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

Abstract

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.

Tim-3 Is Differentially Expressed during Cell Activation and Interacts with the LSP-1 Protein in Human Macrophages

“…These results suggest that the regulation of TIM-3 and ADAM-10 in activated macrophages may not occur at the gene expression level. ADAM-10 is known to maintain its proteolytic activity even in its soluble form [ 31 ]. Although existing information has primarily focused on the function of membrane-anchored ADAM-10, recent findings indicate that the soluble form of ADAM-10 (sADAM-10) exhibits different substrate specificity compared to its membrane-bound counterpart (mADAM-10) [ 32 ].…”

“…When ADAM-10 is inactivated, it is released in exosomes or eliminated through lysosomal degradation, even in the presence of substrate [ 38 ]. However, sADAM have catalytic activity and the substrate specificity can be different between mADAM-10 and sADAM-10 [ 31 , 32 ].…”

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer’s Disease

“…In this study, the neuroprotective role of P110 was explored using a human neuronal cell culture model. Exposure of SH-SY5Y cells to P110 reduced the expression of proteins involved in Aβ formation (APP, the precursor protein of Aβ peptide, and BACE1, the β-secretase cleavage enzyme required for the generation of amyloid-β peptides) and increased the levels of neuroprotective proteins (ADAM10, an α-secretase responsible of cleavage of APP through a non-amyloidogenic pathway and Klotho, involved in amyloid clearance) [32][33][34][35]. Further, P110 increased mitochondrial function and reduced ROS production.…”

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

“…Since the α-secretase activity of ADAM10 gives rise to the non-amyloid pathway, it has been proposed that increased activity protects against amyloid beta deposition. In vitro studies have shown that exogenous treatment with the ADAM10 variant inhibits the formation and aggregation of neuronal extracellular amyloid β [129]. Furthermore, ADAM10 is a synaptic protein involved in the structural plasticity of dendritic spines.…”