NPD1 and DHA are reduced in AD brain. (A) When compared with age-matched controls, NPD1 and unesterified DHA were significantly reduced in AD hippocampus (HIP) and temporal lobe (TEM) but not in the thalamus (THA) or occipital lobe (OCC) of the same AD brains. In AD, thalamic and occipital regions were relatively spared AD neuropathology. Signals for NPD1 and unesterified DHA in AD hippocampus averaged about one-twentieth and one-half, respectively, of those values seen in age-matched controls. LC-PDA-ESI-MS-MS–based lipidomic analysis (sensitivity 0.05 pmol/mg total protein). n = 6. *P < 0.01 (ANOVA). (B) Characterization of NPD1 using LC-PDA-ESI-MS-MS–based lipidomic analysis (5, 6). (C) Mass spectrographic identification of 10,17S-docosatriene (NPD1) in human hippocampus. (D) Proposed biosynthetic pathways from DHA to NPD1 and bioactivity. DHA is highly enriched as an acyl side chain of brain and retinal membrane phospholipids, suggesting its importance as an essential component of brain and retinal function (2, 29). Esterified DHA is liberated by PLA₂ action upon membrane phospholipids, whereupon it is oxygenated, initially via a 15-LOX–like enzyme, into 10,17S-docosatriene (NPD1). sAPPα, a secreted neurotrophic peptide, stimulates NPD1 biosynthesis. NPD1 exhibits neuroprotective activity against Aβ42 action, represses apoptosis, and promotes the expression of antiapoptotic genes encoding Bcl-2 and Bfl-1(A1) (37).