Browsing by Subject "Amyloid beta-Protein Precursor"
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Item Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan(2011-08-10) Warren, Rebekkah Lynn; Russell, David W.In vitro alterations in cellular cholesterol content or synthesis affect the cleavage of amyloid precursor protein (APP) to amyloidogenic peptides characteristic of Alzheimer’s disease (AD). To determine whether a decrease in cholesterol synthesis would affect APP processing in vivo, we crossed cholesterol 24-hydroxylase knockout (KO) mice, which exhibit a 50 percent reduction in sterol synthesis, with transgenic mice (B6.Cg-Tg(APPswe, PSEN1E9)85Dbo/J) that develop AD and followed progression of the disease and lipid metabolism in the offspring. APP expression and amyloid plaque deposition in the cortex and hippocampus of 3- to 15-month-old male and female AD mice were similar in the presence and absence of cholesterol 24-hydroxylase. At 15 months of age, a modest but statistically significant decline in insoluble A-beta 40 and A-beta 42 peptide levels was detected in the hippocampus but not cortex of KO/AD mice versus WT/AD mice. Amyloid plaque accumulation did not affect brain sterol or fatty acid synthesis rates in 24-hydroxylase WT or KO mice. Unexpectedly, loss of one or two 24-hydroxylase alleles increased longevity in AD mice. These studies suggest that reducing de novo cholesterol synthesis in the brain will not substantially alter the course of AD, but may confer a survival advantage.Item Studying Physiological Functions of APP Using Mice Models(2008-09-18) Li, Hongmei; Südhof, Thomas C.Beta-amyloid precursor protein (APP) is sequentially cleaved by alpha /beta - secrease and gamma-secrease into three pieces: a soluble ectodomain (sAPPalpha or sAPPbeta ), a p3 or Abeta peptide, and an APP intracellular domain (AICD). Mounting evidence indicates the neuroprotective and neurotrophic effects of sAPP domain. In order to find out whether sAPP domain carries out the major physiological function of APP, we have generated knock-in mice that express truncated ectodomain of APP at beta-cleavage site (sAPPbeta ) with FLAG tag at C-terminus. The knock-in mice were viable and fertile, with no obvious phenotype. However, when sAPPbeta - FLAG knock-in mice were bred to APLP2 knockout background ("knockin/ knockout" mice), the expression of sAPPbeta -FLAG failed to fully rescue the postnatal lethal phenotype of APP/APLP2 double knockout pups, suggesting sAPPbeta alone cannot substitute for the function of full length APP. We quantified the expression levels of a series of synaptic proteins and AICD-interacting proteins in the brains of new born APP/APLP2 double knockout (DKO) pubs, as well as in the "knock-in/knockout" (KI/KO) pubs, and found that Fe65 protein expression level is upregulated in brains from DKO pubs but not the KI/KO pubs. Collaborating with Dr. Yi Sun's lab investigating the DNA sequences in genome that potentially bind to AICD binding partners has shown that various promoters of a broad set of genes can bind to Fe65 and their expressions might be influenced by Fe65/AICD.