Premium
P1‐277: Genetic targeting female hormone synthesizing enzyme aromatase in male amyloid precursor protein (APP) transgenic mice prevents Alzheimer‐like pathology and improves cognition
Author(s) -
Li Rena
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.829
Subject(s) - aromatase , estrogen , endocrinology , medicine , testosterone (patch) , androgen , amyloid precursor protein , genetically modified mouse , biology , transgene , alzheimer's disease , hormone , gene , disease , biochemistry , cancer , breast cancer
increased disease development in APOE e4 carriers and endosomal abnormalities. Conversely, cholesterol-reducing therapies have shown promising results in AD. Although NPC patients lack beta-amyloid (Ab) plaques, NPC-like cells accumulate intracellular Ab in vitro. To pin-point the effects of excessive cellular cholesterol on amyloid metabolism in vivo in humans we examined amyloid in cerebrospinal fluid (CSF) in NPC patients. Methods: Thirty-eight NPC patients (20 females) and 14 healthy controls (9 females) underwent lumbar puncture with spinal tapping. CSF was analyzed for Ab38, Ab40, Ab42, a-cleaved soluble (sAPP-a), b-cleaved soluble (sAPP-b), total-tau (T-tau) and phospho-tau (P-tau). Results: Compared to controls, NPC patients had significantly higher Ab38 (mean 297 vs. 489 ng/L, p 1⁄4 0.002), Ab40 (2573 vs. 5033 ng/L, p < 0.0001) and Ab42 (151 vs. 415 ng/L, p < 0.0001). Also, ratios of Ab42:Ab38 and Ab42:Ab40 were increased in NPC (62 vs. 94; 5.4 vs. 7.9, p < 0.0001). Controls and NPC patients had similar levels of sAPPa (391 vs. 459 ng/L, p 1⁄4 0.27) and sAPP-b (108 vs. 134, p 1⁄4 0.38). T-tau was elevated in NPC patients (80 vs. 338 ng/L, p < 0.0001) although the groups did not differ in P-tau (24 vs. 27 ng/L, p 1⁄4 0.40). Conclusions: We found signs of increased Ab production in NPC patients. The increased ratios of Ab42:Ab38 and Ab42:Ab40 demonstrate a shift of production towards Ab42. Significant alterations in production or transport of APP were unlikely due to stable concentrations of sAPP-a. Also, since sAPP-b concentrations were stable, the increased Ab production was likely caused by augmented activity of y-secretase rather than b-secretase. Increased CSF Ab42 argues against amyloid deposition in NPC brains, which is in accordance with autopsy studies. This suggests that increased Ab load is insufficient for plaque formation. Besides opening for CSF Ab as NPC biomarkers, these results raise questions about the precise mechanisms of amyloid fibrillation in the brain.