Shifting the balance: soluble ADAM10 as a potential treatment for Alzheimer's disease

Frontiers in Aging Neuroscience

Aging Neuroscience

Rawad Hanna¹  Oded Kleifeld¹  Sivan Gelley²  Ayelet Fishman²  Ayelet Sarah Hershkovits³  Avidor Shulman⁴ 

[1] Department of Biology Technion-Israel Institute of Technology, Haifa, Israel;Department of Biotechnology and Food Engineering Technion-Israel Institute of Technology, Haifa, Israel;Department of Biotechnology and Food Engineering Technion-Israel Institute of Technology, Haifa, Israel;The Interdisciplinary Program for Biotechnology, Technion-Israel Institute of Technology, Haifa, Israel;Independent Researcher, Rakefet, Israel;

关键词: Alzheimer's disease;    ADAM10;    amyloid beta;    soluble amyloid precursor protein;    terminomics;    proteomics;   

DOI  :  10.3389/fnagi.2023.1171123

 received in 2023-02-21, accepted in 2023-04-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAccumulation of amyloid β in the brain is regarded as a key initiator of Alzheimer's disease pathology. Processing of the amyloid precursor protein (APP) in the amyloidogenic pathway yields neurotoxic amyloid β species. In the non-amyloidogenic pathway, APP is processed by membrane-bound ADAM10, the main α-secretase in the nervous system. Here we present a new enzymatic approach for the potential treatment of Alzheimer's disease using a soluble form of ADAM10.MethodsThe ability of the soluble ADAM10 to shed overexpressed and endogenous APP was determined with an ADAM10 knockout cell line and a human neuroblastoma cell line, respectively. We further examined its effect on amyloid β aggregation by thioflavin T fluorescence, HPLC, and confocal microscopy. Using N-terminal and C-terminal enrichment proteomic approaches, we identified soluble ADAM10 substrates. Finally, a truncated soluble ADAM10, based on the catalytic domain, was expressed in Escherichia coli for the first time, and its activity was evaluated.ResultsThe soluble enzyme hydrolyzes APP and releases the neuroprotective soluble APPα when exogenously added to cell cultures. The soluble ADAM10 inhibits the formation and aggregation of characteristic amyloid β extracellular neuronal aggregates. The proteomic investigation identified new and verified known substrates, such as VGF and N-cadherin, respectively. The truncated variant also exhibited α-secretase capacity as shown with a specific ADAM10 fluorescent substrate in addition to shedding overexpressed and endogenous APP.DiscussionOur in vitro study demonstrates that exogenous treatment with a soluble variant of ADAM10 would shift the balance toward the non-amyloidogenic pathway, thus utilizing its natural neuroprotective effect and inhibiting the main neurotoxic amyloid β species. The potential of such a treatment for Alzheimer's disease needs to be further evaluated in vivo.

【 授权许可】

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Copyright © 2023 Hershkovits, Gelley, Hanna, Kleifeld, Shulman and Fishman.