Presenilin function in APP processing.

Familial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD), and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins.