S2‐02‐04: Phospholipase D3 contributes to Alzheimer's disease risk via disruption in app trafficking and Aβ generation

• DOI: 10.1016/j.jalz.2015.07.106
• Publication Date: 2015-12-15T10:31:35Z
• Authors: Celeste Karch; Simon Hsu; Lubov Ezerskiy; Rita Martinez; Joanne Norton; Carlos Cruchaga; Alison M. Goate
• Keywords: PSEN1; Pathogenesis

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in brain. Rare mutations APP, PSEN1, and PSEN2 have contributed to our understanding APP processing AD pathogenesis. APOE4 a major risk factor for late onset (LOAD) that produces genotype-specific differences Aβ clearance rates, illustrating value studying variants understand We recently identified several coding phospholipase D3 (PLD3) gene double LOAD. While normal function PLD3 poorly understood, highly expressed neurons regions brain are most susceptible pathology. used immortalized cell models induced pluripotent stem (iPSC) study effects on metabolism using molecular biochemical assays. found overexpression cells decreases extracellular levels while shRNA silencing increases levels. Overexpression also produced significant reduction cell-surface Holo-APP. variants, M6R V232M, accelerated turnover. Inhibition lysosomal rescued effect synonymous variant (A442A) was predicted modify splicing enhancer binding site disrupting recognition such reduced. confirmed these findings human tissue carrying A442A. Human fibroblasts were obtained from PLD3A442A carrier, reprogrammed into iPSCs subsequently differentiated neural progenitor cells. These displayed similar deficit as observed difference compared with unrelated control lines. Together, demonstrate plays an important role trafficking generation. By defining precise mechanisms which regulate we will gain novel insights underlying facilitate identification therapeutic targets this devastating disease.