Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113761 - 113761

Опубликована: Фев. 1, 2024

Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, together produce β-peptide (Aβ). Nevertheless, whether Aβ is primary driver remains controversial. We report here FAD mutations disrupt initial proteolytic events multistep processing APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals a mimetic traps γ-secretase during transition state, this structure aligns with activated enzyme-substrate complex captured molecular dynamics simulations. In silico simulations cellulo fluorescence support stabilization complexes mutations. Neuronal expression and/or presenilin-1 Caenorhabditis elegans leads to synaptic loss only FAD-mutant transgenes. Designed stabilize block production likewise led loss. Collectively, these findings implicate stalled process—not products—of cleavage substrates pathogenesis.

Язык: Английский

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The advent of Alzheimer treatments will change the trajectory of human aging

Nature Aging, Год журнала: 2024, Номер 4(4), С. 453 - 463

Опубликована: Апрель 19, 2024

Язык: Английский

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Proteomic analysis of Alzheimer’s disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment

Science Translational Medicine, Год журнала: 2024, Номер 16(753)

Опубликована: Июнь 26, 2024

Alzheimer’s disease (AD) is currently defined by the aggregation of amyloid-β (Aβ) and tau proteins in brain. Although biofluid biomarkers are available to measure Aβ pathology, few markers complex pathophysiology that associated with these two cardinal neuropathologies. Here, we characterized proteomic landscape cerebrospinal fluid (CSF) changes pathology 300 individuals using different technologies—tandem mass tag spectrometry SomaScan. Integration both data types allowed for generation a robust protein coexpression network consisting 34 modules derived from 5242 measurements, including disease-relevant autophagy, ubiquitination, endocytosis, glycolysis. Three strongly apolipoprotein E ε4 ( APOE ε4) AD risk genotype mapped oxidant detoxification, mitogen-associated kinase signaling, neddylation, mitochondrial biology overlapped previously described lipoprotein module serum. Alterations all three blood were dementia more than 20 years before diagnosis. Analysis CSF samples an phase 2 clinical trial atomoxetine (ATX) demonstrated abnormal elevations glycolysis module—the most correlated cognitive function—were reduced ATX treatment. Clustering based on their profiles revealed heterogeneity pathological not fully reflected tau.

Язык: Английский

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Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer’s disease

Cell Reports, Год журнала: 2025, Номер unknown, С. 115109 - 115109

Опубликована: Янв. 1, 2025

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies infectious agents, with herpes simplex virus 1 (HSV-1) being leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression herpesvirus protein ICP27 increases severity strongly colocalizes p-tau but not Aβ. Modeling organoids shows that HSV-1 infection elevates phosphorylation. Notably, reduces expression markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB IRF-3, which AD. Furthermore, experimental activation STING enhances phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest phosphorylation acts as an innate immune response AD, driven by cGAS-STING.

Язык: Английский

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Second-generation anti-amyloid monoclonal antibodies for Alzheimer’s disease: current landscape and future perspectives

Translational Neurodegeneration, Год журнала: 2025, Номер 14(1)

Опубликована: Янв. 27, 2025

Abstract Alzheimer’s disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from brains patients with AD, U.S. Food Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), donanemab (Kisunla™). Notably, received traditional approval after demonstrating clinical benefit, supporting cascade hypothesis. These MABs are categorized affinity to diverse conformational features Aβ, including monomer, fibril, protofibril, plaque forms well pyroglutamate Aβ. First-generation non-toxic monomeric solanezumab, bapineuzumab, crenezumab, failed demonstrate benefit trials. In contrast, second-generation aducanumab, lecanemab, donanemab, gantenerumab directed against species aggregates have shown that reducing deposition can be an effective strategy slow cognitive impairment AD. this review, we provide comprehensive overview current status, mechanisms, outcomes, limitations treatment Moreover, discuss perspectives future directions

Язык: Английский

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