Abstract
Autism Spectrum Disorder (ASD) is a spectrum of disorders that are characterized by problems in social interaction and repetitive behavior. The disease is thought to develop from changes in brain development at an early age, although the exact mechanisms are not known yet. In addition, a significant number of people with ASD develop problems in the intestinal tract. A Disintegrin And Metalloproteases (ADAMs) include a group of enzymes that are able to cleave membrane-bound proteins. ADAM10 and ADAM17 are two members of this family that are able to cleave protein substrates involved in ASD pathogenesis, such as specific proteins important for synapse formation, axon signaling and neuroinflammation. All these pathological mechanisms are involved in ASD. Besides the brain, ADAM10 and ADAM17 are also highly expressed in the intestines. ADAM10 and ADAM17 have implications in pathways that regulate gut permeability, homeostasis and inflammation. These metalloproteases might be involved in microbiota-gut–brain axis interactions in ASD through the regulation of immune and inflammatory responses in the intestinal tract. In this review, the potential roles of ADAM10 and ADAM17 in the pathology of ASD and as targets for new therapies will be discussed, with a focus on the gut–brain axis.
Highlights
Autism Spectrum Disorder (ASD) is a spectrum of neurodevelopmental disorders that are generally diagnosed early in life and might persist across the whole lifespan
There are more than a hundred substrates cleaved by ADAM10 in the Central Nervous System (CNS) [35], and its expression, maturation and substrates selectivity are regulated by the TspanC8 subfamily of tetraspanin, consisting of Tspan5, 10, 14, 15, 17 and 33 [61,62,63], as different Tspan-ADAM10 complexes might adopt different conformations and spaces to their substrates [62,64,65]
It was shown that ADAM17 expression levels increased with age in juvenile people diagnosed with ASD [130], this was reported in relation to the elevation of sAPPα and not with respect to neuroinflammation, inflammation and immune responses
Summary
Autism Spectrum Disorder (ASD) is a spectrum of neurodevelopmental disorders that are generally diagnosed early in life and might persist across the whole lifespan. The estimated heritability of ASD was 83% in a recent population-based cohort of children born in Sweden [22], and Bailey et al reported a similar result [23] Among these genetic predispositions, the membrane-bound synaptic genes for the Amyloid Precursor Protein (APP), Neural glial-related Cell Adhesion Molecule (NrCAM), Neuroligins (NLGNs), Neurexins (NRXNs) and Protocadherins (PCDHs) were widely identified as candidate genes of ASD [24,25,26,27,28], as their deficiency in mice led to ASD-like behaviors, such as deficits in spatial memory and learning, increased repetitive and stereotype grooming behaviors and compromised social interactions [29,30,31]. We aim to elaborate on the potential role of ADAM10 and ADAM17 in the pathogenesis of ASD with a major focus on the gut–brain axis
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