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A1-Reactive Astrocytes and a loss of TREM2 are associated to an early state of pathology in a mouse model of Cerebral Amyloid Angiopathy

ABSTRACT: A1-Reactive Astrocytes and a loss of TREM2 are associated to an early state of pathology in a mouse model of Cerebral Amyloid Angiopathy

PROVIDER: PRJNA631972 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11777747_1.fastq.gz	Fastqsanger.gz
	SRR11777747_2.fastq.gz	Fastqsanger.gz
	SRR11777748_1.fastq.gz	Fastqsanger.gz
	SRR11777748_2.fastq.gz	Fastqsanger.gz
	SRR11777749_1.fastq.gz	Fastqsanger.gz

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Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation [II]

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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Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation [I]

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A1-Reactive Astrocytes and a loss of TREM2 are associated to an early state of pathology in a mouse model of Cerebral Amyloid Angiopathy

Project description:In this study, we dissect in detail the glial and immune responses associated to early stages of CAA. To do so, RNAseq gene expression analysis were performed in a mouse model for Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. Findings observed in this CAA mouse model were complemented with primary culture assays.

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Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

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Expression data from WT and TREM2 deficient microglia in a mouse model of Alzheimer's disease

Project description:We examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease Microglia were FACS-purified from 8.5 month old WT, Trem2-/-, 5XFAD, and Trem2-/- 5XFAD mice

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A Human Model of Cerebral Amyloid Angiopathy Using Neural Crest-Derived Vascular Smooth Muscle Cells

Project description:There is a growing recognition of cerebrovascular contribution to neurodegenerative diseases. Cerebral amyloid angiopathy (CAA), characterised by amyloid-beta (AM-NM-2) deposits in the walls of intracerebral and leptomeningeal arteries, is evident in a majority of AlzheimerM-bM-^@M-^Ys disease patients and aged people. Here, we leverage on human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain vasculature-specific attributes in AM-NM-2 metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural crest-derived SMCs to mediate AM-NM-2 uptake and intracellular proteasomal degradation. Hypoxia significantly compromises the ability of SMCs in AM-NM-2 clearance by suppressing LRP1 expression. This enables us to develop an assay of AM-NM-2 uptake using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high throughput format, demonstrating the value of stem cell-based phenotypic screening for novel CAA therapeutics and drug repurposing. We adopted our previous SMC differentiation protocol (Cheung et al., 2012) to differentiate this intermediate neural crest population using platelet-derived growth factor BB (PDGF-BB, 10 ng/ml) and transforming growth factor-beta 1 (TGF-M-NM-21, 2ng/ml) for another 12 days. The resultant neural crest-derived SMCs (NCSMC) were then characterised in comparison to neuroectoderm-derived SMCs (NESMC) (Cheung et al., 2012) and positive control, human brain vascular SMCs (BVSMC).

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Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation

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