Increase of ADAM10 Protein Expression in the Brain as an Alzheimer’s Disease Therapeutic

The research team aims to determine if adeno-associated virus (AAV)- or antisense oligonucleotide (ASO)-mediated increase of ADAM10 expression attenuates Alzheimer’s disease-related pathogenesis in mouse models.

ADAM10 is an enzyme that prevents the generation of amyloid-beta, the main component of senile plaques in Alzheimer’s disease brains. Previous studies consistently showed that loss of ADAM10 function increases Alzheimer’s risk, suggesting that increasing ADAM10 expression can be a promising therapeutic target. This study will test if brain-selective modulation of ADAM10 expression affects Alzheimer’s pathogenesis and develop an experimental antisense oligonucleotide drug that increases ADAM10 expression for Alzheimer’s treatment. 

If successful, Dr. Suh and others could screen FDA-approved drugs or other medicinal libraries to identify small molecule compounds that increase ADAM10 expression and develop them as Alzheimer’s drugs. In addition, ADAM10 antisense oligonucleotides identified from the proposed study can be optimized for human sequences and further tested and developed for Alzheimer’s treatment. 

To avoid potential side effects in other tissues, brain-selective increase of ADAM10 expression is highly preferred approach as AD therapeutic. We attempt to achieve this with antisense oligonucleotides (ASOs) that can be applied directly to the central nervous system. Our proposed study aims to identify ASOs that destabilize G-quadruplex motif, a translational inhibitory structure in ADAM10 5’ untranslated region (UTR) and thus increase the translation. The select ASOs would lead to the decreases of amyloidogenic cleavage of APP and Abeta pathology in the brain.

If completed successfully, research findings from the proposed study would strongly support that increased ADAM10 expression in the brain is a promising therapeutic target for AD. We and others could screen FDA-approved drugs or other medicinal libraries to identify small molecule compounds that increase ADAM10 expression in vitro and in vivo and develop them as AD drugs. In addition, ADAM10 ASOs identified from the proposed study can be optimized for human sequences and further tested and developed for AD treatment.