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 β-peptide (Aβ). Aβ is generated by proteolytic processing of the β-amyloid precursor protein (βAPP) involving the combined action of β- and γ-secretase. Cleavage within the Aβ domain by α-secretase prevents Aβ generation. In some very rare cases of familial AD (FAD), mutations have been identified within the βAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect βAPP processing by increasing Aβ production, specifically its highly amyloidogenic 42 amino acid variant (Aβ42). 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 βAPP gene, mutations in PS1 and PS2 cause the increased generation of Aβ42. PS1 has been shown to be functionally involved in Notch signaling, a key process in cellular differentation, and in βAPP 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 γ-secretase cleavage and leads to an accumulation of βAPP C-terminal fragments and decreased amounts of Aβ. Recent work may suggest that PS1 could be the γ-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 Aβ production as observed in the PS1 knockout. A corresponding mutation in PS2 interfered with βAPP processing and Notch signaling suggesting a functional redundancy of both presenilins. In this issue, some of the recent work on the molecular mechanisms involved in Alzheimer's disease (AD) as well as novel diagnostic approaches and risk factors for AD will be discussed. In the first article, we like to give an overview on mechanisms involved in the proteolytic generation of Amyloid β-peptide (Aβ), the major pathological player of this devastating disease. In the second part of this article recent results will be described, which demonstrate an unexpected biological and pathological function of an AD associated gene.