Genes and mechanisms involved in β-amyloid generation and Alzheimer's disease

Alzheimer's disease is characterized by the invariable accumulation of senile plaques that are predominantly composed of amyloid beta-peptide (AP). A beta is generated by proteolytic processing of the beta-amyloid precursor protein (beta APP) involving the combined action of beta- and gamma-secretase. Cleavage within the A beta domain by alpha-secretase prevents A beta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the beta APP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect beta APP processing by increasing A beta production, specifically its highly amyloidogenic 42 amino acid variant (A beta 42). Most of the mutations associated with FAD have been identified in the two presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the beta APP gene, mutations in PS1 and PS2 cause the increased generation of A beta 42, PS1 has been shown to be functionally involved in Notch signaling, a key process in cellular differentation, and in beta APP processing. A gene knock out of PS1 in mice leads to an embryonic lethal phenotype similar to that of mice lacking Notch. In addition, absence of PS1 results in reduced gamma-secretase cleavage and leads to an accumulation of beta APP C-terminal fragments and decreased amounts of A beta. Recent work may suggest that PS1 could be the gamma-secretase itself, exhibiting the properties of a novel aspartyl protease. Mutagenesis of either of two highly conserved intramembraneous aspartate residues of PS1 leads to reduced A beta production as observed in the PS1 knockout. A corresponding mutation in PS2 interfered with beta APP processing and Notch signaling suggesting a functional redundancy of both presenilins.