Potential New Amyloid-β-Targeting Therapeutic Pathway

An article published in Nature Aging in September 2023 by a research group (Lau et al.) from Hong Kong identified a potential new target for an Alzheimer’s treatment capable of slowing the progression of the disease.1 In Alzheimer’s disease (AD), the amyloid-β protein aggregates to form senile plaques which contribute to the worsening of the disease. Microglia, which are immune cells of the nervous system, have an essential role to clear these plaques by engulfing and degrading damaged proteins through a process called phagocytosis.

This study revealed specific receptors involved in the process of microglial clearance of amyloid-β plaques. The research group previously identified that the signalling molecule interleukin-33 (IL-33) initiated the activation of microglia to clear amyloid-β in a mouse model simulating AD-like amyloid-β aggregation. In the current study, they revealed two main steps of this clearance, which are the migration of the microglia to the plaque, followed by phagocytosis (engulfing) of the aggregated amyloid-β. They identified VCAM1 as an important molecule on the surface of microglia that is present in increased numbers following IL-33 signalling. VCAM1 is attracted to the ApoE protein, a component of amyloid-β plaques. VCAM1 was found to guide microglia towards amyloid-β plaques and induce the transformation of microglia into performing phagocytosis of amyloid-β plaques.

Importantly, they found that in AD patients there were higher levels of dysregulated VCAM1 signalling which prevented clearance of amyloid-β plaques. The identification of this pathway which triggers the clearing of amyloid-β plaques could be a critical target for therapeutics. More experiments would be needed to determine the efficacy of delivering substances such as IL-33 in animal models, but based on this preliminary study, this may be an exciting new avenue for disease-modifying AD therapeutics. 

Reference

(1) Lau, S.-F.; Wu, W.; Wong, H. Y.; Ouyang, L.; Qiao, Y.; Xu, J.; Lau, J. H.-Y.; Wong, C.; Jiang, Y.; Holtzman, D. M.; Fu, A. K. Y.; Ip, N. Y. The VCAM1–ApoE Pathway Directs Microglial Chemotaxis and Alleviates Alzheimer’s Disease Pathology. Nat. Aging 2023, 3 (10), 1219–1236. https://doi.org/10.1038/s43587-023-00491-1.