Think of Alzheimer’s disease like a monstrous puzzle with amyloid β accumulation as the first piece that sets everything off. But what if we could shift the balance and rearrange the pieces? A team of scientists has discovered a potential new way to treat Alzheimer’s by using a soluble form of ADAM10, an enzyme that processes a protein called APP. This enzymatic approach not only releases a neuroprotective agent, but also inhibits the formation and aggregation of the toxic amyloid β species. The scientists identified other substrates for soluble ADAM10, shedding light on its broader impact in the brain. Now, while this exciting research has shown promising results in the lab, there is still work to be done to evaluate its potential in living organisms. So, buckle up and join us as we dive deeper into this groundbreaking research and explore the potential of unlocking Alzheimer’s with soluble ADAM10!

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.

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