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P2‐331: Knockout of P75NTR Ligand‐Binding Domain Decreases the Hyperphosphorylation of TAU in P301L Mice Model
Author(s) -
Manucat-Tan Noralyn Basco,
Bobrovskaya Larisa,
Wang Yan-Jiang,
Zhou Xin Fu
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1461
Subject(s) - hyperphosphorylation , morris water navigation task , phosphorylation , cyclin dependent kinase 5 , tauopathy , hippocampus , tau protein , neun , biology , microbiology and biotechnology , neuroscience , chemistry , neurodegeneration , medicine , alzheimer's disease , immunohistochemistry , immunology , protein kinase a , mitogen activated protein kinase kinase , disease
Background:Women with apoE4 allele show a higher vulnerability to AD than men with the same apoE4 allele and the mechanisms are not fully understood. Methods: We evaluated the sex-dependent ApoE4 effects on learning and memory using the radial arm water maze and novel arm discrimination tests, Ab deposition and potential mechanisms, in mice bearing both sporadic (ApoE4) and familial (APPSwe, PS1M146V, tauP301L; 3xTg) risk factors and compared with sexand age-matched 3xTg or nonTg mice at different ages. Results: All transgenic mice of both sexes showed spatial learning andmemory deficits vs. non-Tg controls.However, significant learning andmemory impairment at much younger age was only noted in ApoE4/3xTg females. In these femaleApoE4/3xTgmice,wealsoobservedhigher protein levels of Ab species, b-site APP cleavage enzyme (BACE1) and Sp1, a transcription factor of BACE1, than female nonTg, female 3xTg and male ApoE4/3xTg mice. More interestingly, higher BACE1 enzymatic activity was observed in both male and female mice carrying ApoE4, while significant higher BACE1 expression was observed only in females. These data indicate that apoE4 plays a role on the increase of BACE1 enzymatic activity, and female sex increasesBACE1expression.Conclusions:The increase of BACE1 activity by apoE4 and a high level of BACE1 expression in females may help to explain the ApoE4 related high Ab deposition and consequent hippocampal-dependent learning and memory deficits in females.