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

Alzheimer's disease is characterized by the invariable accumulation of seni le plaques that are predominantly composed of amyloid beta-peptide (AP). A beta is generated by proteolytic processing of the beta-amyloid precursor p rotein (beta APP) involving the combined action of beta- and gamma-secretas e. Cleavage within the A beta domain by alpha-secretase prevents A beta gen eration. In some very rare cases of familial AD (FAD), mutations have been identified within the beta APP gene. These mutations are located close to o r at the cleavage sites of the secretases and pathologically effect beta AP P processing by increasing A beta production, specifically its highly amylo idogenic 42 amino acid variant (A beta 42). Most of the mutations associate d with FAD have been identified in the two presenilin (PS) genes, particula rly the PS1 gene. Like the mutations identified within the beta APP gene, m utations in PS1 and PS2 cause the increased generation of A beta 42, PS1 ha s 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-secret ase 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 p rotease. Mutagenesis of either of two highly conserved intramembraneous asp artate residues of PS1 leads to reduced A beta production as observed in th e PS1 knockout. A corresponding mutation in PS2 interfered with beta APP pr ocessing and Notch signaling suggesting a functional redundancy of both pre senilins.