Journal Article

DZNE-2026-00688

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology.

Candlish, M. ; Hofmann, J. ; Brösamle, D.DZNE* ; Haessler, A. ; DeMeglio, M. ; Skodras, A. ; Tushev, G. ; De Biasi, E. S. ; Günther, S. ; Wiegandt, R. ; Theis, H.DZNE* ; De Domenico, E.DZNE* ; Hermann, N. S.DZNE* ; Breunig, P. ; Sauerland, C. ; Nilsson, K. P. R. ; Beyer, M. D.DZNE* ; Looso, M. ; Windbergs, M. ; Roeber, S. ; Herms, J.Extern* ; Neher, J. J.DZNE* ; Chiocchetti, A. G. ; Hefendehl, J. K.

2026
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12974-026-03897-x

Abstract: Microglia are highly plastic cells that are capable of integrating subsequent insults. As the majority of Alzheimer's Disease (AD) patients also show cerebrovascular pathology, we here aimed to dissect the interactions between AD and ischemic brain injury on the microglial response to amyloid beta (Aβ) pathology. Unexpectedly, ischemic stroke in the context of cerebral β-amyloidosis drives the emergence of a neuroprotective microglial phenotype characterized by an ApoE-enriched transcriptional state and enhanced lipid handling. These microglia promote the rapid formation of highly compact Aβ plaques that are relatively inert and strikingly reminiscent of those observed in cognitively resilient AD patients. Our findings thus reveal that the microglial response to Aβ pathology is not a fixed trajectory toward dysfunction, but retains a capacity for beneficial reprogramming when engaged by the appropriate stimulus. Beyond characterizing this comorbid state, our data identify specific molecular pathways, centered on ApoE, complement activation, and lysosomal processing, that may be amenable to therapeutic targeting to promote protective microglial function in AD.

Keyword(s): Microglia: pathology (MeSH) ; Microglia: metabolism (MeSH) ; Animals (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides: toxicity (MeSH) ; Mice (MeSH) ; Phenotype (MeSH) ; Brain Ischemia: pathology (MeSH) ; Brain Ischemia: metabolism (MeSH) ; Humans (MeSH) ; Mice, Transgenic (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Apolipoproteins E: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Alzheimer’s disease ; Co-morbidity ; Microglia ; Stroke ; Amyloid beta-Peptides ; Apolipoproteins E ; Amyloid beta-Protein Precursor

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Contributing Institute(s):

1. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Immunogenomics and Neurodegeneration (AG Beyer)
4. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2026

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