报告题目：Inhibition of BACE1 for benefiting Alzheimer's disease patients
报告人：Riqiang Yan, Ph.D.
Scoville Endowed Professor in Neuroscience and Chair Department of Neuroscience
University of Connecticut School of Medicine
时 间：2018 年10 月20 日（星期六）上午10:30
Abnormal accumulation of β amyloid peptide (Aβ) contributes to synaptic dysfunctions in Alzheimer’s disease (AD) patients, and decrease Aβ in AD patients’ brains is actively explored to treat AD. BACE1 is the β-secretase that initiates the generation of the β-amyloid peptide, which likely causes Alzheimer's disease (AD) when accumulated abnormally. Inhibition of BACE1 will reduce Aβ generation. BACE1 inhibitory drugs are therefore being developed to treat AD patients. To mimic BACE1 inhibition in adults, we generated BACE1 conditional knockout (BACE1fl/fl) mice and bred BACE1fl/fl mice with ubiquitin-CreER mice to induce deletion of BACE1 after passing early developmental stages. Strikingly, sequential and increased deletion of BACE1 in an adult AD mouse model (5xFAD) was capable of completely reversing amyloid deposition. This reversal in amyloid deposition also resulted in significant improvement in gliosis and neuritic dystrophy. Moreover, synaptic functions, as determined by long-term potentiation and contextual fear conditioning experiments, were significantly improved, correlating with the reversal of amyloid plaques. Our results demonstrate that sustained and increasing BACE1 inhibition in adults can reverse amyloid deposition in an AD mouse model, and this observation will help to provide guidance for the proper use of BACE1 inhibitors in human patients.？
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