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Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit
Xinghua Liu1,2, Kuan Zeng1, Mengzhu Li1
1Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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.
Insights
Mutant tau in the medial entorhinal cortex (MEC) triggers widespread tau pathology and memory deficits in Alzheimer's disease (AD) models. This study reveals a new mechanism for early AD initiation and progression.
Area of Science:
- Neuroscience
- Pathology
- Molecular Biology
Background:
- Alzheimer's disease (AD) is characterized by abnormal tau protein accumulation.
- Early AD pathology, including tau modification and neuronal dysfunction, begins in the entorhinal cortex (EC).
- The precise mechanism linking mutant tau (P301L hTau) to dementia remains unclear.
Purpose of the Study:
- To investigate the effects of P301L hTau in the medial EC (MEC) of mice.
- To analyze tau phosphorylation, accumulation, and cognitive deficits following MEC transduction.
- To elucidate the neuropathological mechanisms underlying early-stage AD.
Main Methods:
- Transduction of mutant P301L human tau (hTau) in the medial entorhinal cortex (MEC) of mice.
- Analysis of tau phosphorylation and accumulation in different brain regions.
- Assessment of neuronal activity, synaptic plasticity (PP-DG), and cognitive function (hippocampus-dependent memory).
Main Results:
- Exogenous mutant tau remained localized in the MEC one month post-transduction.
- Mutant tau expression in MEC induced endogenous tau hyperphosphorylation and accumulation in the hippocampus and cortex.
- Neuronal activity was inhibited, leading to impaired PP-DG synapse plasticity and hippocampus-dependent memory deficits.
- Olfactory function remained intact.
Conclusions:
- Tau accumulation in the MEC initiates a cascade of tau pathology in connected brain regions.
- This study proposes a novel neuropathological mechanism for early Alzheimer's disease.
- The findings establish a valuable tau pathological model for studying early-stage AD.
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