Neuronal activity and secreted amyloid ¦Â lead to altered amyloid ¦Â precursor protein and presenilin 1 interactions

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• 作者：Xuejing Li^a ; Kengo Uemura^b ; Tadafumi Hashimoto^a ; Navine Nasser-Ghodsi^a ; Muriel Arimon^a ; Christina M. Lill^c ; Isabella Palazzolo^a ; Dimitri Krainc^a ; Bradley T. Hyman^a ; Oksana Berezovska^a ; ^{oberezovska@partners.org}
• 关键词：A¦Â ; amyloid ¦Â ; APP ; amyloid ¦Â precursor protein ; AD ; Alzheimer's disease ; BACE1 ; ¦Â-secretase ; DIV ; days in vitro ; FLIM ; fluorescence lifetime imaging microscopy ; FRET ; fluorescence resonance energy transfer ; mAb ; monoclonal antibody ; NDS ; normal donke
• 刊名：Neurobiology of Disease
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：50
• 期：Complete
• 页码：127-134
• 全文大小：850 K

文摘

Deposition of amyloid ¦Â (A¦Â) containing plaques in the brain is one of the neuropathological hallmarks of Alzheimer's disease (AD). It has been suggested that modulation of neuronal activity may alter A¦Â production in the brain. We postulate that these changes in A¦Â production are due to changes in the rate-limiting step of A¦Â generation, APP cleavage by ¦Ã-secretase. By combining biochemical approaches with fluorescence lifetime imaging microscopy, we found that neuronal inhibition decreases endogenous APP and PS1 interactions, which correlates with reduced A¦Â production. By contrast, neuronal activation had a two-phase effect: it initially enhanced APP-PS1 interaction leading to increased A¦Â production, which followed by a decrease in the APP and PS1 proximity/interaction. Accordingly, treatment of neurons with naturally secreted A¦Â isolated from AD brain or with synthetic A¦Â resulted in reduced APP and PS1 proximity. Moreover, applying low concentration of A¦Â₄₂ to cultured neurons inhibited de novo A¦Â synthesis. These data provide evidence that neuronal activity regulates endogenous APP-PS1 interactions, and suggest a model of a product-enzyme negative feedback. Thus, under normal physiological conditions A¦Â may impact its own production by modifying ¦Ã-secretase cleavage of APP. Disruption of this negative modulation may cause A¦Â overproduction leading to neurotoxicity.