ADAM10 as a therapeutic target for brain diseases: from developmental disorders to Alzheimer’s disease

ABSTRACT

Introduction: In the central nervous system a disintegrin and metalloproteinase 10 (ADAM10) controls several functions such as neurodevelopment, synaptic plasticity and dendritic spine morphology thanks to its activity towards a high number of substrates, including the synaptic cell adhesion molecules as the Amyloid Precursor Protein, N-cadherin, Notch and Ephrins. In particular, ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer’s Disease.

Areas covered: We describe the most recent discoveries in understanding of the role of ADAM10 activity at the glutamatergic excitatory synapse and its involvement in the onset of neurodevelopmental and neurodegenerative disorders.

Expert opinion: A progress in the understanding of the molecular mechanisms driving ADAM10 activity at synapses and its alterations in brain disorders is the first step before designing a specific drug able to modulate ADAM10 activity.

KEYWORDS:

• Autism spectrum disorders
• neurodegeneration
• synapse
• trafficking

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Article highlights

• ADAM10 is a synaptic protein underlying the structural plasticity of dendritic spines and, thereby, learning and memory processes.

• ADAM10 activity towards the amyloid precursor protein is increased in neurodevelopmental disorders, such as Fragile-X syndrome and Autism Spectrum Disorders, while it is reduced in Alzheimer Disease.

• The upregulation of ADAM10 activity as therapeutic strategy for Alzheimer Disease holds a great potential because it is well tolerated and can target different pathways involved in the pathogenesis.

• The main concern of affecting ADAM10 activity is related to the vast array of substrates recently identified. Therefore, the main challenge is to identify the preferential substrate of ADAM10 in the different stages of development and in the specific diseases.

• Understanding the neuron-specific mechanisms controlling ADAM10 activity is critical for realizing the true potential of ADAM10 as target for brain diseases.

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Additional information

Funding

This work was supported by the Progetto di Ricerca di Interesse Nazionale (PRIN2015N4FKJ4) to M. Di Luca, by AIRAlzh Onlus-COOP Italia (fellowship to S. Pelucchi), by funding from Veronesi Foundation Young Investigator Research Programme 2013 to E. Marcello, from the Alzheimer’s Association (NIRP-14-304969) to E. Marcello, from an ADR program research fellowship (A2014314F) to E. Marcello and from an intramural grant of University of Milan to E. Marcello (Fondo di sviluppo unimi- linea 2 - PSR2015-1716GRACA02_05_M). Acknowledgement is made to the donors of the ADR, a program of the BrightFocus Foundation, for support of this research.