Dr. Carmela Abraham of Boston University, through a grant from Cure Alzheimer’s Fund, screened 75,000 small molecules with the hope of discovering a molecule that would reduce the formation of amyloid beta plaques – one of the pathological hallmarks of Alzheimer’s disease. In a recent paper, Dr. Abraham and her colleagues identified two targets, one that can be inhibited in Alzheimer’s disease to decrease amyloid production. The twist in the research comes from the fact that the identified inhibitor of this pathway also serves as an anti-cancer therapy. This paper provides more evidence for the interesting intersection between pathways that are implicated in both cancer and neurodegeneration.

The results of this paper revolve around a highly dynamic cellular process known as protein phosphorylation. In this cellular process, players called kinases and phosphatases respond to environmental stimuli in order to activate or inhibit specific signaling pathways. This paper identifies a drug that changes the phosphorylation state of the amyloid beta precursor protein (AbPP).

The compound that has been newly identified as playing a role in amyloid beta reduction is called Y10. One of the targets of interest of this compound is cKit. The investigators found that inhibiting cKit lowered amyloid beta levels. In an elegant series of biochemistry experiments, they identified a molecule called Shp2 phosphatase that is regulated by cKit levels. Inhibiting Shp2 also resulted in the ability to lower amyloid beta levels.

This study provides new direction by characterizing the role of cKit and Shp2 in reducing amyloid b production. Small molecule kinase inhibitors have already successfully completed Phase III clinical trials for the treatment of cancer suggesting that FDA-approved drugs that are already being used have the potential to be repurposed for the treatment of Alzheimer’s disease.

Eureka Alert https://www.eurekalert.org/pub_releases/2019-02/buso-ppt021919.php

Boston University: Possible Pathway to New Therapy for Alzheimer’s Disease

https://www.bumc.bu.edu/busm/2019/02/19/possible-pathway-to-new-therapy-for-alzheimers-disease/

The research paper is available from the Journal of Alzheimer’s disease:

Small Molecule Amyloid-b Protein Precursor Processing Modulators Lower Amyloid-b Peptide levels via cKit signaling

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180923