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• W2897466329 abstract "Most neurodegenerative disorders are characterized by the accumulation of protein aggregates in certain neurons and the progressive loss of specific neuronal cell populations. Previous studies have suggested that excitatory (EX) neurons are preferentially impacted by tau pathology in the vulnerable regions (e.g. the entorhinal cortex (EC) and the CA1 region of the hippocampus) at early stages of Alzheimer's disease (AD). However, the exact cellular features and biochemical pathways mediating this selective neuronal vulnerability are largely unknown. The number of cell type-specific neuronal markers and their colocalization ratios with tau are measured by sequential immunofluorescent staining and counted by Image J. A differential expression analysis was performed on two single-nucleus RNA-seq datasets. Raw data were first log-normalized, and then a z-score normalization was performed for all genes across the samples to enable a direct comparison between them. Here we report that tau exclusively colocalizes with EX neurons not only in the EC, but also in the secondary spreading areas in AD patients and a mouse model of tauopathy. We rationalize these results by analyzing two single-nucleus RNA-seq datasets, showing that EX neurons are more likely than inhibitory (IN) neurons to be susceptible to dysregulated protein homeostasis that could impact tau accumulation (“tau homeostasis”) in healthy 40-60 years old people. Furthermore, we find that in the human brain, regions impacted by tauopathy early in the disease are more likely to be susceptible to dysregulated tau homeostasis than regions impacted later in the disease. We confirm these observations for several of the differentially expressed genes by single-molecule FISH. These results suggest that intrinsic or cell-autonomous differences in tau homeostasis signatures may contribute to the selective neuronal and regional vulnerability to tau pathology and excitatory neuronal loss that define the early stages of AD and other tauopathies. Since protein homeostasis dysfunction has long been considered to play important roles in the pathogenesis of age-related neurodegenerative diseases, we anticipate that the present tau homeostasis signature will offer key targets for therapeutic intervention." @default.
• W2897466329 created "2018-10-26" @default.
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• W2897466329 date "2018-07-01" @default.
• W2897466329 modified "2023-10-16" @default.
• W2897466329 title "O2‐01‐04: CELL TYPE–SPECIFIC TAU HOMEOSTASIS SIGNATURES ASSOCIATED WITH SELECTIVE VULNERABILITY OF EXCITATORY NEURONS TO TAU PATHOLOGY" @default.
• W2897466329 doi "https://doi.org/10.1016/j.jalz.2018.06.2642" @default.
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