Emerging diagnostics and therapeutics for Alzheimer disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(9), P. 2187 - 2199

Published: Sept. 1, 2023

Language: Английский

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A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Nature Neuroscience, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 12, 2023

Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared standard anti-TREM2 antibody. In induced pluripotent stem cell (iPSC)-derived microglia, proliferation mitochondrial metabolism. Single-cell RNA sequencing morphometry revealed shifted microglia metabolically responsive states, which were distinct from those by amyloid pathology. an AD mouse model, boosted microglial activity glucose Thus, represents promising approach improve function treat hypometabolism found patients AD.

Language: Английский

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TREM2 dependent and independent functions of microglia in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Dec. 23, 2022

Abstract Microglia are central players in brain innate immunity and have been the subject of extensive research Alzheimer’s disease (AD). In this review, we aim to summarize genetic functional discoveries that advanced our understanding microglia reactivity AD pathology. Given heightened risk posed by rare variants microglial triggering receptor expressed on myeloid cells 2 (TREM2), will focus studies addressing impact responses amyloid plaques, tauopathy demyelination pathologies mouse human. Finally, discuss implications recent TREM2 biology potential therapeutic strategies for AD.

Language: Английский

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Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(10), P. 1704 - 1721.e6

Published: Aug. 21, 2023

Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate therapeutic of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key components including behavioral timing, pathology, hippocampal transcription, memory two transgenic (TG) mouse models AD. We found TRF had remarkable capability simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep memory, normalizing daily transcription patterns multiple genes, those associated AD neuroinflammation. Thus, our study unveils for first time pleiotropic nature timed on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration misalignment circadian rhythmicity. Since can substantially modify trajectory, this intervention immediate translational potential, addressing urgent demand accessible approaches reduce or halt progression.

Language: Английский

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Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist

Neuron, Journal Year: 2023, Volume and Issue: 112(3), P. 384 - 403.e8

Published: Nov. 22, 2023

Language: Английский

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Updates on mouse models of Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: March 11, 2024

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative in United States (US). Animal models, specifically mouse models have been developed to better elucidate mechanisms and test therapeutic strategies for AD. A large portion of effort field was focused on developing transgenic (Tg) through over-expression genetic mutations associated with familial AD (FAD) patients. Newer generations knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, both sporadic risk genes hope more accurately model proteinopathies without human brains. In this review, we summarized phenotypes a few commonly used as well newly translational research laboratories including presence absence key pathological features such amyloid tau pathology, synaptic neuronal degeneration cognitive behavior deficits. addition, advantages limitations these elaborated along discussions any sex-specific features. More importantly, omics data from available analyzed categorize molecular signatures each reminiscent brain changes, guide future selection suitable specific questions be addressed field.

Language: Английский

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Pharmacological modulation of septins restores calcium homeostasis and is neuroprotective in models of Alzheimer’s disease

Science, Journal Year: 2024, Volume and Issue: 384(6699)

Published: May 30, 2024

Abnormal calcium signaling is a central pathological component of Alzheimer's disease (AD). Here, we describe the identification class compounds called ReS19-T, which are able to restore homeostasis in cell-based models tau pathology. Aberrant accumulation leads uncontrolled activation store-operated channels (SOCCs) by remodeling septin filaments at cell cortex. Binding ReS19-T septins restores filament assembly state and restrains entry through SOCCs. In amyloid-β tau-driven mouse disease, agents restored synaptic plasticity, normalized brain network activity, attenuated development both Our findings identify cytoskeleton as potential therapeutic target for disease-modifying AD treatments.

Language: Английский

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Human and mouse proteomics reveals the shared pathways in Alzheimer’s disease and delayed protein turnover in the amyloidome

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Murine models of Alzheimer's disease (AD) are crucial for elucidating mechanisms but have limitations in fully representing AD molecular complexities. Here we present the comprehensive, age-dependent brain proteome and phosphoproteome across multiple mouse amyloidosis. We identified shared pathways by integrating with human metadata prioritized components multi-omics analysis. Collectively, two commonly used (5xFAD APP-KI) replicate 30% protein alterations; additional genetic incorporation tau splicing pathologies increases this similarity to 42%. dissected proteome-transcriptome inconsistency 5xFAD brains, revealing that inconsistent proteins enriched within amyloid plaque microenvironment (amyloidome). Our analysis turnover demonstrates formation delays degradation amyloidome components, including Aβ-binding autophagy/lysosomal proteins. proteomic strategy defines pathways, identifies potential targets, underscores contributes discrepancies during progression. This study maps changes models, identifying humans, amyloid-driven turnover, differences, offering insights into targets.

Language: Английский

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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Language: Английский

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Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(4), P. 324 - 339

Published: Oct. 13, 2022

Loss-of-function heterozygous mutations in GRN, the gene encoding progranulin (PGRN), were identified patients with frontotemporal lobar degeneration (FTLD) almost two decades ago and are generally linked to reduced PGRN protein expression levels. Although initial characterization of function primarily focused on its role extracellular signaling as a secreted protein, more recent studies revealed critical roles regulating lysosome function, including proteolysis lipid degradation, consistent lysosomal localization. Emerging from these is notion that regulates glucocerebrosidase activity via direct chaperone activities interaction prosaposin (i.e., key regulator sphingolipid-metabolizing enzymes), well anionic phospholipid bis(monoacylglycero)phosphate. This emerging biology novel promising opportunities therapeutic discovery biomarker development.

Language: Английский

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