APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice

Molecular Neurodegeneration

Xiao-chun Chen²  Mary Jo LaDu³  Yuan-gui Zhu²  Leon M Tai³  Meng Zhou³  Xiao-man Dai²  Manel Ben Aissa³  Kevin P Koster³  Arron M Cole³  Nicole C Collins³  Hui Shen¹  Jing Zhang²  Xiao-dong Pan²  De-shan Liu² 

[1] Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China;Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China;Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S.Wood St., M/C 512, Chicago, 60612, IL, USA

关键词: Transgenic mice;    Signaling pathways;    Synaptic proteins;    Behavior;    Apolipoprotein E;    Alzheimer’s disease;   

Others  :  1160778
DOI  :  10.1186/s13024-015-0002-2

 received in 2014-11-26, accepted in 2015-01-26,  发布年份 2015

【 摘 要 】

Background

Alzheimer’s disease (AD) causes progressive loss of memory and cognition, exacerbated by APOE4, the greatest genetic risk factor for AD. One proposed mechanism for apolipoprotein E (apoE) effects on cognition is via NMDAR-dependent signaling. APOE genotype-specific effects on this pathway were dissected using EFAD-transgenic (Tg) mice (5xFAD mice, that over-express human amyloid-beta (Aβ) via 5 familial-AD (FAD) mutations, and express human apoE), and 5xFAD/APOE-knockout (KO) mice. Previous data from EFAD-Tg mice demonstrate age-dependent (2-6 months), apoE-specific effects on the development of Aβ pathology. This study tests the hypothesis that apoE4 impairs cognition via modulation of NMDAR-dependent signaling, specifically via a loss of function by comparison of E4FAD mice with 5xFAD/APOE-KO mice, E3FAD and E2FAD mice.

Results

Using female E2FAD, E3FAD, E4FAD and 5xFAD/APOE-KO mice aged 2-, 4-, and 6-months, the Y-maze and Morris water maze behavioral tests were combined with synaptic protein levels as markers of synaptic viability. The results demonstrate a greater age-induced deficit in cognition and reduction in PSD95, drebrin and NMDAR subunits in the E4FAD and 5xFAD/APOE-KO mice compared with E2FAD and E3FAD mice, consistent with an apoE4 loss of function. Interestingly, for NMDAR-mediated signaling, the levels of p-CaMK-II followed this same apoE-specific pattern as cognition, while the levels of p-CREB and BDNF demonstrate an apoE4 toxic gain of function: E2FAD > E3FAD > 5xFAD/APOE-KO > E4FAD.

Conclusion

These findings suggest that compared with E2FAD and E3FAD, E4FAD and 5xFAD/APOE-KO mice exhibit enhanced age-induced reductions in cognition and key synaptic proteins via down-regulation of an NMDAR signaling pathway, consistent with an apoE4 loss of function. However, levels of p-CREB and BDNF, signaling factors common to multiple pathways, suggest a gain of toxic function. Publications in this field present contradictory results as to whether APOE4 imparts a loss or gain of function. As with the results reported herein, the overall effect of APOE4 on a given CNS-specific measure will be the product of multiple overlapping mechanisms. Thus, caution remains critical in determining whether APOE gene inactivation or therapies that correct the loss of positive function related to apoE4, are the appropriate therapeutic response.

【 授权许可】

   
2015 Liu et al.; licensee BioMed Central.

【 图 表 】

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