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Transcriptomic study of human brain organoids in Alzheimer's Disease

ABSTRACT: Transcriptomic study of human brain organoids in Alzheimer's Disease

PROVIDER: PRJNA1106822 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28863500_1.fastq.gz	Fastqsanger.gz
	SRR28863500_2.fastq.gz	Fastqsanger.gz
	SRR28863501_1.fastq.gz	Fastqsanger.gz
	SRR28863501_2.fastq.gz	Fastqsanger.gz
	SRR28863502_1.fastq.gz	Fastqsanger.gz

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Transcriptomic study of human brain organoids in Alzheimer's Disease

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Project description:FK506 binding protein 51kDa (FKBP51/FKBP5) is part of a mature heat shock protein 90kDa (Hsp90) chaperone complex that preserves tau. Microarray analysis of human brains reveal that FKBP51 gene expression selectively increased with age and Alzheimer's disease, which correlated with demethylation of the regulatory regions in the FKBP5 gene. Moreover, FKBP51 levels significantly correlated with Braak pathological staging. In addition, we show that in brains devoid of FKBP51, tau levels are reduced. Recombinant FKBP51 and Hsp90 synergize to block tau clearance through the proteasome and produce T22-positive tau oligomers. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved tau species, including phosphorylated and oligomeric tau that have been linked to Alzheimer's disease pathogenesis. FKBP51 blocked amyloid formation and decreased tangle load in the brain. These alterations in tau turnover and aggregate structure culminated in enhanced neurotoxicity. We propose a model where age-associated increases in FKBP51 levels can out-compete the association of other pro-degradation Hsp90 co-chaperones, resulting in neurotoxic tau accumulation. Thus, strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 could be therapeutically relevant for Alzheimer's disease and other tauopathies. These AD cases were processed simultaneously with the control cases (young and aged) included in GSE11882 Postmortem brain tissue was collected from ADRC brain banks. Cases were preferentially selected where 3 or more brain regions were available

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