Distinct tau and alpha-synuclein molecular signatures in Alzheimer’s disease with and without Lewy bodies and Parkinson’s disease with dementia

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Jan. 10, 2024

Abstract Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer’s disease (AD) cases at autopsy and might impact the age-of-onset progression AD. Here, we aimed to determine whether tau aSyn profiles differ between AD with Lewy bodies (AD-LB), pure Parkinson’s dementia (PDD) using epitope-, post-translational modification- (PTM) isoform-specific antibody panels spanning from N- C-terminus. We included middle temporal gyrus (MTG) amygdala (AMY) clinically diagnosed pathologically confirmed performed dot blotting, western blotting immunohistochemistry combined quantitative morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated AD-LB compared PDD control cases, but no significant differences observed subjects. In addition, antibodies targeting proline-rich regions C-terminus showed preferential binding brain homogenates. Antibodies C-terminal epitopes pS129 stronger cases. Two pTau species (pS198 pS396) specifically detected soluble protein fractions subjects, indicative early involvement these PTMs multimerization process tau. Other phospho-variants for both (pT212/S214, pT231 pS422) (pS129) only insoluble fraction AD-LB/AD AD-LB/PDD respectively. load was higher AMY suggesting aggravated under presence pathology, while similar Co-localization could be within astrocytes MTG. These findings highlight a unique pathological signature

Language: Английский

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Alterations in the Processing of Platelet APP (Amyloid Beta Precursor Protein) in Alzheimer Disease: The Possible Nexus

Neuropsychopharmacology Reports, Journal Year: 2025, Volume and Issue: 45(1)

Published: Jan. 5, 2025

Alzheimer's disease (AD) is the most common neurodegenerative associated with development of dementia. The hallmarks AD neuropathology are accumulations amyloid peptide (Aβ) and neurofibrillary tangles (NFTs). Aβ derived from processing APP (amyloid beta precursor protein) by BACE1 (beta-secretase 1) γ-secretase through an amyloidogenic pathway. However, ADAM10/α-secretase (ADAM metallopeptidase domain 10) enzymes a non-amyloidogenic pathway produces soluble alpha (sAPPα), which has neuroprotective effect. It been shown that activated platelets implicated in pathogenesis AD, also increases platelet activation. Under physiological conditions, regulate synaptic plasticity increase neuronal differentiation regulation inflammatory response. overactivated contribute to AD. Activated represent main source circulating may be involved neuropathology. Therefore, there close relationship between platelets. This review discusses potential role how targeting reduce

Language: Английский

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The GLP-1 Agonist Semaglutide Ameliorates Cognitive Regression in P301S Tauopathy Mice Model via Autophagy/ACE2/SIRT1/FOXO1-Mediated Microglia Polarization

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177305 - 177305

Published: Jan. 1, 2025

Language: Английский

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The Oral-Gut-Brain AXIS: The Influence of Microbes in Alzheimer’s Disease

Frontiers in Cellular Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: April 14, 2021

Alzheimer’s disease (AD) is one of the most frequently diagnosed neurodegenerative disorders worldwide and poses a major challenge for both affected individuals their caregivers. AD progressive neurological disorder associated with high rates brain atrophy. Despite its durable influence on human health, understanding has been complicated by enigmatic multifactorial nature. Neurofibrillary tangles deposition amyloid-beta (Aβ) protein are typical pathological features fundamental causes cognitive impairment in patients. Dysbiosis oral gut microbiota reported to induce accelerate formation Aβ plaques neurofibrillary tangles. For instance, some microbes can spread through cranial nerves or cellular infections, which suggested increase risk developing AD. Importantly, interaction between intestinal cells recognized as influencing development well other diseases. In particular, metabolites produced certain microorganisms affect activity microglia further mediate neuroinflammation, leading cause neuronal necrosis pathogenesis. Which pathogens pathways involved progression remains be elucidated; however, it well-known that direct indirect means. Understanding specific mechanisms these nervous system vital early intervention this review, we aim comprehensively discuss possible mechanistic underlying oral-brain, gut-brain oral-gut-brain associations.

Language: Английский

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Association of Aβ deposition and regional synaptic density in early Alzheimer’s disease: a PET imaging study with [11C]UCB-J

Alzheimer s Research & Therapy, Journal Year: 2021, Volume and Issue: 13(1)

Published: Jan. 5, 2021

Abstract Background Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in Alzheimer’s disease (AD) have thus far been limited small numbers of postmortem studies. Aβ plaque burden is not well-correlated indices clinical severity or neurodegeneration—at least the dementia stage—as deposition reaches a ceiling. In this study, we examined vivo association between fibrillar and density early AD using positron emission tomography (PET). We hypothesized that global would be more strongly inversely associated hippocampal participants amnestic mild cognitive impairment (aMCI; stage continued accumulation) compared those (a relative plateau). Methods measured SV2A binding ([ 11 C]UCB-J) C]PiB) 14 aMCI due 24 dementia. Distribution volume ratios ( DVR ) cerebellar reference region were calculated for both tracers investigate hippocampus. Exploratory analyses correlations regional across broad range brain regions ROI- surface-based approaches. Results observed significant inverse r = − 0.55, P 0.04), but 0.05, 0.82; difference statistically by Fisher z 1.80, 0.04). other ROIs whole demonstrated no consistent associations either diagnostic group. ROI-based also revealed pattern suggested “paradoxical” positive local Conclusions Our findings lend support model which still accumulating stages approaching plateau, point at may uncouple from neurodegenerative processes including loss. Future research should relationship larger cohorts beginning preclinically followed longitudinally conjunction biomarkers.

Language: Английский

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Whole‐genome sequencing reveals new Alzheimer's disease–associated rare variants in loci related to synaptic function and neuronal development

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 17(9), P. 1509 - 1527

Published: April 2, 2021

Abstract Introduction Genome‐wide association studies have led to numerous genetic loci associated with Alzheimer's disease (AD). Whole‐genome sequencing (WGS) now permits genome‐wide analyses identify rare variants contributing AD risk. Methods We performed single‐variant and spatial clustering–based testing on (minor allele frequency [MAF] ≤1%) in a family‐based WGS‐based study of 2247 subjects from 605 multiplex families, followed by replication 1669 unrelated individuals. Results identified 13 new candidate that yielded consistent rare‐variant signals discovery cohorts (4 single‐variant, 9 spatial‐clustering), implicating these genes: FNBP1L, SEL1L, LINC00298, PRKCH, C15ORF41, C2CD3, KIF2A, APC, LHX9, NALCN, CTNNA2, SYTL3 , CLSTN2 . Discussion Downstream novel highlight synaptic function, contrast common AD‐associated variants, which implicate innate immunity amyloid processing. These not been previously AD, emphasizing the ability WGS particularly outside exome.

Language: Английский

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What is ‘Alzheimer's disease’? The neuropathological heterogeneity of clinically defined Alzheimer's dementia

Current Opinion in Neurology, Journal Year: 2021, Volume and Issue: 34(2), P. 237 - 245

Published: Feb. 11, 2021

Purpose of review Beta-amyloid with paired helical filaments (PHF)-tau neurofibrillary tangles define hallmark Alzheimer's disease neuropathologic changes (AD-NC). Yet persons dementia, defined broadly as an amnestic multidomain progressive often exhibit postmortem evidence other neuropathologies including neurodegenerative (Lewy body and transactive response DNA-binding protein disease) vascular-related brain lesions. Clinicopathologic epidemiologic analyses demonstrate the significance these substrates, coinciding mitigate threshold for diagnosis dementia. In addition, biologic processes may also independently underlie a Advances in research on relationship between age-related cognitive decline underlying substrates indicate that consensus criteria or nomenclature need new considerations refinement. This appraises seminal literature well mixed pathologies biological factors be determinants clinical pathologic disease. Recent findings Cognition aging (spanning from normal cognition to dementia) represents continuum. Traditional dementia however do not explain variability decline. Conversely, all patients AD-NC symptomatology addition diagnostic plaques tangles, neurodegenerative, cerebrovascular, perivascular manifest through discrete tissue Factors related energetics, neurogenetics, neuroimmunology, resilience, proteinopathies, waste clearance are increasingly suggested general drivers Recognition novel neuroimmune pathways brain–body connections further suggest there broader extracranial person-specific Summary is pathologically heterogeneous biologically multilayered studies exercises reveal shortcomings existing terminologies. Recognizing overcoming limitations required experts effectively communicate about ultimately prevent treat

Language: Английский

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Recent Advances in the Treatment of Alzheimer’s Disease Using Nanoparticle-Based Drug Delivery Systems

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(4), P. 835 - 835

Published: April 11, 2022

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. Most existing treatments only provide symptomatic solutions. Here, we introduce currently available commercial drugs new therapeutics, including repositioned drugs, to treat AD. Despite tremendous efforts, targeting the hallmarks of AD show limited efficacy. Challenges in treating are partly caused by difficulties penetrating blood-brain barrier (BBB). Recently, nanoparticle (NP)-based systems have shown promising potential as precision medicines that can effectively penetrate BBB enhance ability numerous drugs. describe how NPs enter brain crossing, avoiding, or disrupting BBB. In addition, overview action microenvironment for treatment Diverse systems, liposomes, micelles, polymeric NPs, solid-lipid inorganic been investigated NP drug loading relieve symptoms, target hallmarks, moieties diagnose We also highlight NP-based immunotherapy, which has recently gained special attention a option disrupt progression. Overall, this review focuses on represent innovative strategies understand pathogenesis suggests diagnostic modalities cure

Language: Английский

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New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1925 - 1925

Published: June 14, 2022

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 by 2050. The exact pathogenic mechanisms AD remain elusive, resulting in fact that current therapeutics solely focus on symptomatic management instead preventative or curative strategies. two widely accepted include amyloid and tau hypotheses. However, it evident these hypotheses cannot fully explain neuronal degeneration shown AD. Substantial evidence growing for vital role neuroinflammation pathology. neuroinflammatory hypothesis provides a new, exciting lead uncovering underlying contributing This review aims highlight new insights into pathogenesis AD, mainly including involvement nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed myeloid 2 (TREM2) cGAS-STING as key influencers augmenting development. inflammasomes related pathways NF-κB, NLRP3, TREM2, biomarkers associated well overview novel treatments based potential drug targets reported literature under clinical trials, are explored.

Language: Английский

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Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Biomolecules, Journal Year: 2022, Volume and Issue: 12(11), P. 1676 - 1676

Published: Nov. 11, 2022

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, synaptic nonsynaptic plasticity the lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury synapses neurons accumulation extracellular amyloid plaques intracellular neurofibrillary tangles are considered main morphological neuropathological features AD. Age, genetic epigenetic factors, environmental stressors, lifestyle contribute risk AD onset progression. These factors associated with structural functional changes brain, leading cognitive decline. Biomarkers reflect cause specific function, especially pathways neurotransmission, neuroinflammation, bioenergetics, apoptosis, oxidative nitrosative stress. Even initial stages, is Aβ neurotoxicity, mitochondrial dysfunction, tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that primary neurotoxicity oligomers oligomers, their mutual synergy. For development new efficient drugs, targeting elimination potentiation effects, unwanted protein interactions biomarkers (mainly dysfunction) early stage seems promising.

Language: Английский

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