered as a continuum in which the initial preclinical phase may take 10 or even 20 years. It is generally thought that this phase offers a window for efficacious treatment. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has become one of the leading causes of health problems in the elderly, and studying its causes and treatments remains a serious challenge for researchers worldwide. The two main pathological features of Alzheimer's disease are the extracellular deposition of β-amyloid (Aβ) to form senile plaques and the intracellular aggregation of hyperphosphorylated Tau protein to form neurofibrillary tangles (NFTs). Researchers have proposed several hypotheses to elucidate the pathogenesis of AD, but due to the complexity of the pathophysiologic factors involved in the development of AD, no effective drugs have been found to stop the progression of the disease. Currently, the mainstay drugs used to treat AD can only alleviate the patient's symptoms and do not have a therapeutic effect. As researchers explore interactions among diseases, much evidence suggests that there is a close link between periodontitis and AD, and that periodontal pathogenic bacteria can exacerbate Aβ deposition and Tau protein hyperphosphorylation through neuroinflammatory mechanisms, thereby advancing the pathogenesis of AD. This article reviews recent advances in the pathogenesis of AD, available therapeutic agents, the relevance of periodontitis to AD, and mechanisms of action. [ABSTRACT FROM AUTHOR]

Nodular amyloidosis (NA) is a rare type of primary localized cutaneous amyloidosis in which light chain amyloid deposits in the skin without concurrent systemic involvement. We report a challenging case of NA on the scalp, mimicking primary scarring alopecia, in a relatively young and healthy 36‐year‐old man. In addition to a nonspecific clinical appearance with a broad differential, NA can be a difficult diagnosis because it may require ancillary testing, such as liquid chromatography–tandem mass spectrometry to type the amyloid protein, and hematology–oncology workup to exclude systemic disease. Pathologists can highlight the importance of systemic evaluation in their reports to ensure patients receive appropriate management. [ABSTRACT FROM AUTHOR]

Amyloidosis is a group of protein-misfolding disorders characterized by the accumulation of amyloid in organs, both in humans and animals. AA-amyloidosis is considered a reactive type of amyloidosis and in humans is characterized by the deposition of AA-amyloid fibrils in one or more organs. In domestic shorthair cats, AA-amyloidosis was recently reported to be frequent in shelters. To better characterize this pathology, we report the distribution of amyloid deposits and associated histological lesions in the organs of shelter cats with systemic AA-amyloidosis. AA-amyloid deposits were identified with Congo Red staining and immunofluorescence. AA-amyloid deposits were then described and scored, and associated histological lesions were reported. Based on Congo Red staining and immunofluorescence nine shelter cats presented systemic AA-amyloidosis. The kidney (9/9), the spleen (8/8), the adrenal glands (8/8), the small intestine (7/7) and the liver (8/9) were the organs most involved by amyloid deposits, with multifocal to diffuse and from moderate to severe deposits, both in the organ parenchyma and/or in the vascular compartment. The lung (2/9) and the skin (1/8) were the least frequently involved organs and deposits were mainly focal to multifocal, mild, vascular and perivascular. Interestingly, among the organs with fibril deposition, the stomach (7/9), the gallbladder (6/6), the urinary bladder (3/9), and the heart (6/7) were reported for the first time in cats. All eye, brain and skeletal muscle samples had no amyloid deposits. An inflammatory condition was identified in 8/9 cats, with chronic enteritis and chronic nephritis being the most common. Except for secondary cell compression, other lesions were not associated to amyloid deposits. To conclude, this study gives new insights into the distribution of AA-amyloid deposits in cats. A concurrent chronic inflammation was present in almost all cases, possibly suggesting a relationship with AA-amyloidosis. [ABSTRACT FROM AUTHOR]

Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid β plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid β plays a key role in the pathogenesis of AD and of CAA. Amyloid β accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid β accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid β level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications. [ABSTRACT FROM AUTHOR]

UVB‐induced photoaging is characterized by wrinkle formation, slackness and senile plaques, affecting the health and beauty of human being. Our previous study revealed that exosomes derived from adipose‐derived stem cells (ADSCs) could efficiently alleviate UVB‐induced photodamage. However, the functional ingredients in exosomes were undefined. LncRNA H19, one of the well‐researched lncRNAs in exosomes, exhibits multiple physiological effects. This study aims to demonstrate the photo‐protective role of lncRNA H19 on skin photoaging in UVB‐irradiated human skin fibroblasts cells (HSFs) and Kunming mice. LncRNA H19‐overexpressing exosomes (H19‐Exo) were isolated from the supernatant of ADSCs infected with lncRNA H19‐loaded lentivirus. The results showed that H19‐Exo significantly inhibited MMPs production, DNA damage and ROS generation while enhancing procollagen type I synthesis in UVB‐irradiated HSFs. Meanwhile, H19‐Exo markedly reversed epidermal thickening and collagen degradation in UVB‐irradiated mice. Furthermore, luciferase reporter assays indicated that lncRNA H19 acted as a sponge for miR‐138 expression, and SIRT1 was targeted by miR‐138. Evidence from both in vitro and in vivo studies also revealed that H19‐Exo could enhance SIRT1 expression by knocking down miR‐138. In conclusion, lncRNA H19 served as a therapeutic candidate in treating UVB‐induced skin photoaging by upregulation of SIRT1 via miR‐138. [ABSTRACT FROM AUTHOR]

Background: Current drug treatments for dementia aren't effective. Studying gene-environment interactions can help develop personalized early intervention strategies for Alzheimer's disease (AD). However, no studies have examined the relationship between screen-based sedentary activities and genetic susceptibility to AD risk, and further understanding of the causal relationship is also crucial. Methods: This study included 462,524 participants from the UK Biobank with a follow-up of 13.6 years. Participants' screen-based sedentary activities time was categorized into three groups based on recorded time: ≥ 4 h/day, 2–3 h/day, and ≤ 1 h/day. Cox proportional risk models were used to analyze the association between computer use/TV viewing groups and the risk of all-cause dementia, AD and vascular dementia (VD). Generalized linear model (GLM) were used to examine the relationship between screen-based sedentary activities and brain structure. Bidirectional Mendelian randomization (MR) was used to validate the causal relationship between TV viewing and AD. Results: Compared to TV viewing ≤ 1 h/day, 1)TV viewing 2–3 h/day was correlated with a higher risk of all-cause dementia (HR = 1.09, 95% CI:1.01–1.18, P < 0.05), and TV viewing ≥ 4 h/day was associated with a higher risk of all-cause dementia (HR = 1.29, 95% CI: 1.19–1.40, P < 0.001), AD (HR = 1.25, 95% CI:1.1–1.42, P < 0.001), and VD (HR = 1.24, 95% CI: 1.04–1.49, P < 0.05); 2) TV viewing ≥ 4 h/day was correlated with a higher AD risk at intermediate (HR = 1.34, 95% CI: 1.03–1.75, P < 0.001) and high AD genetic risk score (AD-GRS) (HR = 2.18, 95% CI: 1.65–2.87, P < 0.001);3) TV viewing 2–3 h/day [β = (-94.8), 95% CI: (-37.9) -(-151.7), P < 0.01] and TV viewing ≥ 4 h/day [β = (-92.94), 95% CI: (-17.42) -(-168.46), P < 0.05] were correlated with a less hippocampus volume. In addition, a causal effect of TV viewing times was observed on AD analyzed using MR Egger (OR = 5.618, 95%CI:1.502–21.013, P < 0.05). Conclusions: There was a causal effect between TV viewing time and AD analyzed using bidirectional MR, and more TV viewing time exposure was correlated with a higher AD risk. Therefore, it is recommended that people with intermediate and high AD-GRS should control their TV viewing time to be less than 4 h/ day or even less than 1 h/day. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most prevalent type of dementia globally. The accumulation of amyloid-beta (Aβ) extracellular senile plaques in the brain is one of the hallmark mechanisms found in AD. Aβ42 is the most damaging and aggressively aggregating Aβ isomer produced in the brain. Although Aβ42 has been extensively researched as a crucial peptide connected to the development of the characteristic amyloid fibrils in AD, the specifics of its pathophysiology are still unknown. Therefore, the main objective was to identify novel compounds that could potentially mitigate the negative effects of Aβ42. 3-[[(3S)-1,2,3,4-Tetrahydroisoquinoline-3-carbonyl]amino]propanoic acid (THICAPA) was identified as a ligand for Aβ42 and for reducing fibrillary Aβ42 aggregation. THICAPA also improved cell viability when administered to PC12 neuronal cells that were exposed to Aβ42. Additionally, this compound diminished Aβ42 toxicity in the current AD Drosophila model by rescuing the rough eye phenotype, prolonging the life span, and enhancing motor functions. Through next-generation RNA-sequencing, immune response pathways were downregulated in response to THICAPA treatment. Thus, this study suggests THICAPA as a possible disease-modifying treatment for AD. [ABSTRACT FROM AUTHOR]

Age‐related hearing loss frequently precedes or coexists with mild cognitive impairment and dementia. The role specific neuropathologies play in this association, as either a cause or a consequence, is unclear. We therefore aimed to investigate whether specific dementia related neuropathologies were associated with hearing impairment in later life. We analysed data on ante‐mortem hearing impairment with post‐mortem neuropathological data for 442 participants from the Brains for Dementia Research Cohort. Binary logistic regression models were used to estimate the association of hearing impairment with the presence of each dementia‐related neuropathology overall, and with specific staged changes. All analyses adjusted for age and sex, and several sensitivity analyses were conducted to test the robustness of findings. Presence and density of neuritic plaques were associated with higher odds of hearing impairment ante‐mortem (OR = 3.65, 95% CI 1.78–7.46 for frequent density of plaques). Presence of any LB disease was likewise associated with hearing impairment (OR = 2.10, 95% CI 1.27–3.48), but this did not increase with higher cortical pathology (OR = 1.53, 95% CI 0.75–3.11). Nonspecific amyloid deposition, neurofibrillary tangle staging, overall AD neuropathology level, and cerebrovascular disease were not clearly associated with increased risks of hearing impairment. Our results provide some support for an association between dementia‐related neuropathology and hearing loss and suggest that hearing loss may be associated with a high neuritic plaque burden and more common in Lewy body disease. [ABSTRACT FROM AUTHOR]

In the clinical setting, routine identification of the main types of tissue amyloid deposits, light-chain amyloid (AL) and serum amyloid A (AA), is based on histochemical staining; rarer types of amyloid require mass spectrometry analysis. Raman spectroscopic imaging is an analytical tool, which can be used to chemically map, and thus characterize, the molecular composition of fluid and solid tissue. In this proof-of-concept study, we tested the feasibility of applying Raman spectroscopy combined with artificial intelligence to detect and characterize amyloid deposits in unstained frozen tissue sections from kidney biopsies with pathologic diagnosis of AL and AA amyloidosis and control biopsies with no amyloidosis (NA). Raman hyperspectral images, mapped in a 2D grid-like fashion over the tissue sections, were obtained. Three machine learning–assisted analysis models of the hyperspectral images could accurately distinguish AL (types λ and κ), AA, and NA 93–100% of the time. Although very preliminary, these findings illustrate the potential of Raman spectroscopy as a technique to identify, and possibly, subtype renal amyloidosis. [ABSTRACT FROM AUTHOR]

To analyze the effect of asymptomatic carotid atherosclerosis on the progression of cerebral small vessel disease (CSVD) in Shunyi cohort community population. Methods A total of 658 residents aged ≥ 35 years old from Shunyi cohort population (from June 2013 to April 2016) were selected as study subjects. Carotid ultrasound was used to assess the presence of baseline carotid plaque, and CSVD progression was assessed by baseline and follow - up MRI, which included lacunes, cerebral microbleeds (CMBs) and white matter hyperintensity (WMH). Univariate and multivariate Logistic regression was used to analyze the effect of carotid plaque on incident lacunes or CMBs, and linear regression was used to analyze the linear correlation between baseline carotid plaque and WMH progression. Results Among 658 people 250 people (37.99%) had carotid plaque at baseline. After (5.57 ± 0.49) years of follow - up, 70 people (10.64%) developed incident lacunes and 56 people (8.51%) had incident CMBs. The annual WMH progression was 0.28 (0.14, 0.55) cm³/year. Logistic regression analysis showed the presence of baseline carotid plaque significantly predicted incident CMBs (OR = 2.411, 95%CI: 1.240- 4.687; P = 0.009). Conclusions Prensence of carotid plaque increased CMBs progression during five-year follow-up, but the influence on lacunes and WMH progression requires a longer cumulative effect. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a physical illness, which damages a person's brain; it is the most common cause of dementia. AD can be characterized by the formation of amyloid-beta (Aβ) deposits. They exhibit diverse morphologies that range from diffuse to dense-core plaques. Most of the histological images cannot be described precisely by traditional geometry or methods. Therefore, this study aims to employ multifractal geometry in assessing and classifying amyloid plaque morphologies. The classification process is based on extracting the most descriptive features related to the amyloid-beta (Aβ) deposits using the Naive Bayes classifier. To eliminate the less important features, the Random Forest algorithm has been used. The proposed methodology has achieved an accuracy of 99%, sensitivity of 100%, and specificity of 98.5%. This study employed a new dataset that had not been widely used before. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. Progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson–Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated Aβ42 to Aβ40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening. [ABSTRACT FROM AUTHOR]

The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro, and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo. Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Impaired autophagy in plaque-associated microglia (PAM) has been reported to accelerate amyloid plaque deposition and cognitive impairment in AD pathogenesis. Recent evidence suggests that the transcription factor EB (TFEB)-mediated activation of the autophagy–lysosomal pathway is a promising treatment approach for AD. Moreover, the complementary therapy of intermittent hypoxia therapy (IHT) has been shown to upregulate autophagy and impart beneficial effects in patients with AD. However, the effect of IHT on PAM remains unknown. Methods: 8-Month-old APP/PS1 mice were treated with IHT for 28 days. Spatial learning memory capacity and anxiety in mice were investigated. AD pathology was determined by the quantity of nerve fibers and synapses density, numbers of microglia and neurons, Aβ plaque deposition, pro-inflammatory factors, and the content of Aβ in the brain. TFEB-mediated autophagy was determined by western blot and qRT-PCR. Primary microglia were treated with oligomeric Aβ 1–42 (oAβ) combined with IHT for mechanism exploration. Differential genes were screened by RNA-seq. Autophagic degradation process of intracellular oAβ was traced by immunofluorescence. Results: In this study, we found that IHT ameliorated cognitive function by attenuating neuronal loss and axonal injury in an AD animal model (APP/PS1 mice) with beta-amyloid (Aβ) pathology. In addition, IHT-mediated neuronal protection was associated with reduced Aβ accumulation and plaque formation. Using an in vitro PAM model, we further confirmed that IHT upregulated autophagy-related proteins, thereby promoting the Aβ autophagic degradation by PAM. Mechanistically, IHT facilitated the nuclear localization of TFEB in PAM, with TFEB activity showing a positive correlation with Aβ degradation by PAM in vivo and in vitro. In addition, IHT-induced TFEB activation was associated with the inhibition of the AKT–MAPK–mTOR pathway. Conclusions: These results suggest that IHT alleviates neuronal damage and neuroinflammation via the upregulation of TFEB-dependent Aβ clearance by PAM, leading to improved learning and memory in AD mice. Therefore, IHT may be a promising non-pharmacologic therapy in complementary medicine against AD. [ABSTRACT FROM AUTHOR]

Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. Objective: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. Methods: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288). Results: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes—the principal cell type of white matter. Conclusions: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD. [ABSTRACT FROM AUTHOR]

Amyloid β (Aβ) oligomers are the most neurotoxic forms of Aβ, and Aβ(1–42) is the prevalent Aβ peptide found in the amyloid plaques of Alzheimer's disease patients. Aβ(25–35) is the shortest peptide that retains the toxicity of Aβ(1–42). Aβ oligomers bind to calmodulin (CaM) and calbindin-D28k with dissociation constants in the nanomolar Aβ(1–42) concentration range. Aβ and histidine-rich proteins have a high affinity for transition metal ions Cu2+, Fe3+ and Zn2+. In this work, we show that the fluorescence of Aβ(1–42) HiLyteTM-Fluor555 can be used to monitor hexa-histidine peptide (His6) interaction with Aβ(1–42). The formation of His6/Aβ(1–42) complexes is also supported by docking results yielded by the MDockPeP Server. Also, we found that micromolar concentrations of His6 block the increase in the fluorescence of Aβ(1–42) HiLyteTM-Fluor555 produced by its interaction with the proteins CaM and calbindin-D28k. In addition, we found that the His6-tag provides a high-affinity site for the binding of Aβ(1–42) and Aβ(25–35) peptides to the human recombinant cytochrome b5 reductase, and sensitizes this enzyme to inhibition by these peptides. In conclusion, our results suggest that a His6-tag could provide a valuable new tool to experimentally direct the action of neurotoxic Aβ peptides toward selected cellular targets. [ABSTRACT FROM AUTHOR]

In this manuscript, we introduced a French EOAD patient in Korea who carried the presenilin-1 (PSEN1) Glu318Gly mutations with four possible risk variants, including sortilin-related receptor 1 (SORL1) Glu270Lys, ATP-binding cassette subfamily A member 7 (ABCA7) Val1946Met, translocase of outer mitochondrial membrane 40 (TOMM40) Arg239Trp, and granulin (GRN) Ala505Gly. The patient started to present memory decline and behavioral dysfunction in his early 60s. His brain imaging presented amyloid deposits by positron emission tomography (PET-CT). The multimer detection system (MDS) screening test for plasma for amyloid oligomers was also positive, which supported the AD diagnosis. It was verified that PSEN1 Glu318Gly itself may not impact amyloid production. However, additional variants were found in other AD and non-AD risk genes, as follows: SORL1 Glu270Lys was suggested as a risk mutation for AD and could increase amyloid peptide production and impair endosome functions. ABCA7 Val1946Met was a novel variant that was predicted to be damaging. The GRN Ala505Gly was a variant with uncertain significance; however, it may reduce the granulin levels in the plasma of dementia patients. Pathway analysis revealed that PSEN1 Glu318Gly may work as a risk factor along with the SORL1 and ABCA7 variants since pathway analysis revealed that PSEN1 could directly interact with them through amyloid-related and lipid metabolism pathways. TOMM40 and PSEN1 could have common mechanisms through mitochondrial dysfunction. It may be possible that PSEN1 Glu318Gly and GRN Ala505Gly would impact disease by impairing immune-related pathways, including microglia and astrocyte development, or NFkB-related pathways. Taken together, the five risk factors may contribute to disease-related pathways, including amyloid and lipid metabolism, or impair immune mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Systemic amyloidosis is a progressive disorder characterized by the extracellular deposition of amyloid fibrils and accessory proteins in visceral organs and tissues. Amyloid accumulation causes organ dysfunction and is not generally cleared by the immune system. Current treatment focuses on reducing amyloid precursor protein synthesis and slowing amyloid deposition. However, curative interventions will likely also require removal of preexisting amyloid deposits to restore organ function. Here we describe a prototypic pan-amyloid binding peptide-antibody fusion molecule (mIgp5) that enhances macrophage uptake of amyloid. Methods: The murine IgG1-IgG2a hybrid immunoglobulin with a pan amyloidreactive peptide, p5, fused genetically to the N-terminal of the immunoglobulin light chain was synthesized in HEK293T/17 cells. The binding of the p5 peptide moiety was assayed using synthetic amyloid-like fibrils, human amyloid extracts and amyloid-laden tissues as substrates. Binding of radioiodinated mIgp5 with amyloid deposits in vivo was evaluated in a murine model of AA amyloidosis using small animal imaging and microautoradiography. The bioactivity of mIgp5 was assessed in complement fixation and in vitro phagocytosis assays in the presence of patient-derived amyloid extracts and synthetic amyloid fibrils as substrates and in the presence or absence of human serum. Results: Murine Igp5 exhibited highly potent binding to AL and ATTR amyloid extracts and diverse types of amyloid in formalin-fixed tissue sections. In the murine model of systemic AA amyloidosis, 125I-mIgp5 bound rapidly and specifically to amyloid deposits in all organs, including the heart, with no evidence of non-specific uptake in healthy tissues. The bioactivity of the immunoglobulin Fc domain was uncompromised in the context of mIgp5 and served as an effective opsonin. Macrophage-mediated uptake of amyloid extract and purified amyloid fibrils was enhanced by the addition of mIgp5. This effect was exaggerated in the presence of human serum coincident with deposition of complement C5b9. Conclusion: Immunostimulatory, amyloid-clearing therapeutics can be developed by incorporating pan-amyloid-reactive peptides, such as p5, as a targeting moiety. The immunologic functionality of the IgG remains intact in the context of the fusion protein. These data highlight the potential use of peptideantibody fusions as therapeutics for all types of systemic amyloidosis. [ABSTRACT FROM AUTHOR]

Melanin, a ubiquitous dark pigment, plays important roles in the immune system, including scavenging reactive oxygen species formed in response to ultraviolet radiation absorption, absorbing metals, thermal regulation, drug uptake, innate immune system functions, redox, and energy transduction. Many tissue types, including brain, heart, arteries, ovaries, and others, contain melanin. Almost all cells contain precursors to melanin. A growing number of diseases in which there is a loss of melanin and/or neuromelanin are increasingly thought to have infectious etiologies, for example, Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and vitiligo. AD, PD, LBD, and vitiligo have been linked with herpesvirus, which enters melanosomes and causes apoptosis, and with gut dysbiosis and inflammation. Herpesvirus is also linked with gut dysbiosis and inflammation. We theorize that under normal healthy states, melanin retains some of the energy it absorbs from electromagnetic radiation, which is then used to fuel cells, and energy from ATP is used to compliment that energy supply. We further theorize that loss of melanin reduces the energy supply of cells, which in the case of AD,PD,andLBDresultsinaninability to sustain immune system defenses and remove the plaques associated with the disease, which appear to be part of the immune system's attempt to eradicate the pathogens seen in these neurodegenerative diseases. In addition, in an attempt to explain why removing these plaques does not result in improvements in cognition and mood and why cognitions andmoods in these individuals have ebbs and flows, we postulate that it is not the plaques that cause the cognitive symptoms but, rather, inflammation in the brain resulting from the immune system's response to pathogens. Our theory that energy retained inmelanin fuels cells in an inverse relationship with ATP is supported by studies showing alterations in ATP production in relationship to melanin levels in melanomas, vitiligo, and healthy cells. Therefore, alteration of melanin levels may be at the core of many diseases. We propose regulating melanin levels may offer new avenues for treatment development. [ABSTRACT FROM AUTHOR]

Background: Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. Methods: We examined 237 men ages 45–74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. Results: There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [− 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [− 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. Conclusions: Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. Trial registration: NCT02798185. [ABSTRACT FROM AUTHOR]

Background: There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Methods: Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed. Results: Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Conclusions: Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy. [ABSTRACT FROM AUTHOR]

Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer's disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch−) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch− diet increased amyloid-β levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-β and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease. [ABSTRACT FROM AUTHOR]

Amyloid plaques are considered to be the pathological hallmark of Alzheimer's disease (AD). Neuroinflammation further aggravates the pathogenesis of Alzheimer's disease. Calpains and NOD‐like receptor protein‐3 (NLRP3) inflammasomes are involved in the neuroinflammatory pathway and affect the progression of Alzheimer's disease. Hyperactivation of calpains is responsible for the activation of NLRP3 inflammasome, thereby affecting each other's molecular mechanism and causing astrogliosis, microgliosis, and neuronal dysfunction. Further, calpain hyperactivation is also associated with calcium homeostasis that acts as one of the triggers in the activation of NLRP3 inflammasome. Calpain activity is required for the maturation of interleukin‐1β, a key mediator of neuroinflammatory responses. The membrane potential/calcium/calpain/caspase‐1 axis acts as an unconventional regulator of inflammasomes. The complex crosstalk between NLRP3 inflammasome and calpain leads to a series of events. Targeting the molecular mechanism associated with calpain‐NLRP3 inflammasome activation and regulation can be a therapeutic and prophylactic perspective towards Alzheimer's disease. This review discusses calpains and NLRP3 inflammasome crosstalk in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Background: APOE is the largest genetic risk factor for Alzheimer's disease (AD), but there is a substantial polygenic component. Polygenic risk scores (PRS) can summarize small effects across the genome but may obscure differential risk across molecular processes and pathways that contribute to heterogeneity of disease presentation. Objective: We examined polygenic risk impacting specific AD-associated pathways and its relationship with clinical status and biomarkers of amyloid, tau, and neurodegeneration (A/T/N). Methods: We analyzed data from 1,411 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We applied pathway analysis and clustering to identify AD-associated "pathway clusters" and construct pathway-specific PRSs (excluding the APOE region). We tested associations with diagnostic status, abnormal levels of amyloid and ptau, and hippocampal volume. Results: Thirteen pathway clusters were identified, and eight pathway-specific PRSs were significantly associated with AD diagnosis. Amyloid-positivity was associated with endocytosis and fibril formation, response misfolded protein, and regulation protein tyrosine PRSs. Ptau positivity and hippocampal volume were both related to protein localization and mitophagy PRS, and ptau-positivity was also associated with an immune signaling PRS. A global AD PRS showed stronger associations with diagnosis and all biomarkers compared to pathway PRSs. Conclusions: Pathway PRS may contribute to understanding separable disease processes, but do not add significant power for predictive purposes. These findings demonstrate that AD-phenotypes may be preferentially associated with risk in specific pathways, and defining genetic risk along multiple dimensions may clarify etiological heterogeneity in AD. This approach to delineate pathway-specific PRS can be used to study other complex diseases. [ABSTRACT FROM AUTHOR]