• Alzheimer's disease

Two forms of early-onset familial Alzheimer disease are associated with presenilin genes in human: PSEN1 is implicated in Alzheimer disease 3 (AD3, FBhh0000120) and PSEN2 is implicated in Alzheimer disease 4 (AD4, FBhh0000121). Both AD3 and AD4 exhibit autosomal dominant inheritance. There is a single presenilin in Drosophila, Dmel\Psn, for which classical hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.

Presenilin is the catalytic component of the gamma-secretase complex. Gamma-secretases (γ-secretases) are transmembrane multiprotein complex comprised of presenilin (PSEN1 or PSEN2), nicastrin (NCSTN), PSENEN, and APH1 (APH1A or APH1B); gamma-secretases are responsible for intramembrane proteolytic cleavage of amyloid precursor protein (APP) and NOTCH receptor proteins. See also the human disease model report 'Alzheimer disease, susceptibility to (postulated), NCSTN-related' (FBhh0000836).

Multiple different UAS constructs of both human genes, Hsap\PSEN1 and Hsap\PSEN2 have been introduced into flies, including wild-type and genes carrying mutational lesions implicated in Alzheimer disease. They have been characterized for interactions using a fly model of Alzheimer disease 1 (FBhh0000119).

In flies, it appears that levels of expression of Dmel\Psn need to be within a precise range: homozygous loss-of-function mutations in the Psn gene are lethal; heterozygous animals develop age-related cognitive defects; overexpression of wild-type Psn is also deleterious. RNAi-effected knockdown of Psn in selected neurons of the adult brain results in shortened lifespan, climbing defects, increases in apoptosis, and age-dependent neurodegeneration; similar phenotypes are observed for RNAi-effected knockdown of Nct in comparable experiments. Physical and genetic interaction(s) of Dmel\Psn have been described; see below and in the gene report for Psn.

[updated Jul. 2018 by FlyBase; FBrf0222196]