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Spatial transcriptomics reveals neuroimmune mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients.

ABSTRACT: Recent advances in Alzheimer's disease (AD) therapeutics involve immunization against amyloid-β (Aβ). Post-mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown. Here, we utilize a novel spatial approach to study brain tissues from 13 AD patients immunized with Aβ. We compare these actively immunized patient brains to tissues from non-immunized AD patients and non-neurologic disease controls. Additionally, we use spatial proteogenomics and single-cell RNA sequencing technologies to investigate the effects of lecanemab, a recently FDA-approved passive anti-Aβ therapeutic. We reveal the transcriptomic neuroimmune response in the Aβ plaque microenvironment following anti-Aβ immunization. This response is characterized by an increase in TREM2, APOC1, A2M and RAB13 in microglia of the immunized AD cortex. Altogether, our data uncover immediate and lasting neuroimmune responses in the AD brain induced by active and passive Aβ immunization.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263079 | GEO | 2025/03/03

REPOSITORIES: GEO

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Project description:Krohn2011 - Cerebral amyloid-β proteostasis regulated by membrane transport protein ABCC1 This model is described in the article: Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. J. Clin. Invest. 2011 Oct; 121(10): 3924-3931 Abstract: In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD. This model is hosted on BioModels Database and identified by: BIOMD0000000618. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Spatial transcriptomics reveals neuroimmune mechanisms of amyloid-β clearance in immunized Alzheimer’s disease patients.

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