A Familial Alzheimer’s Disease Associated Mutation in Presenilin-1 Mediates Amyloid-Beta Independent Cell Specific Neurodegeneration

Abstract

AbstractMutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer’s disease (fAD). An ortholog ofPSin the genetic model organismCaenorhabditis elegans (C. elegans)issel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aβ), however this hypothesis has been challenged by recent evidence. AsC. eleganslack amyloid beta (Aβ), the goal of this work was to examine Aβ-independent effects of mutations insel-12andPS1/PS2on behaviour and sensory neuron morphology across the lifespan in aC. elegansmodel. Olfactory chemotaxis experiments were conducted onsel-12(ok2078) loss-of-function mutant worms. Adultsel-12mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype insel-12mutant worms is rescued by transgenic over-expression of human wild-typePS1, but not the classic fAD-associated variantPS1C410Y, when expression was driven by either the endogenoussel-12promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6,Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation inPS1(PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time insel-12mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aβ-independent neurodegeneration inC. elegansthat was rescued by cell specific over-expression of wild-type human presenilin.