Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms

Alzheimer's disease (AD) is the most common cause of dementia in the elderl y population. Dementia is associated with massive accumulation of fibrillar y aggregates in various cortical and subcortical regions of the brain. Thes e aggregates appear intracellularly as neurofibrillary tangles, extracellul arly as amyloid plaques and perivascular amyloid in cerebral blood vessels. The causative factors in AD etiology implicate both, genetic and environme ntal factors. The large majority of early-onset familial Alzheimer's diseas e (FAD) cases are linked to mutations in the genes coding for presenilin 1 (PS1) and presenilin 2 (PS2). The corresponding proteins are 467 (PS1) and 448 (PS2) amino-acids long, respectively. Both are membrane proteins with m ultiple transmembrane regions. Presenilins show a high degree of conservati on between species and a presenilin homologue with definite conservation of the hydrophobic structure has been identified even in the plant Arabidopsi s thaliana. More than 50 missense mutations in PS1 and two missense mutatio ns in PS2 were identified which are causative for FAD. PS mutations lead to the same functional consequence as mutations on amyloid precursor protein (APP), altering the processing of APP towards the release of the more amylo idogenic form 1-42 of A beta (A beta 42). In this regard, the physical inte raction between APP and presenilins in the endoplasmic reticulum has been d emonstrated and might play a key role in A beta 42 production. It was hypot hesized that PS1 might directly cleave APP. However, extracellular amyloido genesis and A beta production might not be the sole factor involved in AD p athology and several lines of evidence support a role of apoptosis in the m assive neuronal loss observed. Presenilins were shown to modify the apoptot ic response in several cellular systems including primary neuronal cultures . Some evidence is accumulating which points towards the beta-catenin signa ling pathways to be causally involved in presenilin mediated cell death. In creased degradation of beta-catenin has been shown in brain of AD patients with PS1 mutations and reduced beta-catenin signaling increased neuronal vu lnerability to apoptosis in cell culture models. The study of presenilin ph ysiological functions and the pathological mechanisms underlying their role in pathogenesis clearly advanced our understanding of cellular mechanisms underlying the neuronal cell death and will contribute to the identificatio n of novel drug targets for the treatment of AD. (C) 2000 Elsevier Science Ltd. All rights reserved.