Chen Zhang, PhD

Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer’s disease (FAD). Studies in cell-free biochemical systems, cell culture, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing g-secretase activity. Mouse genetic analysis and Drosophila studies demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, the molecular mechanisms by which PS protects neurons during aging remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila Psn model that exhibits age-dependent neurodegeneration and increases apoptosis. Following a bioinformatic analysis, we tested the top ranked 25 candidate genes by selective knockdown (KD) of each gene expression in adult neurons using two independent RNAi lines. Interestingly, neuron-specific KD of lipophorin receptors (LpR1 or LpR2) results in neurodegeneration and worsens Psn KD phenotypes. Furthermore, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 also lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that proteins involved in lipid transport and metabolism, such as LpRs, modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.