EFFECTS OF PRESENILIN 1 MUTATIONS ON THE BETA-SECRETASE CLEAVAGE OF BETA-AMYLOID PRECURSOR PROTEIN AND ON GENE EXPRESSION. THE SUBSTRATE OF THE PHENOTYPIC HETEROGENEITY OF FAMILIAL ALZHEIMER’S DISEASE

Familial early-onset Alzheimer’s disease (FAD) caused by mutations of presenilin 1 gene is heterogeneous in term of presentation, symptoms, and distribution of brain lesions. Presenilin 1 is the major co-factor of the gamma-secretase, the cellular enzyme that cleaves the beta-amyloid peptide from its precursor. The common biological effect of presenilin 1 mutations is the increased production of beta-amyloid (Abeta) 42, the Abeta variant that accumulates in the brain of patients with Alzheimer’s disease and exerts a toxic effect on neurons. The increased production of Abeta42 alone cannot explain the wide spectrum of the clinical features expressed by presenilin 1 mutations. On the basis of our previous studies, we have speculated that presenilin 1 mutations may alter not only the gamma-secretase, but also the activity of the beta-secretase, the other enzyme that allows the cleavage of Abeta from the precursor. Our project aims to investigate the effect of presenilin 1 mutations on the expression of the beta-secretase, and to understand the mechanisms that mediate this event. The study will extend the understanding of genetically determined AD. More important, it will shed light on the mechanisms of Abeta production.