Project description:The overall goal of the project is to assess whether small RNA, especially microRNA (miR) alterations in tauopathy conditions contribute to pathological changes that later lead to neurodegeneration. The animal model selected for this study is a well characterized tauopathy animal model, known as rTg4510 murine model. rTg4510 (tau) is a transgenic mouse model of human tauopathy expressing human tau containing the P301L mutation that is associated with familial frontotemporal dementia and parkinsonism linked to chromosome 17. The expression of P301L tau driven by CaMKII promoter peaks around two month-of-age and mainly in the forebrain. 2-month of age is considered the asymptomatic stage of neurodegeneration. The global expression of miRs was evaluated by small RNA sequencing in the hippocampus of tau mice at 2 months of age. The levels of several miRs were altered in the hippocampus of tau mice at 2 months. Many important candidates were further evaluated for their molecular and functional contributions to the process of neurodegeneration.
Project description:The overall goal of the project is to assess whether small RNA, especially microRNA (miR) alterations in tauopathy conditions contribute to pathological changes that later lead to neurodegeneration. The animal model selected for this study is a well characterized tauopathy animal model, known as rTg4510 murine model. rTg4510 (tau) is a transgenic mouse model of human tauopathy expressing human tau containing the P301L mutation that is associated with familial frontotemporal dementia and parkinsonism linked to chromosome 17. The expression of P301L tau driven by CaMKII promoter peaks around two month-of-age and mainly in the forebrain. 6-month of age is considered the aymptomatic stage of neurodegeneration. The global expression of miRs was evaluated by small RNA sequencing in the hippocampus of tau mice at 6 months of age. The levels of several miRs were altered in the hippocampus of tau mice at 6 months which were compared to deep sequencing data from 2-month of age. Many important candidates were further evaluated for their molecular and functional contributions to the process of neurodegeneration.
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.
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.
Project description:The overall goal of the project is to assess the mRNA alterations in tauopathy conditions that occur at the presymptomatic stage of neurodegeneration. The animal model selected for this study is a well characterized tauopathy animal model, known as rTg4510 murine model. rTg4510 (tau) is a transgenic mouse model of human tauopathy expressing human tau containing the P301L mutation that is associated with familial frontotemporal dementia and parkinsonism linked to chromosome 17. The expression of P301L tau driven by CaMKII promoter peaks around two month-of-age and mainly in the forebrain. 2-month of age is considered the presymptomatic stage of neurodegeneration. The global expression of mRNAs was evaluated by mRNA deep sequencing in the hippocampus of tau mice at 2 months of age. The levels of several mRNAs were altered in the hippocampus of tau mice at 2 months. Many important candidates were further evaluated for their molecular and functional contributions to the process of neurodegeneration.
