神经药理学报 ›› 2017, Vol. 7 ›› Issue (2): 19-19.

• 2017年全国老年痴呆与认知障碍相关疾病学术会议论文摘要—大会报告 • 上一篇    下一篇

Implication of Lipid Related Risk Factor for Preclinical Stage Alzheimer’s Disease:Lipoprotein Lipase deficiency Leads to α-synuclein Aggregation and Impaired Learning and Memory Function

CHUI De-hua,YANG Huan,JIN Ying-lan,ZHAO Lei,GUO Xiang-yang,HAN Hong-bin,FAN Dong-sheng   

  • 出版日期:2017-04-26 发布日期:2017-12-01
  • 作者简介:崔德华,博士,教授,博士生导师。留学日本获得医学博士学位后,在日本国立神经精神研究所及 RIKEN 脑研究所AD 研究室任高级研究员20 余年。现任北京大学神经科学研究所教授、北京大学 第三医院神经内科老年痴呆首席专家。主要研究方向:PCAD 的分子生物学机制、预警? 早期诊断 生物标记物及早期预防干预。主持多项国家自然科学基金、国际合作、863、973 及科技部重大慢病项 目等。发表100 余篇学术论文,包括Nature Medicine,PNAS 等国际权威期刊。学会任职:APAC 血管性认知障碍发起人及国际出版专业委员会主席,中国老年学会老年认知障碍专业委员会副主 任委员。
  • 基金资助:

    This work was supported by the National High Technology Research and Development Program of China (No.2016YFC1306302,2016YFC1305903) and the National Natural Science Foundation of China (NSFC;Grants No. 81171015 and No. 81241040),the National Science Fund for Distinguished Young Scholars( No. 61625102)

  • Online:2017-04-26 Published:2017-12-01

摘要: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects the elderly. Clinical studies have found that the amyloid deposits in the brain are aggravated along with the deterioration of the AD pathology. Indeed,Aβ peptides change particularly significantly early in the preclinical stage,and then detection of Aβ is of great importance in early diagnosis. Therefore,it is critical to diagnose and treat AD at the preclinical stage,and Aβ becomes the key target of international research. We also focus on risk factors for preclinical Alzheimer’s disease,especially imbalance in lipid metabolism. Our current study presented a novel model with early onset of cognitive dysfunction by phospholipid transfer protein (PLTP) deficiency in APP/PS1ΔE9 mice without appearance of amyloid deposition. Dysfunction of PLTP might be a risk factor for the elevated Aβ in the preclinical stage of AD. We first found several potential functions of PLTP deficiency in the AD model mice: impairing cognitive performance;involvement in APP trafficking/processing and intracellular Aβ generation;inducing Aβ42 related alteration of BDNF. These established PLTP deficient AD mouse models could provide insights to early stages in AD like mild cognitive impairment( MCI) or preclinical AD (PCAD). Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons,although its function is unclear. Lipoprotein lipase (LPL) is expressed at high levels in hippocampal neurons,although its function is unclear. We previously reported that LPL-deficient mice have learning and memory impairment and fewer synaptic vesicles in hippocampal neurons,but properties of synaptic activity in LPL-deficient neurons remain unexplored. In this study,we found reduced frequency of miniature excitatory postsynaptic currents (mEPSCs) and readily releasable pool (RRP) size in LPLdeficient neurons,which led to presynaptic dysfunction and plasticity impairment without altering postsynaptic activity. We demonstrated that synaptic vesicle recycling,which is known to play an important role in maintaining the RRP size in active synapses,is impaired in LPL-deficient neurons. Moreover,lipid assay revealed deficient docosahexaenoic acid (DHA) and arachidonic acid (AA) in the hippocampus of LPL-deficient mice;exogenous DHA or AA supplement partially restored synaptic vesicle recycling capability. These results suggest that impaired synaptic vesicle recycling results from defi cient DHA and AA and contributes to the presynaptic dysfunction and plasticity impairment in LPL-defi cient neurons. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study,we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL defi cient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore,defi ciency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-defi cient mice may affect synaptic function.