Abstract
Intracellular accumulation of abnormally phosphorylated tau in different types of neurons is a pathological characteristic of Alzheimer’s disease (AD). While tau modification and associated neuronal loss and hypometabolism start in the entorhinal cortex (EC) in early AD patients, the mechanism by which mutant P301L hTau leads to dementia is not fully elucidated. Here, we studied the effects of P301L hTau transduction in the medial EC (MEC) of mice on tau phosphorylation and accumulation, and cognitive deficit. We found that the exogenous mutant tau protein was restricted in MEC without spreading to other brain regions at one month after transduction. Interestingly, expression of the mutant tau in MEC induces endogenous tau hyperphosphorylation and accumulation in hippocampus and cortex, and inhibits neuronal activity with attenuated PP-DG synapse plasticity, leading to hippocampus-dependent memory deficit with intact olfactory function. These findings suggest a novel neuropathological mechanism of early AD, which is initiated by tau accumulation in MEC, and demonstrate a tau pathological model of early stage AD.
Highlights
The tauopathies, which characterized by hyperphosphorylation and aggregation of tau, are found in various neurodegenerative disorders such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17), Pick’s disease, and Alzheimer’s disease (AD)[1,2,3]
Injection of the same volume of Recombinant adeno-associated virus (rAAV)-GFP vector was used as control and the mice were sacrificed one month later to confirm the expression of tau protein
We found that autofluorescence showing a restriction of target protein expression in medial EC (MEC) and its projection fibers to the middle molecular layer of hippocampal dentate gyrus (DG) ((B) vector; (D) P301L, arrows point cell bodies) one month after transduction via rAAV delivery, while no GFP was observed in the granular layer of the dentate gyrus, which is outlined with a white dotted line
Summary
The tauopathies, which characterized by hyperphosphorylation and aggregation of tau, are found in various neurodegenerative disorders such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17), Pick’s disease, and Alzheimer’s disease (AD)[1,2,3]. In patients with AD, abnormal tau proteins are preferentially deposited in vulnerable brain regions, initially in entorhinal cortex (EC) and followed by the hippocampus, which is essential for learning and memory formation[5]. It remains controversial whether expression of human P301L mutant Tau (P301L hTau) in EC could lead to amnesia. We investigated the toxic effects of MEC expression of P301L hTau on hippocampus-dependent spatial memory and the neuronal activity. We found that expression of P301L hTau in MEC for a month induced hippocampal tau hyperphosphorylation and suppressed neuronal activity, resulting in impaired hippocampus-dependent memory with intact olfactory functions
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