Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer’s Disease Treatment

Abstract

ADAM (a disintegrin and metalloproteinase) is a family of widely expressed, transmembrane and secreted proteins of approximately 750 amino acids in length with functions in cell adhesion and proteolytic processing of the ectodomains of diverse cell-surface receptors and signaling molecules. ADAM10 is the main α-secretase that cleaves APP (amyloid precursor protein) in the non-amyloidogenic pathway inhibiting the formation of β-amyloid peptide, whose accumulation and aggregation leads to neuronal degeneration in Alzheimer’s disease (AD). ADAM10 is a membrane-anchored metalloprotease that sheds, besides APP, the ectodomain of a large variety of cell-surface proteins including cytokines, adhesion molecules and notch. APP cleavage by ADAM10 results in the production of an APP-derived fragment, sAPPα, which is neuroprotective. As increased ADAM10 activity protects the brain from β-amyloid deposition in AD, this strategy has been proved to be effective in treating neurodegenerative diseases, including AD. Here, we describe the physiological mechanisms regulating ADAM10 expression at different levels, aiming to propose strategies for AD treatment. We report in this review on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or translational and post-translational levels. In addition, we describe the conditions that can change ADAM10 expression in vitro and in vivo, and discuss how this knowledge may help in AD treatment. Regulation of ADAM10 is achieved by multiple mechanisms that include transcriptional, translational and post-translational strategies, which we will summarize in this review.

Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

“…Further, defects in CX3CR1-CX3CL1 signaling and ADAM10 have been identified to either enhance or suppress neurodegeneration in a variety of neurological disease models depending on the disease, insult, brain region, etc. 38,[61][62][63][64][65][66] . Here, we identify that neuronal ADAM10 is modulated in the cortex by sensory lesioning and disruption of ADAM10, CX3CL1 (an ADAM10 substrate), or CX3CR1 results in profound defects in microglial synaptic engulfment and synapse elimination following a peripheral sensory lesion known to dampen activity in the cortex 38,[64][65][66] .…”

“…38,[61][62][63][64][65][66] . Here, we identify that neuronal ADAM10 is modulated in the cortex by sensory lesioning and disruption of ADAM10, CX3CL1 (an ADAM10 substrate), or CX3CR1 results in profound defects in microglial synaptic engulfment and synapse elimination following a peripheral sensory lesion known to dampen activity in the cortex 38,[64][65][66] . This mechanism is particularly intriguing in light of recent data in mouse models of Alzheimer's disease where changes in neural activity modulates microglial morphology, Aβ, and amyloid plaques 67,68 .…”

Substrate-Specific Activation of α-Secretase by 7-Deoxy-Trans-Dihydronarciclasine Increases Non-Amyloidogenic Processing of β-Amyloid Protein Precursor

“…Recent studies have implicated that activation of α-secretase can induce unfavorable effects because ADAM proteins can increase the processing of other substrates, resulting in the promotion of tumorigenesis, tumor growth, and inflammation [13]. Thus, the importance of substrate-specific ADAM targeting has been highlighted in the AD research field to avoid side-effect [14]. Our data showed that E144 decreased the secreted level of TNF-α, ruling out the possibility that E144 might cause putative side-effects by increasing TNF-α.…”

“…α-Secretase can be a constitutive cleavage enzyme or be stimulated by several G protein-coupled receptors (GPCRs) activating drugs and several kinases such as protein kinase C (PKC), phosphatidyl-inositol 3-kinase, and mitogen-activated protein kinase [12,13]. Among three family members, ADAM10 is considered as sheddase for APP and other diverse cell-surface proteins, including cytokines, cell adhesion molecules (CAMs), and Notch [13,14]. In contrast, ADAM9 and ADAM17 are believed to undertake regulated APP cleavage [13,15,16].…”

“…Thus, stimulating α-secretase mediated APP processing is a therapeutic option for the treatment of amyloid pathology by decreasing Aβ production. There have been intensive efforts to find small molecule ADAM activators, and several activators for ADAM are demonstrated [14]. However, this strategy should consider proteolysis of APP as well as various substrates, including TNFα and epidermal growth factor receptor ligands involved in inflammation and cancer [13].…”