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Z-RNA drives Tau-mediated neurodegeneration of Alzheimer’s disease

ABSTRACT: Z-RNA drives Tau-mediated neurodegeneration of Alzheimer’s disease

PROVIDER: PRJNA1041713 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26858068_1.fastq.gz	Fastqsanger.gz
	SRR26858068_2.fastq.gz	Fastqsanger.gz
	SRR26858069_1.fastq.gz	Fastqsanger.gz
	SRR26858069_2.fastq.gz	Fastqsanger.gz
	SRR26858070_1.fastq.gz	Fastqsanger.gz

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Z-RNA drives Tau-mediated neurodegeneration of Alzheimer’s disease [lncRNA-Seq]

Project description:Tau aggregates lead to progressive neurodegeneration in Alzheimer’s disease (AD) (ref). Neuron death is one of the hallmarks of neurodegeneration (ref). However, the pathological influence of neuronal death is undetermined, and the connection between Tau aggregates and neuronal death remains elusive. Here we demonstrated the essential role of neuron death in Tau-related neurodegeneration. Tau-neurons died in necroptosis, dependent on ZBP1 sensitized by Z-RNAs (an unusual left-handed conformation). Those endogenous Z-RNAs were transcripts of reactivated transposable elements (TEs) originally silenced in heterochromatin.

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Project description:Tau aggregates lead to progressive neurodegeneration in Alzheimer’s disease (AD). Neuron death is one of the hallmarks of neurodegeneration.However, the pathological influence of neuronal death is undetermined, and the connection between Tau aggregates and neuronal death remains elusive. Here we demonstrated the essential role of neuron death in Tau-related neurodegeneration. Tau-neurons died in necroptosis, dependent on ZBP1 sensitized by Z-RNAs (an unusual left-handed conformation). Those endogenous Z-RNAs were transcripts of reactivated transposable elements (TEs) originally silenced in heterochromatin.

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Project description:Z-RNA drives Tau-mediated neurodegeneration of Alzheimer’s disease [RIP-Seq]

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Microglia-mediated T cell Infiltration Drives Neurodegeneration in Tauopathy

Project description:Extracellular amyloid-β (Aβ) deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles (NFT) are two of the characteristic hallmarks in Alzheimer’s disease (AD). The regional progression of brain atrophy in AD highly correlates with tau accumulation but not amyloid deposition and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. To date, little is known about the extent or role of the adaptive immune response in the presence of Aβ or tau pathology. We systematically compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T-cells blocked tau-mediated neurodegeneration. T cells, especially cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of IFN-γ and PD-1signaling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in AD and primary tauopathies.

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Project description:Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration.

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