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Presenilin 1 (PS1) forms the γ-secretase complex with at least three components: nicastrin, APH-1, and PEN-2. This complex mediates intramembrane cleavage of amyloid precursor protein (APP) to generate β-amyloid protein (Aβ) as well as other type 1 transmembrane proteins. Although PS1 mutations linked to familial Alzheimer's disease influence these cleavages, their biological consequences have not been fully understood. In this study, we used mRNA differential display analysis to identify a gene, denoted adoplin-1/ORMDL-1, which displays significantly reduced expression in association with PS1 mutations. Adoplin-1 and two highly homologous genes (adoplin-2,-3) constitute a gene family that encodes transmembrane proteins. The mRNA and protein levels of adoplins (particularly adoplin-1, -2) were markedly elevated in PS-deficient fibroblasts, compared to wild-type cells. Moreover, knockdown of the three adoplins by RNA interference affected maturation of nicastrin and its association with PS1. Adoplin knockdown additionally resulted in elevated levels of APP C-terminal fragments and decreased A[3 production, suggestive of reduced γ-secretase activity. Our data collectively indicate that adoplins are unique molecules with PS-related expression and functions that may play important role(s) in the maturation and activity of the γ-secretase complex. [ABSTRACT FROM AUTHOR]

Presents a study which investigated the mechanisms of PHF-1 hyperphosphorylation of tau with a FTDP17 mutation R406W that causes Alzheimer disease-like dementia and taupathy in humans but has a unique ability to reduce tau phosphorylation at the PHF-1 site in vitro and in cultured cells. Inhibition of tau phosphorylation at Ser404 by the R406W mutation; Involvement of JNK in the phosphorylation of R406W tau at the PHF-1 site.

Presents a study which determined the role of the intracellular amyloid β-protein 42 (Aβ42) and p53 expression in Alzheimer's disease (AD) pathology. Cytosolic Aβ42 expression and induction of p53-dependent apoptosis; Direct binding of Aβ42 to p53 promoter and activation of promoter activity; Intracellular Aβ42 accumulation and p53 expression in degenerating neurons in AD brain.

Deals with a study which explored the role of Aβ binding heparan sulfate proteoglycans (HSPG) in the human brain. Identification of glypican-1 as an Aβ binding HSPG; Role of glypican-1 in Aβ42 accumulation; Effect of glypican-1 overexpression on cell viability.