HE AUTOSOMAL RECESSIVE HYPERCHOLESTEROLEMIA (ARH) ADAPTOR PROTEIN IS A POSSIBLE LINKER BETWEEN APP PROCESSING AND CHOLESTEROL METABOLISM IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is the most common senile dementia in the world. A genetic cause has already been described with the identification of mutations in three genes, associated with familial forms of AD (FAD). One of these genes codifies for the b-Amyloid Precursor Protein (APP). APP is a transmembrane protein that undergoes a series of enzymatic cleavages, which cause the release of extracellular fragments, and a small intracellular fragment named AID. It has been recently demonstrated that AID has signaling functions, and can induce “programmed cell death”. The FAD mutations identified to date are found in APP itself, and in two highly homologous genes known as Presenilins. A common feature of all FAD mutations is that they accelerate APP processing, increasing the accumulation of peptides that are toxic to the neurons and cause the AD pathology. Several evidences indicate that there is a correlation between cholesterol metabolism and AD, but the molecular mechanisms are not clear yet. We identified a novel APP interacting protein, which is also involved in the Autosomal Recessive Hypercholesterolemia (ARH). Patients with mutations in the ARH gene have high plasma cholesterol levels and an increased risk for cardiovascular diseases, and probably for AD too. Dermal cells from an ARH patient show an alteration in the APP processing. Our data suggest that the ARH protein could represent the linker between cholesterol metabolism and AD. We propone to characterize the alteration observed in APP processing and identify the molecular interaction between ARH protein, APP and other molecules important for cholesterol pathway.