Pathophysiology Of AD Research Articles

Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity

Preclinical models of Alzheimer’s disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.

Atopic dermatitis in the elderly

Atopic dermatitis (AD, also known as atopic eczema) is a chronic and relapsing skin disease, affecting over 230 million people worldwide. It commonly is seen in patients who have other allergic conditions including asthma and allergic rhinitis (hay fever) and is recognised by an itchy rash and dry irritated skin. The majority of patients first develop AD at a young age, however it can occur later in life as well. With a growing elderly population and expectations for a good quality of life, the impact of AD in the elderly deserves some attention. Many elderly patients present with itching and dry skin to dermatology, allergy, and primary care clinics, and there is a lack of information available to clinicians regarding the proper diagnosis and management of these patients. Indeed, most investigations and clinical care guidelines about AD do not include patients aged 60 years and older as a separate group from younger adults. This review article, from the United States, aimed to present an overview of changes in the body that naturally occur with aging, that may cause elderly patients to be susceptible to developing AD. Interestingly, many age‐related changes overlap with key characteristics of AD, such as reduced skin barrier function, impaired inflammation, and increased bacterial (especially Staphylococcal) infections. This work aims to provide a better understanding of the aging‐related pathophysiology (workings within the body) of AD and identify gaps in knowledge, thus opening new areas of research for future investigation. This summary relates to the study: Atopic dermatitis in the elderly: a review of clinical and pathophysiological hallmarks

Validation of a priori candidate Alzheimer\u2019s disease SNPs with brain amyloid-beta deposition

The accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.

International research initiatives in Alzheimer’s disease

With continuing population increases and increasing life expectancy, ~100 million individuals worldwide will be affected with Alzheimer disease in 2050. Dementia was the fifth largest cause of death globally in 2016 and its annual global costs are US $315 billion. The absence of truly effective AD therapies ensures that these costs will steadily increase for the foreseeable future. Targeting lifestyle factors such as physical activity, dietary guidance, and attention to metabolic and vascular health may prevent cognitive decline in older adults. There also has been the advent of “secondary prevention” trials of experimental anti-Alzheimer drugs in cognitively normal individuals with elevated risk for developing symptomatic AD because they carry a pathogenic mutation that causes AD or have positive molecular AD biomarker studies (i.e., amyloid PET; CSF assays of Aβ42 and tau). The goal of secondary prevention trials is to delay or even avert the occurrence of symptomatic AD. Although studies of autosomal dominant AD (ADAD) have greatly advanced understanding of AD pathophysiology, it is as yet uncertain whether ADAD is a clone of the far more common “sporadic” late onset AD (LOAD). Two international multi-center studies of molecular biomarkers to characterize preclinical and early symptomatic AD, DIAN (ADAD) and ADNI (LOAD), were examined as to whether biomarker profiles in these disorders were similar or different. Both groups had largely identical AD biomarker profiles, suggesting that they share a common pathophysiology. There thus is cautious optimism that secondary prevention trial results in ADAD will extrapolate to LOAD.

Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

AbstractAlzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer's Disease.

After years of failed therapeutic attempts targeting beta-amyloid (Aβ) in AD, there is now increasing evidence suggesting that inflammation holds a pivotal role in AD pathogenesis and immune pathways can possibly comprise primary therapeutic targets. Inflammation is a key characteristic of numerous diseases including neurodegenerative disorders and thus not surprisingly suppression of inflammation frequently constitutes a major therapeutic strategy for a wide spectrum of disorders. Several brain-resident and peripherally-derived immune populations and inflammatory mediators are involved in AD pathophysiology, with microglia comprising central cellular player in the disease process. Systemic inflammation, mostly in the form of infections, has long been observed to induce behavioral alterations and cognitive dysfunction, suggesting for a close interaction of the peripheral immune system with the brain. Systemic inflammation can result in neuroinflammation, mainly exhibited as microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells in the brain, thus shaping a cerebral inflammatory milieu that may seriously impact neuronal function. Increasing clinical and experimental studies have provided significant evidence that acute (e.g. infections) or chronic (e.g. autoimmune diseases like rheumatoid arthritis) systemic inflammatory conditions may be associated with increased AD risk and accelerate AD progression. Here we review the current literature that links systemic with CNS inflammation and the implications of this interaction for AD in the context of acute and chronic systemic pathologies as acute infection and rheumatoid arthritis. Elucidating the mechanisms that govern the crosstalk between the peripheral and the local brain immune system may provide the ground for new therapeutic approaches that target the immune-brain interface and shed light on the understanding of AD.

Fluorescence Detection and Dissociation of Amyloid‐β Species for the Treatment of Alzheimer's Disease

AbstractAlzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disease. It is well established that the β‐amyloid peptide (Aβ) species existing in several forms, such as soluble monomers, oligomers, and insoluble aggregates, play an essential role in the pathophysiology of AD. Therefore, much effort has been made to specifically detect Aβ species and to inhibit Aβ aggregation for the treatment of AD. In this review, an overview of recent advances in detecting different Aβ forms mainly containing Aβ aggregates, Aβ oligomers, and Aβ protofibrils is provided. In addition, photodynamic therapy (PDT) and photothermal therapy (PTT) are considered to be promising modalities for the treatment of AD because of the minimal invasiveness and high spatial selectivity. Herein, the strategies of inhibiting Aβ aggregation and dissociating Aβ aggregates using PDT, PTT, and Aβ inhibitors for the treatment of AD are summarized.

Dementia 2. Alzheimer's disease: diagnosis, treatment and managment

In the UK, an estimated 954 000 people have dementia. Alzheimer's-type dementia (AD) is the most common type of dementia and affects around 591 480 people ( Prince et al, 2014 ). This article, the second in a series, explains about the pathophysiology and clinical features of AD, how it is diagnosed and the medication used to treat it.

Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer's Disease.

Early-onset Alzheimer's disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.

Identification of exon skipping events associated with Alzheimer\u2019s disease in the human hippocampus

BackgroundAt least 90% of human genes are alternatively spliced. Alternative splicing has an important function regulating gene expression and miss-splicing can contribute to risk for human diseases, including Alzheimer’s disease (AD).MethodsWe developed a splicing decision model as a molecular mechanism to identify functional exon skipping events and genetic variation affecting alternative splicing on a genome-wide scale by integrating genomics, transcriptomics, and neuroimaging data in a systems biology approach. In this study, we analyzed RNA-Seq data of hippocampus brain tissue from Alzheimer’s disease (AD; n = 24) and cognitively normal elderly controls (CN; n = 50) and identified three exon skipping events in two genes (RELN and NOS1) as significantly associated with AD (corrected p-value < 0.05 and fold change > 1.5). Next, we identified single-nucleotide polymorphisms (SNPs) affecting exon skipping events using the splicing decision model and then performed an association analysis of SNPs potentially affecting three exon skipping events with a global cortical measure of amyloid-β deposition measured by [18F] Florbetapir position emission tomography (PET) scan as an AD-related quantitative phenotype. A whole-brain voxel-based analysis was also performed.ResultsTwo exons in RELN and one exon in NOS1 showed significantly lower expression levels in the AD participants compared to CN participants, suggesting that the exons tend to be skipped more in AD. We also showed the loss of the core protein structure due to the skipped exons using the protein 3D structure analysis. The targeted SNP-based association analysis identified one intronic SNP (rs362771) adjacent to the skipped exon 24 in RELN as significantly associated with cortical amyloid-β levels (corrected p-value < 0.05). This SNP is within the splicing regulatory element, i.e., intronic splicing enhancer. The minor allele of rs362771 conferred decreases in cortical amyloid-β levels in the right temporal and bilateral parietal lobes.ConclusionsOur results suggest that exon skipping events and splicing-affecting SNPs in the human hippocampus may contribute to AD pathogenesis. Integration of multiple omics and neuroimaging data provides insights into possible mechanisms underlying AD pathophysiology through exon skipping and may help identify novel therapeutic targets.

The relevance of cerebrospinal fluid \u03b1-synuclein levels to sporadic and familial Alzheimer\u2019s disease

Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer’s disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer’s Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline αSyn levels (p = 0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p = 0.02). In the same patients, there was a dose-dependent positive association between CSF αSyn and the APOEε4 allele. Further, CSF αSyn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p = 0.03), and positively correlated to the estimated years from symptom onset (p = 0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating < 0.5) PET amyloid-positive ADAD mutation carriers CSF αSyn was positively correlated to 11C-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOEε4-positive ADAD mutation carriers exhibited an association between CSF αSyn levels and mean cortical PiB retention (p = 0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of αSyn, tau and amyloid-β1–40.Our results suggest that higher CSF αSyn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOEε4 may promote the processes driven by αSyn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.

Anthocyanins Extracted from Aronia melanocarpa Protect SH-SY5Y Cells against Amyloid-beta (1-42)-Induced Apoptosis by Regulating Ca2+ Homeostasis and Inhibiting Mitochondrial Dysfunction.

We investigated the cytoprotective effects of anthocyanins in Aronia melanocarpa against apoptosis induced by Aβ1-42, a key mediator of AD pathophysiology. We measured intracellular calcium with a colorimetric kit, cellular apoptosis with DAPI, intracellular ROS with the fluorescent marker 2,3-dimethoxy-1,4-naphthoquinone, mitochondrial membrane potential with JC-1, and ATP with a colorimetric kit. Gene transcription and protein expression levels of calmodulin, cytochrome c, caspase-9, cleaved caspase-3, Bcl-2, and Bax were analyzed by RT-PCR and Western blotting. The results showed that pretreatment with anthocyanins significantly inhibited Aβ1-42-induced apoptosis, decreased intracellular calcium and ROS, and increased ATP and mitochondrial membrane potential. RT-PCR and Western blotting revealed that anthocyanins upregulated the gene transcription and protein expression of calmodulin and Bcl-2 and downregulated those of cytochrome c, caspase-9, cleaved caspase-3, and Bax. A. melanocarpa anthocyanins protected SH-SY5Y cells against Aβ1-42-induced apoptosis by regulating Ca2+ homeostasis and apoptosis-related genes and inhibiting mitochondrial dysfunction.

Alzheimer-associated cerebrospinal fluid fragments of neurogranin are generated by Calpain-1 and prolyl endopeptidase

BackgroundNeurogranin (Ng) is a small 7.6 kDa postsynaptic protein that has been detected at elevated concentrations in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), both as a full-length molecule and as fragments from its C-terminal half. Ng is involved in postsynaptic calcium (Ca) signal transduction and memory formation via binding to calmodulin in a Ca-dependent manner. The mechanism of Ng secretion from neurons to CSF is currently unknown, but enzymatic cleavage of Ng may be of relevance. Therefore, the aim of the study was to identify the enzymes responsible for the cleavage of Ng, yielding the Ng fragment pattern of C-terminal fragments detectable and increased in CSF of AD patients.MethodsFluorigenic quenched FRET probes containing sequences of Ng were utilized to identify Ng cleaving activities among enzymes known to have increased activity in AD and in chromatographically fractionated mouse brain extracts.ResultsHuman Calpain-1 and prolyl endopeptidase were identified as the candidate enzymes involved in the formation of endogenous Ng peptides present in CSF, cleaving mainly in the central region of Ng, and between amino acids 75_76 in the Ng sequence, respectively. The cleavage by Calpain-1 affects the IQ domain of Ng, which may deactivate or change the function of Ng in Ca2+/calmodulin -dependent signaling for synaptic plasticity. While shorter Ng fragments were readily cleaved in vitro by prolyl endopeptidase, the efficiency of cleavage on larger Ng fragments was much lower.ConclusionsCalpain-1 and prolyl endopeptidase cleave Ng in the IQ domain and near the C-terminus, respectively, yielding specific fragments of Ng in CSF. These fragments may give clues to the roles of increased activities of these enzymes in the pathophysiology of AD, and provide possible targets for pharmacologic intervention.

The Relationship of Current Cognitive Activity to Brain Amyloid Burden and Glucose Metabolism

Several studies have investigated how lifetime cognitive engagement affects levels of amyloid-beta (Aβ) deposition in the brain. However, there has been some disagreement, leaving the relationship of cognitive activity (CA) to Aβ a largely open question. The present study investigated the relationship between CA, Aβ deposition, and glucose metabolism. One hundred nine cognitively normal participants underwent Pittsburgh Compound-B (PiB) and [18F]fluorodeoxyglucose-positron emission tomography and completed a questionnaire designed to measure current CA. Statistical analyses revealed significant differences in PiB retention between those in the high and low CA groups. Linear regression models revealed a significant negative relationship between PiB retention and CA and a significant positive relationship between glucose metabolism and CA. These data suggest that CA may have a direct beneficial effect on the pathophysiology of AD or reflect another underlying process that results in both higher CA and lower AD pathophysiology.

Integrated biology approach reveals molecular and pathological interactions among Alzheimer\u2019s A\u03b242, Tau, TREM2, and TYROBP in Drosophila models

BackgroundCerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP.MethodsIn this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts.ResultsGlial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD.ConclusionsThe comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.

Modeling Spatial and Temporal Patterns of APOE ε4 Mediated Glucose Uptake in Mild Cognitive Impairment and Normal Controls

Abstract Apolipoprotein E (APOE) e4 allele is a risk factor for developing Alzheimer’s disease. In this study, we analyzed longitudinal changes in fluorodeoxyglucose (FDG) uptake between APOE e4 carriers and non-carriers in normal control (NC) and Mild Cognitive Impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We reported forebrain and limbic regions that exhibit APOE e4-mediated declines in FDG uptake over a 96 month period in subjects with MCI but not NCs. Using voxel-based and ROI-based analysis, we compared the longitudinal changes in glucose uptake between APOE e4 carriers and non-carriers from 34 NCs with no cognitive impairment and 48 subjects with MCI. Parietal, temporal and frontal regions had greater longitudinal decreases in FDG uptake in APOE e4 carriers compared to non-carriers. The Superior parietal lobe, inferior temporal gyrus, thalamus, caudate, parahippocampal gyrus, fusiform gyrus and middle temporal gyrus showed greater longitudinal decreases in FDG uptake in APOE e4 carriers compared to non-carriers in subjects with MCI but not NC. These findings suggest APOE e4 genotype is associated with decline in glucose uptake over time and that specific limbic and forebrain structures exhibit APOE e4-mediated FDG decline in MCI but not NCs. Our work in identifying the brain regions most associated with APOE e4 related AD pathophysiology will improve quantitative FDG imaging as a biomarker in precision medicine.

Donepezil suppresses intracellular Ca2+ mobilization through the PI3K pathway in rodent microglia

BackgroundMicroglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer’s disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca2+ signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca2+ signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca2+ mobilization in microglial cells.MethodsWe examined whether pretreatment with donepezil affects the intracellular Ca2+ mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells.ResultsIn this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca2+ elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca2+ elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca2+ elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway.ConclusionsThese suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.

Long-Term Culture of Organotypic Hippocampal Slice from Old 3xTg-AD Mouse: An ex vivo Model of Alzheimer's Disease.

Objective Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer’s disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. Methods OHSC was performed with old 3xTg-AD mice (12–14 months), old wild type mice (12–14 months) and young 3xTg-AD mice (2–4 months) using serum-free medium for 4 weeks. Hippocampal structure was evaluated by 4’, 6-diamidino-2-phenylindole (DAPI) intensity and neuronal metabolism was measured by Alamarblue assay. Pathologic characteristics of AD were also investigated; β-amyloid levels by ELISA, amyloid plaque deposition by Thioflavin-S staining, and glial activation by immunohistochemistry. Results Following 4-week culture in serum-free media, hippocampal cells and layers were well preserved in cultured slices from old AD mice as was in those from young AD and old wild type mice. On the contrary, excessive regression of total visible cells was observed in conventional serum-containing medium regardless of genotype of mice. In parallel with this well preserved structure, major pathologic characteristics of AD were also well manifested in hippocampal slices from old AD mice. Conclusion Our findings suggest that long-term OHSC from old 3xTg-AD mouse can serve as a promising ex vivo system for studies on pathophysiology of AD, especially with the minimum number of sacrifice of experimental animals.

Current understanding of AD pathophysiology

Current understanding of AD pathophysiology

Brain ureido degenerative protein modifications are associated with neuroinflammation and proteinopathy in Alzheimer\u2019s disease with cerebrovascular disease

BackgroundBrain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer’s disease with cerebrovascular disease (AD + CVD) is the most prevalent form of dementia in the elder population. Thus, understanding the role(s) of brain DPMs in this dementia subtype may provide novel insight on the disease pathogenesis and may aid on the development of novel diagnostic and therapeutic tools. Two essential DPMs known to promote inflammation in several human diseases are the ureido DPMs (uDPMs) arginine citrullination and lysine carbamylation, although they have distinct enzymatic and non-enzymatic origins, respectively. Nevertheless, the implication of uDPMs in the neuropathology of dementia remains poorly understood.MethodsIn this study, we use the state-of-the-art, ultracentrifugation-electrostatic repulsion hydrophilic interaction chromatography (UC-ERLIC)-coupled mass spectrometry technology to undertake a comparative characterization of uDPMs in the soluble and particulate postmortem brain fractions of subjects diagnosed with AD + CVD and age-matched controls.ResultsAn increase in the formation of uDPMs was observed in all the profiled AD + CVD brains. Citrulline-containing proteins were found more abundant in the soluble fraction of AD + CVD whereas homocitrulline-containing proteins were preferentially abundant in the particulate fraction of AD + CVD brains. Several dementia-specific citrulline residues were also identified in soluble proteins previously categorized as pro-immunogenic, which include the receptor P2X7, alpha-internexin, GFAP, CNP, MBP, and histones. Similarly, diverse dementia-specific homocitrulline residues were also observed in the particulate fractions of AD + CVD in proteins that have been vastly implicated in neuropathology. Intriguingly, we also found that the amino acids immediately flanking arginine residues may specifically influence the increase in protein citrullination.ConclusionsTaken together, these results indicate that uDPMs widely contribute to the pathophysiology of AD + CVD by promoting neuroinflammation and proteinopathy. Furthermore, the obtained results could help to identify disease-associated proteins that can act as potential targets for therapeutic intervention or as novel biomarkers of specific neuropathology.