Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells

Abstract

Mutations in two recently identified genes appear to cause the majority of early-onset familial Alzheimer's disease (FAD). These two novel genes, presenilin 1 (PS1) and presenilin 2 (PS2) are members of an evolutionarily conserved gene family. The normal biological role(s) of the presenilins and the mechanism(s) by which the FAD-associated mutations exert their effect remain unknown. Employing in situ hybridization, we demonstrate that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations. Immunochemical analyses indicate that PS1 and PS2 are similar in size and localized to similar intracellular compartments (endoplasmic reticulum and Golgi complex). FAD-associated mutations in PS1 and PS2 do not significantly modify either their migration patterns on SDS-polyacrylamide gel electrophoresis or their overall subcellular localization, although subtle differences in perinuclear staining were noted for mutant PS1.

Immunohistochemical analysis of presenilin‐1 expression in the mouse brain

“…PS-1 immunostaining is localized intracellularly as recently described in transfected cells by Kovacs et al [11]. PS-1 immunostaining appears as thick granules resembling vesicles located mainly at the periphery of cell bodies, and occasionally around the nucleus.…”

Gene expression of Alzheimer‐associated presenilin‐2 in the frontal cortex of Alzheimer and aged control brain

“…First, message for PS2 showed a laminar distribution in cerebral cortex and was primarily detectable in neurons. This result is consistent with previous reports from normal human temporal lobes for PS2 expression visualized by radioactive hybridization [17] and is also comparable with PS1 expression pattern in murine brain observed using non-radioactive hybridization and immunohistochemistry [14,18]. Second, stronger hybridization signal was found in large neurons while mild or weak signal appeared in small neurons.…”

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

“…Affinity-purified 28 kDa products showed no reactivity with 2 polyclonal antisera directed against the first part of the large hydrophilic loop and the carboxyl-terminus of PSI. It is unlikely that the 28 kDa product we observed is the truncated form, presenilin 1-374, that was recently described [22], since presenilin 1-374 is not expressed in brain. In addition, the absence of reactivity with our polyclonal antiserum PSI-M, directed against the loop region, also indicates that 28 kDa is different from presenilin 1-374.…”

“…The converging mechanisms that lead different genotypes to similar Alzheimer's disease pathology may therefore all include presenilins in their pathway. A recent study showed, by using in situ hybridization techniques, that presenilin expression in brain is almost exclusively restricted to neuronal populations [22]. In vitro translation and transfection experiments in that study have shown that recombinant FLAG-tagged proteins of PS1 and PS2 appear in SDS-PAGE at approximate Mr 50 000 but no differences were observed in the migration patterns for wild-type or mutant proteins.…”