P1‐435: Selective estrogen receptor modulators differentially regulate Alzheimer‐like neuropathology in female triple transgenic mice

(N1D and N3pE). Amino-terminal structures of deposited A s were determined by MALDI-TOF mass spectrometry. Results: None of the ADmodel mice established so far present prominent accumulation of A N3pE in the brain, but genetic deficiency of neprilysin, a potent physiological A -degrading enzyme, promotes the accumulation and increases thioflavinor [C]PIB (Pittsburgh Compound B)-positive amyloid plaques in the brain of APP tg mice, suggesting that a reduction in neprilysin activity may trigger abnormal metabolism A , in which exopeptidases, such as aminopeptidase or dipeptidyl peptidase, and glutamyl cyclase may be involved, thus generating A N3pE. Given that neprilysin in the hippocampus and cerebral cortex is actually down-regulated from an early stage of AD development, our results appear to corroborate observation that A N3pE is generated and accumulated in the AD brains. Conclusions: A N3pE is more resistant to proteolytic degradation (4-fold) as proven by in vivo experiments tracing the catabolism of radiolabeled A variants in brain, and is more easily self-aggregated (250-fold) than amino-terminally intact A . Recently it has been reported that administration of a glutamyl cyclase inhibitor to AD-model mice not only suppresses the formation of A N3pE, but also decreases the total amount of amyloid in the brain. Thus, A N3pE may be a seed, and co-aggregate with other A species, thereby promoting the formation of amyloid plaque. Therefore, inhibition of A N3pE formation appears to be a novel target for therapy and prevention of AD.