Tau Microbiome
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB55869 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10693500_1.fastq.gz | Fastqsanger.gz | |||
| ERR10693500_2.fastq.gz | Fastqsanger.gz | |||
| ERR10693600_1.fastq.gz | Fastqsanger.gz | |||
| ERR10693600_2.fastq.gz | Fastqsanger.gz | |||
| ERR10693700_1.fastq.gz | Fastqsanger.gz |
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Project description:Tau-mediated neurodegeneration (TN) is a hallmark of Alzheimer's disease. Primary tauopathies are characterized by pathological tau accumulation and neuronal and synaptic loss. Studies have shown that ApoE-mediated neuroinflammation is involved in progression of TN and emerging evidence suggests that the gut microbiota regulates neuroinflammation in an APOE-genotype dependent manner. However, there is no evidence showing a causal link of the microbiota to TN. Therefore, we have characterized a genetically engineered mouse model of tauopathy expressing human ApoE isoforms, reared under germ-free conditions or after perturbation of their gut microbiota with antibiotics. Both these manipulations produced a striking reduction of gliosis, taupathology, and neurodegeneration in a sex- and ApoE isoform-dependent manner. The findings reveal mechanistic and translationally relevant interrelationships between the microbiota, neuroinflammation, and TN."
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Project description:In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4.
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Project description:APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here we show that overexpressing a low-density lipoprotein receptor (LDLR) transgene in P301S tau transgenic mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. ApoE specifically interacts with a high-molecular-weight tau species, and highly correlates with phospho-tau and insoluble tau levels. Microglial expression of the LDLR transgene reduces intracellular apoE and is associated with less microglial activation. snRNA-seq analysis of apoE-deficient or LDLR-overexpressing brains reveals that apoE deficiency drives microglial catabolism and increases the oligodendrocyte progenitor cell population. LDLR overexpression shares overlapping mechanisms, but uniquely upregulates microglial expression of specific ion channels and neurotransmitter receptors in tauopathy. A subset of disease-associated astrocytes with both neuroprotective and neurotoxic gene signatures is also identified.
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Project description:Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer’s disease (AD) with APOE4 increasing and APOE2 decreasing risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared to ApoE3 or the absence of ApoE. However, the role of ApoE isoforms in regulating lipid metabolism in the setting of tauopathy is unknown. Here, by using targeted lipidomics coupled with histological analysis, we demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation along with significant perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via administration of the LXR agonist GW3965 reduces lipid droplet accumulation in primary E4 microglia in vitro and GW3965 or Abca1 overexpression strongly attenuates tau pathology, neurodegeneration, and synapse loss in P301S/ApoE4 mice. By immunostaining, bulk and snRNA sequencing, we demonstrate reductions in reactive astrocytes and microglia as well as significant changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids via Abca1 could serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.
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