Nanostring protein expression of immune cell recruitment and BBB breakdown following Aβ immunotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE253388 | GEO | 2024/11/29
REPOSITORIES: GEO
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Project description:Nanostring protein expression of immune cell recruitment and BBB breakdown following Aβ immunotherapy
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Project description:Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in CAA patients but are usually considered as consequences of CAA pathology. Here, we report that chronic stress promotes CAA progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in CAA development. Aβ that accumulated in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. We demonstrate that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate CAA severity in the context of chronic stress. Therefore, we propose that stress-associated psychological disorders and NETs are promising therapeutic targets in CAA.
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Project description:The majority of Alzheimer’s disease patients and 20–40% of non-demented elderly experience amyloid deposits along their cerebral vasculature, a condition known as cerebral amyloid angiopathy (CAA). CAA impairs the function of the blood-brain barrier (BBB) leading to ischemia, hemorrhages, and accelerated cognitive dysfunction. The APOE4 allele is the strongest known genetic risk factor for CAA and sporadic AD, however the pathogenic mechanisms underlying this predisposition are unknown. Here, we recreate the human BBB in vitro by co-culturing the three cellular components of the BBB, endothelial cells, pericytes, and astrocytes in 3D scaffolding to construct a tractable model that recapitulates key anatomical and physiological properties of the BBB. Similar to the in vivo BBB, we find amyloid accumulates on our in vitro BBB (iBBB) and both APOE4 homozygous and heterozygous iBBBs exhibit significantly more amyloid accumulation than APOE3/3 iBBBs. Combinatorial experiments revealed that pericytes have a causal role in the development of CAA. We found that APOE expression is markedly up-regulated in APOE4 pericytes, but not in astrocytes or endothelial cells. Transcriptional profiling revealed that calcineurin/NFAT signaling is dysregulated in APOE4 pericytes. Pharmacologically inhibiting calcineurin led to downregulation of APOE and subsequently reduced amyloid deposition on the iBBB. These results demonstrate an unexpected role of pericytes in cerebral amyloid deposition and advocate for inhibiting calcineurin/NFAT-signaling as a therapeutic strategy to mitigate APOE4 predisposition to CAA and potentially AD.
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