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P2‐476: A Phase 1, dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral daily doses of ELND006 in healthy elderly subjects
Author(s) -
Liang Earvin,
Liu Wenzhong Jerry,
Lohr Lisa,
Nguyen Van,
Lin Holly,
Munson Marie Lou,
Crans Gerald,
Cedarbaum Jesse
Publication year - 2011
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.2011.05.1347
Subject(s) - tolerability , pharmacokinetics , pharmacodynamics , medicine , placebo , adverse effect , discontinuation , nausea , pharmacology , toxicity , cerebrospinal fluid , anesthesia , gastroenterology , pathology , alternative medicine
a positive association of estrogens and cognitive function and preventing AD, while others report no effect or even an inverse relationship between estrogens and AD. Recent studies showed that estrogens might play different roles in brain function depending on type of estrogens, dose and time of administration. Here, we studied the effect of 17b-estradiol, 17a-estradiol, genistein and black cohosh on BACE1 regulation and neuropathology in APP23 transgenic mice. Methods: Female APP23 and age-matched wild type mice received continuously treatments of 17b-estradiol, 17a-estradiol, genistein or black cohosh for 3 and 9 months, respectively. Various neuropathological measurements were performed at end of the treatments, such as analyses of brain amyloid plaques, beta amyloid levels, BACE1 protein and activities and cognitive function.Results:Our studies showed that early and long term treatment of 17b-estradiol and genistein caused a significant reduction of brain plaque density compared to placebo treatments. The BACE1 is mainly responsible for the 17b-estradiol induced delay of plaque formation in the APP23 mice. In contrast, no change of plaque pathology was observed in the APP23 transgenic mice after 17a-estradiol or black cohosh treatments regardless. There is no significant effect of late and short term estrogen treatments. Early estrogen treatment also prevented cognitive function impairment in APP23/Ar 6 mice. Conclusions: Our results suggest that estrogen treatments might help to prevent AD pathologies in women through regulation of BACE1 when early and long term usage of 17b-estradiol and genistein were taking place. No advantage of estrogen treatments in treating AD when brain has formed AD-liked neuropathology.