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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Rapidly progressive dementias — aetiologies, diagnosis and management

Nature Reviews Neurology, Год журнала: 2022, Номер 18(6), С. 363 - 376

Опубликована: Май 4, 2022

Язык: Английский

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Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(2), С. 678 - 678

Опубликована: Янв. 20, 2020

Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer's disease (AD). Many studies have defined phenotypes reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach goal characterizing distribution purinergic receptor P2RY12-positive marker previously as identifying homeostatic or non-activated microglia. examined expression P2RY12 by dual-color light and fluorescence immunohistochemistry using sections middle temporal gyrus from AD, high plaque low non-demented cases relation amyloid beta (Aβ) plaques phosphorylated tau, pathology, HLA-DR, IBA-1, CD68, progranulin, microglial phenotype markers. In cases, microglia mostly had morphologies, while morphologies AD brains were highly variable, suggesting its could encompass wider range than originally hypothesized. differed depending on types tangles they associated with. Areas inflammation characterized lack around mature be observed, but many diffuse showed colocalization Based these results, should not solely resting immunoreactivity was positive for progranulin limited extent activation.

Язык: Английский

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Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau

Neuropsychopharmacology, Год журнала: 2020, Номер 46(1), С. 98 - 115

Опубликована: Сен. 8, 2020

Abstract The repeated failures of amyloid-targeting therapies have challenged our narrow understanding Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms disease. Increasing evidence indicates that AD develops from an intricate web biochemical cellular processes extend far beyond amyloid tau accumulation. This growing recognition surrounding diversity pathophysiology underscores need for holistic systems-based approaches to explore pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool its application brain provided informative framework complex protein Furthermore, outline network proteome can be leveraged advance additional scientific translational efforts, including discovery novel biomarkers

Язык: Английский

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Quantitative proteomics reveals distinct composition of amyloid plaques in Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2018, Номер 15(3), С. 429 - 440

Опубликована: Ноя. 28, 2018

Abstract Introduction We investigated the proteomic profiles of amyloid plaques (APs) from Alzheimer's disease (AD) and age‐matched non‐AD brains APP/PS1 transgenic model mice. Methods APs adjacent control regions were collected fresh‐frozen brain sections using laser capture dissection. Proteins quantitated tag‐labeling coupled high‐throughput mass spectra. Results Over 4000 proteins accurately quantified, more than 40 identified as highly enriched in both AD APs, including apoE, midkine, VGFR1, complement C4. Intriguingly, synaptic structural C1r, C5, C9 found to be upregulated but not APs. Moreover, pattern was distinct exhibited correlation with aging hippocampus. Discussion Our results provide new insight into AP composition. demonstrate unexpected differences between AD, non‐AD, mouse which may relate different pathological processes.

Язык: Английский

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The CSF neurofilament light signature in rapidly progressive neurodegenerative dementias

Alzheimer s Research & Therapy, Год журнала: 2018, Номер 10(1)

Опубликована: Янв. 11, 2018

Neurofilament light chain protein (NfL) is a surrogate biomarker of neurodegeneration that has never been systematically tested, either alone or in combination with other biomarkers, atypical/rapidly progressive neurodegenerative dementias (NDs). Using validated, commercially available enzyme-linked immunosorbent assay kits, we measured cerebrospinal fluid (CSF) NfL, total tau (t-tau), phosphorylated tau, and β-amyloid 42 subjects neuropathological clinical diagnosis prion disease (n = 141), Alzheimer’s (AD) 73), dementia Lewy bodies (DLB) 35), frontotemporal lobar degeneration (FTLD) 44). Several cases an course were included each group. We evaluated the diagnostic accuracy every CSF their combinations by ROC curve analyses. In patient group NfL showed higher levels than control subjects, reaching highest values those Creutzfeldt-Jakob (CJD). latter, divergent, subtype-specific correlation t-tau, depending on degree subcortical involvement duration. Most significantly, patients classic sporadic CJD (sCJD) MM1 significantly lower concentration sCJD MV2, despite much t-tau more rapid course. High also detected most atypical cases, showing duration longer 2 years and/or borderline/negative results assays (e.g., 14-3-3, real-time quaking-induced conversion). Rapidly progressive/atypical typical FTLD, but not AD DLB. similar to discriminating from NDs, it had efficacy differentiating forms, especially regard disease. The present data indicate reflect distinct pathophysiological mechanisms support use as fast screening for differential NDs.

Язык: Английский

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Recent update on the heterogeneity of the Alzheimer’s disease spectrum

Journal of Neural Transmission, Год журнала: 2021, Номер 129(1), С. 1 - 24

Опубликована: Дек. 17, 2021

Язык: Английский

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A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(19), С. 4724 - 4724

Опубликована: Сен. 24, 2019

The increase in the incidence of neurodegenerative diseases, particular Alzheimer’s Disease (AD), is a consequence world′s population aging but unfortunately, existing treatments are only effective at delaying some symptoms and for limited time. Despite huge efforts by both academic researchers pharmaceutical companies, no disease-modifying drugs have been brought to market last decades. Recently, several studies shed light on Carbonic Anhydrases (CAs, EC 4.2.1.1) as possible new targets AD treatment. In present review we summarized preclinical clinical findings regarding role CAs their inhibitors/activators cognition, neurodegeneration discuss future challenges opportunities field.

Язык: Английский

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Four Distinct Subtypes of Alzheimer’s Disease Based on Resting-State Connectivity Biomarkers

Biological Psychiatry, Год журнала: 2022, Номер 93(9), С. 759 - 769

Опубликована: Июнь 26, 2022

Язык: Английский

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CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Cell, Год журнала: 2024, Номер 187(22), С. 6309 - 6326.e15

Опубликована: Сен. 26, 2024

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for monitoring and treatment strategies. We examined CSF proteins 286 mutation carriers (MCs) 177 non-carriers (NCs). The developed multi-layer regression model distinguished with different pseudo-trajectories between these groups. validated our findings independent ADAD as well sporadic AD datasets employed machine learning develop validate predictive models. Our identified 137 distinct trajectories MCs NCs, including eight that changed before traditional biomarkers. These are grouped into three stages: stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle (neuronal death, apoptosis), late presymptomatic (microglial changes, cell communication). revealed a six-protein subset more effectively differentiated from compared conventional

Язык: Английский

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