High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice.
High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice.
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DOI：
10.1111/j.1471-4159.2008.05415.x
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发表时间：
2008-07
影响因子：
4.7
通讯作者：
Bhat NR
中科院分区：
文献类型：
--
作者：
Thirumangalakudi L;Prakasam A;Zhang R;Bimonte-Nelson H;Sambamurti K;Kindy MS;Bhat NR
Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer’s disease (AD)-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of AD pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory (WM) load compared to counterparts receiving a control diet while the hypercholesterolemic LDLR−/− mice showed impaired WM regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR−/− mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including TNFα, IL-1β, IL-6, NOS2 and COX2. There was also an induced expression of the key APP processing enzyme i.e., BACE1 in both high fat/cholesterol-fed C57BL/6 and LDLR−/− mice accompanied by an increased generation of C-terminal fragments (CTFs) of APP. Although ELISA for Aβ failed to record significant changes in the non-transgenic mice, a 3-fold increase in Aβ-40 accumulation was apparent in a strain of transgenic mice expressing wt hAPP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.
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DOI：
10.1083/jcb.200207113
发表时间：
2003-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ehehalt R;Keller P;Haass C;Thiele C;Simons K
通讯作者：
Simons K
影响因子：
2.7
作者：
Hunter, CL;Bimonte, HA;Granholm, ACE
通讯作者：
Granholm, ACE
影响因子：
1.7
作者：
Frears, ER;Stephens, DJ;Austen, BM
通讯作者：
Austen, BM
影响因子：
4.7
作者：
Elder, Gregory A.;Cho, Julie Y.;Buxbaum, Joseph D.
通讯作者：
Buxbaum, Joseph D.
影响因子：
6.5
作者：
Buga, Georgette M.;Frank, Joy S.;Fogelman, Alan M.
通讯作者：
Fogelman, Alan M.