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【院长论坛】Inhibition of BACE1 for benefiting Alzheimer's disease patients

发布日期:2018-10-10    浏览次数:

北京大学基础医学院

院长论坛

 

报告题目:Inhibition of BACE1 for benefiting Alzheimer's disease patients

Riqiang Yan, Ph.D.

                    Scoville Endowed Professor in Neuroscience and Chair Department of Neuroscience

                   University of Connecticut School of Medicine

    间:2018 10 20 日(星期六)上午10:30

    点:生化楼三层中厅

人:研究员

报告简介:

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.?

 

Representative Publications:

1. He W, Lu Y, Qahwash I, Hu XY, Chang A, Yan R. (2004) Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med. 10(9):959-65.

2. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 9(12):1520-5.

3. Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R. (2007) Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities. EMBO J. 26(11):2755-67.

4. Hu X, He W, Diaconu C, Tang X, Kidd GJ, Macklin WB, Trapp BD, Yan R. (2008) Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J. 22(8):2970-80.

5. Hu X, Zhou X, He W, Yang J, Xiong W-C, Wong P, Wilson CW, Yan R. (2010) BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci. 30(26):8819-29.

6. Hu X, He W, Luo X, Tsubota KE, Yan R. (2013) BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 4(1):40-9.

7. Shi Q, Ge Y, Sharoar MG, He W, Xiang R, Hu X, Yan R. (2014) Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci. 34(42):13954-62.

8. Hu X, Hu J, Dai L, Trapp B, Yan R. (2015) Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. J. Neurosci. 35(9):3806-3814.

9. Sharoar MG, Shi Q, Ge Y, He W, Hu X, Perry G, Zhu X, Yan R. (2016) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry 21:1263-1271.

10. Hou H, Fan Q, He W, Suh H, Hu X, Yan R. (2017) BACE1 deficiency causes abnormal neuronal clustering in the dentate gyrus. Stem Cell Reports 9(1):217-230.

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