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

C Czech, G Tremp, L Pradier
Progress in Neurobiology 2000, 60 (4): 363-84
Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. Dementia is associated with massive accumulation of fibrillary aggregates in various cortical and subcortical regions of the brain. These aggregates appear intracellularly as neurofibrillary tangles, extracellularly as amyloid plaques and perivascular amyloid in cerebral blood vessels. The causative factors in AD etiology implicate both, genetic and environmental factors. The large majority of early-onset familial Alzheimer's disease (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 multiple transmembrane regions. Presenilins show a high degree of conservation between species and a presenilin homologue with definite conservation of the hydrophobic structure has been identified even in the plant Arabidopsis thaliana. More than 50 missense mutations in PS1 and two missense mutations 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 amyloidogenic form 1-42 of Abeta (Abeta42). In this regard, the physical interaction between APP and presenilins in the endoplasmic reticulum has been demonstrated and might play a key role in Abeta42 production. It was hypothesized that PS1 might directly cleave APP. However, extracellular amyloidogenesis and Abeta production might not be the sole factor involved in AD pathology and several lines of evidence support a role of apoptosis in the massive neuronal loss observed. Presenilins were shown to modify the apoptotic response in several cellular systems including primary neuronal cultures. Some evidence is accumulating which points towards the beta-catenin signaling pathways to be causally involved in presenilin mediated cell death. Increased degradation of beta-catenin has been shown in brain of AD patients with PS1 mutations and reduced beta-catenin signaling increased neuronal vulnerability to apoptosis in cell culture models. The study of presenilin physiological 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 identification of novel drug targets for the treatment of AD.

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