HIGH CHOLESTEROL-INDUCED NEUROINFLAMMATION AND AMYLOID PRECURSOR PROTEIN PROCESSING CORRELATE WITH LOSS OF WORKING MEMORY IN MICE.
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Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR.
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
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 TNFalpha, IL-1beta, 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 Abeta failed to record significant changes in the non-transgenic mice, a 3-fold increase in Abeta-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.
PMID: 18410513 [PubMed - as supplied by publisher]
PubMed ID and Record
Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR.
Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
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 TNFalpha, IL-1beta, 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 Abeta failed to record significant changes in the non-transgenic mice, a 3-fold increase in Abeta-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.
PMID: 18410513 [PubMed - as supplied by publisher]
PubMed ID and Record
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