Amyloid Plaques Research Articles

A guide to selecting high-performing antibodies for human Midkine for use in Western blot and immunoprecipitation

Midkine is a secreted protein that acts as a growth factor or cytokine involved in cell survival and inflammatory processes. It accumulates in amyloid plaques, which are hallmarks of Alzheimer’s Disease (AD). The reproducibility of Midkine research would be enhanced if the community had access to well-characterized anti-Midkine antibodies. In this study, we characterized 8 commercial Midkine antibodies for Western blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in a knockout cell line and isogenic parental control. These studies are part of a larger, collaborative initiative seeking to address the antibody reproducibility issue by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Pharmacological Potential of Bioactive Peptides for the Treatment of Diseases Associated with Alzheimer's and Brain Disorders.

Bioactive peptides are a promising class of therapeutics for the treatment of diseases associated with Alzheimer's and brain disorders. These peptides are derived from naturally occurring proteins and have been shown to possess a variety of beneficial properties. They may modulate neurotransmitter systems, reduce inflammation, and improve cognitive performance. In addition, bioactive peptides have the potential to target specific molecular pathways involved in the pathogenesis of Alzheimer's and brain disorders. For example, peptides have been shown to interact with amyloid-beta, a major component of amyloid plaques found in Alzheimer's disease, and have been shown to reduce its accumulation in the brain. Furthermore, peptides have been found to modulate the activity of glutamate receptors, which are important for memory and learning, as well as to inhibit the activity of enzymes involved in the formation of toxic amyloid-beta aggregates. Finally, bioactive peptides have the potential to reduce oxidative stress and inflammation, two major components of many neurological disorders. These peptides could be used alone or in combination with traditional pharmacological treatments to improve the management of diseases associated with Alzheimer's and brain disorders.

Navigating Prevention: A Systematic Review of Strategies for Alzheimer's Disease in High-Risk and Affected Individuals.

Alzheimer's disease (AD) remains a widespread cause of dementia globally, and its prevalence is increasing due to the aging population. Two key pathologies typically identify this neurodegenerative disease process: the accumulation of amyloid plaques and the formation of neurofibrillary tangles containing hyperphosphorylated tau. Diagnosis relies on the patient's clinical presentation meeting specific criteria, along with the use of fluid and imaging biomarkers. The current treatment focuses on addressing symptoms, with ongoing trials aiming to decrease the production and overall impact of brain pathology. Here, we explore various methods to minimize the risks of AD in patients and individuals at high risk of developing it. To address this, we carefully selected 10 articles that discuss various prevention methods used today to promote brain health, including diets that are believed to have neuroprotective properties. The study findings emphasize the importance of further strengthening the evidence and conducting larger randomized controlled trials to gain a better understanding of the potential benefits for individuals at high risk of developing AD, as well as those already diagnosed with it.

Exploring Angiogenesis and Artificial Intelligence in Alzheimer’s Disease: Implications for Early Detection and Therapeutic Strategies

Background: Alzheimer’s disease (AD) presents a significant global health challenge, affecting millions and imposing substantial socioeconomic burdens, with healthcare costs exceeding US$100 billion annually. The disease's complexity is underscored by its slow progression and the pivotal role of amyloid plaques in its pathology. Despite advancements in understanding AD, critical questions regarding the mechanisms of amyloid plaque development and their relationship with neuroinflammation and angiogenesis remain. Methods: This study employed advanced imaging techniques and artificial intelligence (AI) to investigate the interplay between amyloid beta (Aβ) accumulation, neuroinflammation, and angiogenesis in AD. Magnetic resonance imaging (MRI) facilitated detailed assessments of brain structure alterations, while machine learning models enhanced diagnostic accuracy by analyzing imaging data and identifying patterns linked to disease progression. Results: The findings revealed a significant association between Aβ deposition and increased angiogenesis, contributing to neurovascular dysfunction and exacerbating neuroinflammation. AI-driven analyses demonstrated improved diagnostic capabilities, detecting early changes in brain structure associated with mild cognitive impairment (MCI) and AD. Specifically, convolutional neural networks (CNNs) such as AlzheimerNet achieved remarkable accuracy in distinguishing AD from other neurodegenerative conditions. Conclusion: This research underscores the multifaceted nature of AD, highlighting the critical roles of amyloid plaques, neuroinflammation, and angiogenesis. The integration of AI and advanced imaging modalities offers promising avenues for early diagnosis and intervention, potentially transforming patient management strategies. Continued exploration of these pathways may yield effective therapeutic targets to mitigate the progression of AD and enhance patient outcomes.

A randomized controlled trial on the effects of traditional Thai mind-body exercise (Ruesi Dadton) on biomarkers in mild cognitive impairment.

Exercise has been shown to reduce the rate of mild cognitive impairment (MCI) and Alzheimer's disease. Although motor coordination movements and poses in Ruesi Dadton (RD) exercises may improve cognitive function, RD is rarely used for MCI. To date, there is insufficient evidence on whether 12 weeks of RD exercise correlates with blood biomarkers related to neurogenesis and plasticity. To determine the effects on blood biomarkers of 12-week RD in MCI. Two-group parallel randomized controlled trial. Community exercise. Individual with MCI. Fifty-eight participants (n.=29 in each group). The RD group performed 60min of RD exercises (15 poses) three times weekly for 12 weeks. The control group received no intervention. In addition, both groups were given information regarding MCI symptoms by the physician on the first day. Peripheral blood was collected to measure serum brain-derived neurotrophic factor (BDNF) and sirtuin 1 (SIRT1) levels before and after intervention. The effects of 12-week RD pre- and post-intervention were examined using 2×2 repeated multivariate analyses, which showed significant differences in interaction by group and time. Student's t-tests and paired t-tests were employed in subsequent analyses to evaluate between-group and within-group differences for both biomarkers. In each test, we discovered increased levels of BDNF and SIRT1 in the RD group but not in the control group. These findings suggested that RD could benefit MCI patients through enhanced BDNF and SIRT1 levels. Twelve weeks of RD might be helpful to patients with MCI and older people who experience cognitive impairment by improving blood biomarkers responsible for brain plasticity and amyloid plaque degradation.

Sequence of Molecular Events in the Development of Alzheimer's Disease: Cascade Interactions from Beta-Amyloid to Other Involved Proteins.

Alzheimer's disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women?

Advances in medications and treatments for reducing memory loss in Alzheimer's disease

Alzheimer's disease (ad) is a disease in which brain cells deteriorate, leading to dementia and cognitive decline. It is mainly caused by cholinergic functional problems and the accumulation of amyloid plaques in the brain. Age, genetics, head damage, vascular disease, infection and environmental factors can also cause the disease. Currently, only two drugs have been approved for the treatment of Alzheimers disease, but they only target symptoms and cannot cure or prevent the disease. Ongoing research aims to better understand Alzheimers disease and develop treatments that can slow or change its progress in response to mechanisms such as beta-amyloid plaques, inflammation and cholinergic dysfunction with abnormal tau metabolism. The focus of this review is on current drug therapy and the causes of Alzheimers disease, including those that change the disease, as a partner, or use natural compounds.

Unveiling the Therapeutic Potential of Kelulut (Stingless Bee) Honey in Alzheimer's Disease: Findings from a Rat Model Study.

Alzheimer's disease (AD) poses a major worldwide health challenge because of its profound impact on cognitive abilities and overall well-being. Despite extensive research and numerous clinical trials, therapeutic options remain limited. Our study aimed to investigate the potential of Kelulut honey (KH) as a novel therapeutic agent for addressing the multifactorial pathology of AD. We tried to evaluate the disease-attenuating and neuroprotective potential of KH in the intrahippocampally induced AD rat model by utilizing histochemistry and enzyme-linked immunosorbent assay (ELISA) studies. A total of 26 male Sprague Dawley rats weighing ~280-380 g were randomly divided into three groups: Control, AD-induced (Aβ), and AD-induced and treated with KH (Aβ+KH). The latter two groups underwent stereotaxic surgery, where 6.25 µg of amyloid β1-42 peptides were injected intrahippocampally. One-week post-surgery, KH was administered to the treatment group at a dose of 1 g/kg body weight for a period of four weeks, after which the rats went through behavior tests. After completion of behavior analysis, the rats were sacrificed, and the brains were processed for histochemistry and ELISA studies. The open field test analysis demonstrated that KH improved the locomotion of Aβ+KH compared to Aβ (p = 0.0013). In comparison, the Morris water maze did not show any nootropic effects on cognition with a paradoxical increase in time spent in the target quadrant by the Aβ group (p = 0.029). Histochemical staining showed markedly increased Congo-red-stained amyloid plaques, which were significantly reduced in dentate gyrus of Aβ+KH compared to Aβ (p < 0.05). Moreover, significantly higher apoptosis was seen in the Aβ group compared to Aβ+KH (p < 0.01) and control groups (p < 0.001). Furthermore, the ELISA studies deduced more phosphorylated tau in the diseased group compared to Aβ+KH (p = 0.038) and controls (p = 0.016). These findings suggest that KH consumption for twenty-eight days has the potential to attenuate the pathological burden of disease while exerting neuroprotective effects in rodent models of AD.

Aggregation Dynamics of a 150 kDa Aβ42 Oligomer: Insights from Cryo Electron Microscopy and Multimodal Analysis.

I.Protein misfolding is a widespread phenomenon that can result in the formation of protein aggregates, which are markers of various disease states, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) peptides, particularly Aβ40 and Aβ42, are key players in the disease's progression, as they aggregate to form amyloid plaques and contribute to neuronal toxicity. Recent research has shifted attention from solely Aβ fibrils to also include Aβ protofibrils and oligomers as potentially critical pathogenic agents. Particularly, oligomers demonstrate greater toxicity compared to other Aβ specie. Hence, there is an increased interest in studying the correlation between toxicity and their structure and aggregation pathway. The present study investigates the aggregation of a 150 kDa Aβ42 oligomer that does not lead to fibril formation over time. Using negative stain transmission electron microscopy (TEM), size exclusion chromatography (SEC), dynamic light scattering (DLS), and cryo-electron microscopy (cryo-EM), we demonstrate that 150 kDa Aβ42 oligomers form higher-order string-like assemblies over time. The strings are unique from the classical Aβ fibril structures. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aβ42 aggregate.

Alzheimer's Disease and Vascular Dementia, Connecting and Differentiating Features.

Alzheimer's disease (AD) and vascular dementia (VD) are the leading causes of dementia, presenting a significant challenge in differential diagnosis. While their clinical presentations can overlap, their underlying pathologies are distinct. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles, leading to progressive neurodegeneration. VD, on the other hand, arises from cerebrovascular insults that disrupt blood flow to the brain, causing neuronal injury and cognitive decline. Despite distinct etiologies, AD and VD share common risk factors such as hypertension, diabetes, and hyperlipidemia. Recent research suggests a potential role for oral microbiota in both diseases, warranting further investigation. The diagnostic dilemma lies in the significant overlap of symptoms including memory loss, executive dysfunction, and personality changes. The absence of definitive biomarkers and limitations of current neuroimaging techniques necessitate a multi-modal approach integrating clinical history, cognitive assessment, and neuroimaging findings. Promising avenues for improved diagnosis include the exploration of novel biomarkers like inflammatory markers, MMPs, and circulating microRNAs. Additionally, advanced neuroimaging techniques hold promise in differentiating AD and VD by revealing characteristic cerebrovascular disease patterns and brain atrophy specific to each condition. By elucidating the complexities underlying AD and VD, we can refine diagnostic accuracy and optimize treatment strategies for this ever-growing patient population. Future research efforts should focus on identifying disease-specific biomarkers and developing more effective neuroimaging methods to achieve a definitive diagnosis and guide the development of targeted therapies.

Development of a 213Bi-Labeled Pyridyl Benzofuran for Targeted α-Therapy of Amyloid-β Aggregates.

Alzheimer disease is a neurodegenerative disorder with limited treatment options. It is characterized by the presence of several biomarkers, including amyloid-β aggregates, which lead to oxidative stress and neuronal decay. Targeted α-therapy (TAT) has been shown to be efficacious against metastatic cancer. TAT takes advantage of tumor-localized α-particle emission to break disease-associated covalent bonds while minimizing radiation dose to healthy tissues due to the short, micrometer-level, distances traveled. We hypothesized that TAT could be used to break covalent bonds within amyloid-β aggregates and facilitate natural plaque clearance mechanisms. Methods: We synthesized a 213Bi-chelate-linked benzofuran pyridyl derivative (BiBPy) and generated [213Bi]BiBPy, with a specific activity of 120.6 GBq/μg, dissociation constant of 11 ± 1.5 nM, and logP of 0.14 ± 0.03. Results: As the first step toward the validation of [213Bi]BiBPy as a TAT agent for the reduction of Alzheimer disease-associated amyloid-β, we showed that brain homogenates from APP/PS1 double-transgenic male mice (6-9 mo old) incubated with [213Bi]BiBPy exhibited a marked reduction in amyloid-β plaque concentration as measured using both enzyme-linked immunosorbent and Western blotting assays, with a half-maximal effective concentration of 3.72 kBq/pg. Conclusion: This [213Bi]BiBPy-concentration-dependent activity shows that TAT can reduce amyloid plaque concentration invitro and supports the development of targeting systems for invivo validations.

Co-administration of Ceratonia siliqua extract nanoparticles promotes the oral bioavailability and neurotherapeutic efficacy of donepezil in a dementia model.

This study aimed to assess the herb-drug interactions between crude/silver nanoparticle (SNP)-loaded carob extract (Car, NCar, respectively) and donepezil-HCl (DPZ) and their impact on neurotherapeutic outcomes in a dementia model. Carob pods were subjected to ethanol extraction, and their phytoconstituents were chromatographically analysed. SNP-loaded extract was synthesized and characterized, and dementia-like symptoms were induced in Wistar rats by repeated dosing with 175mg/kg AlCl3 for 60 days, after which the animals were treated with Car, NCar, DPZ, and combinations of Car/NCar-DPZ for 30 days. The effect of carob formulations on DPZ bioavailability was in-silico profiled and the herb-drug interactions were mathematically assessed as combination indices. Different formulations significantly improved cognitive/spatial memory functions, restored dysregulated brain redox and cholinergic functions, and markedly inhibited cholinesterase, as reflected by the reduction/absence of amyloid plaques and neurofibrillary tangles. In silico profiling of the major phytoconstituents revealed their non-P-glycoprotein substrate nature and CYP3A4, 2C19, and 2C9 inhibition, which might have improved the oral bioavailability of DPZ. The combination index calculations revealed strong synergy between DPZ and both carob formulations, with the strongest effect exhibited by the DPZ/NCar combination. The co-administration of carob extract/SNPs represents a promising approach for enhancing the neurotherapeutic efficacy of DPZ.

A guide to selecting high-performing antibodies for human Midkine for use in Western blot and immunoprecipitation.

Midkine is a secreted protein that acts as a growth factor or cytokine involved in cell survival and inflammatory processes. It accumulates in amyloid plaques, which are hallmarks of Alzheimer's Disease (AD). The reproducibility of Midkine research would be enhanced if the community had access to well-characterized anti-Midkine antibodies. In this study, we characterized 8 commercial Midkine antibodies for Western blot and immunoprecipitation, using a standardized experimental protocol based on comparing read-outs in a knockout cell line and isogenic parental control. These studies are part of a larger, collaborative initiative seeking to address the antibody reproducibility issue by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

Ubiquitin-Proteasome System in the Different Stages of Dominantly Inherited Alzheimer's Disease.

This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.

Neuronostatin regulates neuronal function and energetic metabolism in Alzheimer's disease in a GPR107-dependent manner

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, which is characterized by the accumulation and aggregation of amyloid in brain. Neuronostatin (NST) is an endogenous peptide hormone that participates in many fundamental neuronal processes. However, the metabolism and function of NST in neurons of AD mice are not known. In this study, by combining the structural analyses, primary cultures, knockout cells, and various assessments, the behavior, histopathology, brain-wide expression and cellular signaling pathways in the APP/PS1 mice were investigated. It was found that NST directly bound to GPR107, which was primarily expressed in neurons. NST modulated the neuronal survivability and neurite outgrowth induced by Aβ via GPR107 in neurons. Intracerebroventricular (i.c.v.) administration of NST attenuated learning and memory abilities, reduced the synaptic protein levels of hippocampus, but improved amyloid plaques in the cortex and hippocampus of APP/PS1 mice. NST modulated glucose metabolism of hypothalamus-hippocampus-cortex axis in APP/PS1 mice and decreased ATP levels via the regulation of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in response to Aβ, suppressed energetic metabolism, and mitochondrial function in neurons via GPR107/protein kinase A (PKA) signaling pathway. In summary, our findings suggest that NST regulates neuronal function and brain energetic metabolism in AD mice via the GPR107/PKA signaling pathway, which can be a promising target for the treatment of AD.

Alpha-lipoic acid alleviates cognitive deficits in transgenic APP23/PS45 mice through a mitophagy-mediated increase in ADAM10 α-secretase cleavage of APP

BackgroundAlpha-lipoic acid (ALA) has a neuroprotective effect on neurodegenerative diseases. In the clinic, ALA can improve cognitive impairments in patients with Alzheimer’s disease (AD) and other dementias. Animal studies have confirmed the anti-amyloidosis effect of ALA, but its underlying mechanism remains unclear. In particular, the role of ALA in amyloid-β precursor protein (APP) metabolism has not been fully elucidated.ObjectiveTo investigate whether ALA can reduce the amyloidogenic effect of APP in a transgenic mouse model of AD, and to study the mechanism underlying this effect.MethodsALA was infused into 2-month-old APP23/PS45 transgenic mice for 4 consecutive months and their cognitive function and AD-like pathology were then evaluated. An ALA drug concentration gradient was applied to 20E2 cells in vitro to evaluate its effect on the expression of APP proteolytic enzymes and metabolites. The mechanism by which ALA affects APP processing was studied using GI254023X, an inhibitor of A Disintegrin and Metalloproteinase 10 (ADAM10), as well as the mitochondrial toxic drug carbonyl cyanide m-chlorophenylhydrazone (CCCP).ResultsAdministration of ALA ameliorated amyloid plaque neuropathology in the brain tissue of APP23/PS45 mice and reduced learning and memory impairment. ALA also increased the expression of ADAM10 in 20E2 cells and the non-amyloidogenic processing of APP to produce the 83 amino acid C-terminal fragment (C83). In addition to activating autophagy, ALA also significantly promoted mitophagy. BNIP3L-knockdown reduced the mat/pro ratio of ADAM10. By using CCCP, ALA was found to regulate BNIP3L-mediated mitophagy, thereby promoting the α-cleavage of APP.ConclusionsThe enhanced α-secretase cleavage of APP by ADAM10 is the primary mechanism through which ALA ameliorates the cognitive deficits in APP23/PS45 transgenic mice. BNIP3L-mediated mitophagy contributes to the anti-amyloid properties of ALA by facilitating the maturation of ADAM10. This study provides novel experimental evidence for the treatment of AD with ALA.Graphical abstract

Amyloid-β peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer’s disease with APPdup and Down syndrome

Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

The Downregulation of ITGAX Exacerbates Amyloid-β Plaque Deposition in Alzheimer's Disease by Increasing Polarization of M1 Microglia.

Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide.

Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into amyloid plaques plays an important role in the pathophysiology of T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contribute to the development of T2D is unclear, but it is proposed to involve disruption of cellular membranes. However, nearly all research on hIAPP-lipid interactions has focused on anionic phospholipids, which are primarily present in the cytosolic face of plasma membranes. We seek here to characterize the effects of three gangliosides, the dominant anionic lipids in the outer leaflet of the plasma membrane, on the aggregation, structure, and toxicity of hIAPP. Our results show a dual behavior that depends on the molar ratio between the gangliosides and hIAPP. For each ganglioside, a low-lipid:peptide ratio enhances hIAPP aggregation and alters the morphology of hIAPP fibrils, while a high ratio eliminates aggregation and stabilizes an α-helix-rich hIAPP conformation. A more negative lipid charge more efficiently promotes aggregation, and a larger lipid headgroup improves inhibition of aggregation. hIAPP also alters the phase transitions of the lipids, favoring spherical micelles over larger tubular micelles. We discuss our results in the context of the available lipid surface area for hIAPP binding and speculate on a role for gangliosides in facilitating toxic hIAPP aggregation.

Comparison of the Amyloid Plaque Proteome in Down Syndrome, Early-Onset Alzheimer's Disease and Late-Onset Alzheimer's Disease.

Down syndrome (DS) is strongly associated with Alzheimer's disease (AD), attributable to APP overexpression. DS exhibits Amyloid-β (Aβ) and Tau pathology similar to early-onset AD (EOAD) and late-onset AD (LOAD). The study aimed to evaluate the Aβ plaque proteome of DS, EOAD and LOAD. Using unbiased localized proteomics, we analyzed amyloid plaques and adjacent plaque-devoid tissue ('non-plaque') from post-mortem paraffin-embedded tissues in four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o) and controls (66.4 ± 13.04). We assessed functional associations using Gene Ontology (GO) enrichment and protein interaction networks. We identified differentially abundant Aβ plaque proteins vs. non-plaques (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192) and in LOAD (n = 128); there were 43 plaque-associated proteins shared between all groups. Positive correlations (p < 0.0001) were observed between plaque-associated proteins in DS and EOAD (R2 = 0.77), DS and LOAD (R2 = 0.73), and EOAD vs. LOAD (R2 = 0.67). Top Biological process (BP) GO terms (p < 0.0001) included lysosomal transport for DS, immune system regulation for EOAD, and lysosome organization for LOAD. Protein networks revealed a plaque enriched signature across all cohorts involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, including 65 altered non-plaque proteins across all cohorts. Differentially abundant non-plaque proteins in DS showed a significant (p < 0.0001) but weaker positive correlation with EOAD (R2 = 0.59) and LOAD (R2 = 0.33) compared to the stronger correlation between EOAD and LOAD (R2 = 0.79). The top BP GO term for all groups was chromatin remodeling (DS p = 0.0013, EOAD p = 5.79×10- 9, and LOAD p = 1.69×10- 10). Additional GO terms for DS included extracellular matrix (p = 0.0068), while EOAD and LOAD were associated with protein-DNA complexes and gene expression regulation (p < 0.0001). We found strong similarities among the Aβ plaque proteomes in individuals with DS, EOAD and LOAD, and a robust association between the plaque proteomes and lysosomal and immune-related pathways. Further, non-plaque proteomes highlighted altered pathways related to chromatin structure and extracellular matrix (ECM), the latter particularly associated with DS. We identified novel Aβ plaque proteins, which may serve as biomarkers or therapeutic targets.