Recent studies have shown that increased levels of Ab peptides are among the earliest detectable abnormalities in Alzheimer's disease and may mediate a chain of downstream events leading to neuronal degeneration and cognitive decline. There is increasing evidence from clinical, epidemiological and laboratory studies that cholesterol plays a role in the pathogenesis of Alzheimer's disease. This body of evidence includes in vitro studies indicating that cellular cholesterol levels modulate Ab production and the enzymatic processing of APP, animal studies demonstrating that cholesterol levels modulate Ab accumulation in the brain (preliminary data) and several observational, clinical studies suggesting that the prevalence and incidence of probable Alzheimer's disease was significantly lower in patients taking cholesterol-lowering drugs. Taken together the studies support the hypothesis that Alzheimer's disease may be a disease in which cholesterol homeostasis is altered and that cholesterol may participate in a chain of events that modulate the disease neuropathology. The application proposes to test the following hypotheses: 1-that in the human brain increased cholesterol content contributes to amyloid accumulation by changing APP processing in a more amyloidogenic manner. 2-that there are correlative interactions between levels of apoE expression, cholesterolemia and amyloid pathology. 3-that certain apoE promoter polymorphisms act in concert with cholesterol levels influencing the extent of apoE expression and amyloid accumulation. Preliminary and recently published data from our laboratory suggest that cholesterol content in plasma and brain of Alzheimer's transgenic mice is strongly correlated with rate of development of amyloid pathology and with apoE expression. These hypotheses are amenable to testing as outlined in the corresponding sections of the proposal and their study will advance our understanding of the pathogenesis of Alzheimer's disease.
| Baranello, Robert J; Bharani, Krishna L; Padmaraju, Vasudevaraju et al. (2015) Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease. Curr Alzheimer Res 12:32-46 |
| Pappolla, Miguel; Sambamurti, Kumar; Vidal, Ruben et al. (2014) Evidence for lymphatic A? clearance in Alzheimer's transgenic mice. Neurobiol Dis 71:215-9 |
| Greig, Nigel H; Tweedie, David; Rachmany, Lital et al. (2014) Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury. Alzheimers Dement 10:S62-75 |
| Ablonczy, Zsolt; Dahrouj, Mohammad; Tang, Peter H et al. (2011) Human retinal pigment epithelium cells as functional models for the RPE in vivo. Invest Ophthalmol Vis Sci 52:8614-20 |
| Sambamurti, Kumar; Greig, Nigel H; Utsuki, Tadanobu et al. (2011) Targets for AD treatment: conflicting messages from ?-secretase inhibitors. J Neurochem 117:359-74 |
| Ramesh, Balenahalli N; Rao, T S Sathyanarayana; Prakasam, Annamalai et al. (2010) Neuronutrition and Alzheimer's disease. J Alzheimers Dis 19:1123-39 |
| Zambon, Daniel; Quintana, Melibea; Mata, Pedro et al. (2010) Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med 123:267-74 |
| Li, Yazhou; Duffy, Kara B; Ottinger, Mary Ann et al. (2010) GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. J Alzheimers Dis 19:1205-19 |
| Poeggeler, Burkhard; Sambamurti, Kumar; Siedlak, Sandra L et al. (2010) A novel endogenous indole protects rodent mitochondria and extends rotifer lifespan. PLoS One 5:e10206 |
| Sambamurti, Kumar; Pappolla, Miguel A; Jagannatha Rao, K S (2008) Value in development of a TAPIR-like mouse monoclonal antibody to Abeta. J Alzheimers Dis 14:175-7 |
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