Alzheimer's disease strips people of memory and independence through a cascade of cellular failures that begin years before symptoms appear. A new study from King's College London offers a measured step toward addressing some of those failures directly.
Researchers reported on 8 July that treatment with KCL-286 reduced neuronal DNA double-strand breaks, lowered markers of neuroinflammation and returned microglia and astrocytes to more normal shapes in the Tg2576 mouse model of Alzheimer's. The results appeared in FEBS Open Bio.
The compound is a first-in-class retinoic acid receptor-beta agonist. It was originally developed for spinal cord injury, yet it crosses the blood-brain barrier efficiently with a one-to-one ratio and can be taken by mouth. Those properties matter because many candidate drugs never reach the tissue where they are needed.
KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully cleared Phase 1 human safety and tolerability trials. This will dramatically cut down the traditional multi-year timeline required for new drug development.
Professor Jonathan Corcoran, professor of neuroscience at King's College London, pointed to the practical advantage of a molecule that has already passed initial human testing. The team measured repair of DNA damage using gamma-H2AX, a standard marker for double-strand breaks, and saw increased levels of the repair protein BRCA1 after treatment.
Corcoran drew a clear analogy. "DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges. We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer’s disease."
The study also recorded changes in Iba1 and GFAP, two proteins linked to immune activity in the brain. Treated mice showed reduced activation of microglia and astrocytes, the brain's resident immune cells, whose abnormal shapes are a common feature in neurodegenerative models.
