Project 3:
Cholesterol, Caffeine and Alzheimer Disease-like Pathology in Rabbit Brain
Investigator: Dr. Othman Ghribi

Alzheimer’s disease (AD) is a complex and devastating neurodegenerative disorder with no known cause and for which there are limited therapeutic interventions. Pathophysiologically, AD has been linked to accumulation of ß-amyloid (Aß) peptide, hyperphosphorylated tau, and oxidative stress. Accumulation of Aß may be particularly important because mutations in genes for the amyloid precursor protein and the presenilins, as occurs in early onset familial forms of AD, cause Aß accumulation. While these genetic mutations are responsible for the accumulation of Aß in familial AD, the causative factors for the accumulation of Aß in sporadic forms of AD are not known. This raises the possibility that Aß accumulation in the absence of genetic mutations might result from factors that increase Aß production or decrease its clearance. Hypercholesterolemia is one such factor others and we have demonstrated to increase Aß accumulation. We have further demonstrated that hypercholesterolemia causes tau hyperphosphorylation and oxidative damage, two important pathological hallmarks of AD. Caffeine, the most commonly ingested psychoactive drug in the world, has been shown by other and us to dose-dependently increase and decrease the production of Aß peptide as well as increase and decrease Aß-induced cell death in vitro. In humans, the risk of developing AD has been reported to be lower in individuals with elevated levels of plasma caffeine. While caffeine-induced over-production of Aß may be due to its facilitatory effect on Ca²⁺ release from the endoplasmic reticulum (ER) through ryanodine receptors (RyR), caffeine-induced protection against Aß effects may be due to blockade of adenosine A_2A receptors (A_2AR). Caffeine may further prevent Aß accumulation and lower the risk of AD in humans through its ability to inhibit Ca²⁺ release from ER through blockade of the inositol-1,4,5-trisphosphate receptors (IP₃R). Our preliminary findings demonstrated that hypercholesterolemia causes an increase in RyR and A_2AR protein levels, and that caffeine, dose-dependently, modulates levels of these receptors. Published findings together with these results suggest that caffeine has both protective and destructive actions directly related to AD pathogenesis. The objective of this proposal is to determine, in a cholesterol-fed rabbit model of sporadic AD, the extent to which and the mechanisms by which caffeine will exacerbate or attenuate Aß accumulation and neuronal damage in brain. The affinity of A_2AR for caffeine is much higher than is the affinity of RyR for caffeine and the affinity of RyR for caffeine is higher than is the affinity of IP₃R for caffeine. Our hypothesis is that caffeine-induced blockade of A_2AR or blockade of Ca²⁺ release through IP₃R will attenuate and caffeine-induced release of Ca²⁺ from RyR-regulated Ca²⁺ channels will exacerbate Aß accumulation and neurodegeneration. The mechanisms by which cholesterol or caffeine cause or protect against cellular damage characteristic of AD are not known. Our rationale for this project is that its successful completion may reveal signaling mechanisms that underlie diet-induced AD pathology. Understanding these mechanisms may help in understanding better the pathogenesis of AD and ultimately may lead to designing strategies that prevent or slow the progression of sporadic forms of this devastating neurodegenerative disorder.