ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Ноя. 8, 2022

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence rapidly increasing due to extended lifespans. Among number genetic risk factors identified, apolipoprotein E (APOE) gene remains strongest prevalent, impacting more than half all AD cases. While ε4 allele APOE significantly increases risk, ε2 protective relative ε3 allele. These alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function mediate lipid transport in brain periphery; however, additional functions diverse biological have been recognized. Pathogenically, seeds amyloid-β (Aβ) plaques with apoE4 driving earlier abundant amyloids. ApoE also differential effects on multiple Aβ-related or Aβ-independent pathways. complexity biology pathobiology presents challenges designing effective apoE-targeted therapeutic strategies. This review examines key pathobiological pathways related targeting strategies a specific focus latest technological advances tools.

Язык: Английский

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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

Nature reviews. Neuroscience, Год журнала: 2022, Номер 24(1), С. 23 - 39

Опубликована: Окт. 31, 2022

Язык: Английский

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Organ aging signatures in the plasma proteome track health and disease

Nature, Год журнала: 2023, Номер 624(7990), С. 164 - 172

Опубликована: Дек. 6, 2023

Abstract Animal studies show aging varies between individuals as well organs within an individual 1–4 , but whether this is true in humans and its effect on age-related diseases unknown. We utilized levels of human blood plasma proteins originating from specific to measure organ-specific differences living individuals. Using machine learning models, we analysed 11 major estimated organ age reproducibly five independent cohorts encompassing 5,676 adults across the lifespan. discovered nearly 20% population strongly accelerated one 1.7% are multi-organ agers. Accelerated confers 20–50% higher mortality risk, relate faster those organs. find with heart have a 250% increased failure risk brain vascular predict Alzheimer’s disease (AD) progression independently pTau-181 (ref. 5 ), current best blood-based biomarker for AD. Our models link calcification, extracellular matrix alterations synaptic protein shedding early cognitive decline. introduce simple interpretable method study using proteomics data, predicting effects.

Язык: Английский

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Shared mechanisms across the major psychiatric and neurodegenerative diseases

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Июль 26, 2022

Several common psychiatric and neurodegenerative diseases share epidemiologic risk; however, whether they pathophysiology is unclear the focus of our investigation. Using 25 GWAS results LD score regression, we find eight significant genetic correlations between diseases. We integrate with human brain transcriptomes (n = 888) proteomes 722) to identify cis- trans- transcripts proteins that are consistent a pleiotropic or causal role in each disease, referred as for brevity. Within disease group, many distinct shared proteins. Remarkably, 30% (13 42) disorders. Furthermore, 2.6-fold more protein-protein interactions among than expected by chance. Together, findings suggest these have molecular pathophysiology, which has important ramifications early treatment therapeutic development.

Язык: Английский

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Multi-platform proteomic analysis of Alzheimer’s disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome

Alzheimer s Research & Therapy, Год журнала: 2022, Номер 14(1)

Опубликована: Ноя. 17, 2022

Abstract Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer’s disease its diverse pathological processes are urgently needed. Here, we undertook an investigation cerebrospinal fluid (CSF) plasma from same subjects ( n= 18 control , AD) using three different proteomic platforms—SomaLogic SomaScan, Olink proximity extension assay, tandem mass tag-based spectrometry—to assess which protein markers in these two biofluids may serve as reliable AD pathophysiology observed unbiased brain proteomics studies. Median correlation overlapping measurements across platforms CSF r ~0.7) ~0.6) was good, with more variability plasma. The SomaScan technology provided most Surprisingly, many proteins altered were found to be opposite direction plasma, including important members co-expression modules. An exception SMOC1, a key member matrisome module associated amyloid-β deposition AD, elevated both Protein analysis on greater than 7000 9500 all revealed strong changes modules related autophagy, ubiquitination, sugar metabolism CSF, endocytosis Cross-platform cross-biofluid represents promising approach for biomarker development.

Язык: Английский

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Cell Reports, Год журнала: 2023, Номер 42(3), С. 112196 - 112196

Опубликована: Март 1, 2023

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial transcriptome, specifically subsets metabolically distinct microglia enriched brain during aging or following an inflammatory challenge. display increased Hif1α expression disrupted tricarboxylic acid (TCA) cycle are inherently pro-glycolytic, while mass spectrometry imaging highlight E4-specific response amyloid characterized by widespread alterations lipid metabolism. Taken together, our emphasize central for regulating microglial immunometabolism provide valuable, interactive resources discovery validation research.

Язык: Английский

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Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1979 - 1988

Опубликована: Авг. 1, 2023

Abstract Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation amyloid-β (Aβ) peptide into plaques and microtubule protein tau neurofibrillary tangles (NFTs)—are hallmarks disease. However, other brain processes are thought to be key mediators Aβ plaque NFT pathology. How these additional pathologies evolve over course is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked coexpression can used characterize evolution a timescale spanning six decades. SMOC1 SPON1 proteins associated with were elevated CSF nearly 30 symptoms, followed by changes synaptic proteins, metabolic axonal inflammatory finally decreases neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers symptom as well or better than measures. Our results highlight multifaceted landscape pathophysiology its temporal evolution. Such knowledge will critical for developing precision therapeutic interventions biomarkers beyond those tau.

Язык: Английский

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Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles

Nature Aging, Год журнала: 2024, Номер 4(1), С. 33 - 47

Опубликована: Янв. 9, 2024

Abstract Alzheimer’s disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity critical for AD drug development. Here we define subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels individuals ( n = 419) compared to controls 187). These had alterations protein that were associated distinct processes: subtype 1 was characterized by proteins related neuronal hyperplasticity; 2 innate immune activation; 3 RNA dysregulation; 4 choroid plexus dysfunction; and 5 blood–brain barrier impairment. Each specific genetic risk variants, example, enriched TREM2 R47H. Subtypes also differed clinical outcomes, survival times anatomical patterns of brain atrophy. results indicate highlight need personalized medicine.

Язык: Английский

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Compilation of reported protein changes in the brain in Alzheimer’s disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 25, 2023

Abstract Proteomic studies of human Alzheimer’s disease brain tissue have potential to identify protein changes that drive disease, and new drug targets. Here, we analyse 38 published proteomic studies, generating a map in across thirteen regions, three stages (preclinical mild cognitive impairment, advanced disease), proteins enriched amyloid plaques, neurofibrillary tangles, cerebral angiopathy. Our dataset is compiled into searchable database (NeuroPro). We found 848 were consistently altered 5 or more studies. Comparison early-stage revealed associated with synapse, vesicle, lysosomal pathways show change early but widespread mitochondrial expression are only seen disease. Protein similar for regions considered vulnerable resistant. This resource provides insight highlights interest further study.

Язык: Английский

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Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease

Physiological Reviews, Год журнала: 2023, Номер 104(1), С. 103 - 197

Опубликована: Окт. 16, 2023

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, it seems to link different hypotheses mechanisms of AD neuropathology high fidelity. The particularly vulnerable damage, mainly because its unique lipid composition, resulting an amplified cascade redox reactions that target several cellular components/functions ultimately leading neurodegeneration. present review highlights the “OS hypothesis AD,” including amyloid beta-peptide-associated role protein oxidation unraveled by proteomics, antioxidant strategies have been investigated modulate progression AD. Collected studies from our groups others contributed unraveling close relationships between perturbation homeostasis elucidating redox-regulated events potentially involved both pathogenesis However, complexity requires in-depth understanding intracellular affecting relevant for functions. This crucial developing pharmacological targeting OS-mediated toxicity may contribute slow well improve quality life persons this severe dementing disorder.

Язык: Английский

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