Implications of Microglia in Alzheimer Disease Drug Development and Clinical Trials: Gareth Howell, PhD

WATCH TIME: 3 minutes

"The real challenge in the field is, how do we keep the microglia doing the good stuff, which is making sure that the toxic byproducts of having an active neuronal system are cleared away...but then try and maybe stop them doing the bad stuff? And for that, we need a lot more information about what are the specific processes, or specific types of microglia."

At the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1, in Philadelphia, Pennsylvania, researchers presented preclinical data from a 2 mouse strains, C57BL/6J (B6) and WSB/EiJ (WSB), exploring how genetic context can impact microglia function, how these differences relate to Alzheimer disease (AD) pathology, and ultimately, cognitive decline. In addition, in animals that carried amyloid driving mutations, the study investigators also performed injections of human-derived tau at 6-months and aged mice to 10-months.

While the data analysis is currently ongoing, results showed that B6 and WSB mice that carried humanized amyloid-ß without mutations did not exhibit significant amyloid pathology at 10 months; however, B6 and WSB mice that carried the Swedish-Artic-Austrian mutations do show significant parenchymal deposition starting at 6 months of age, and WSB exhibited mature cerebral amyloid angiopathy. Overall, the study authors concluded that incorporating humanized amyloid and tau into genetically diverse mouse strains could significantly improve the alignment of neuroimmune responses in mouse to human AD.

During the conference, study author Gareth Howell, PhD, a professor of neurology at the Jackson Laboratory, spoke on the importance of microglia and the potential they play in the clinical trials. Howell, who also serves as the Diana Davis Spencer Foundation Chair, discussed how microglia effects neurodegeneration, the emergence of biomarkers and imaging, and the potential for more microglia-targeted approaches. In addition, he stressed that the success of targeting microglia in AD is anticipated to improve as more is understood about the specific states or subtypes of microglia.

Click here for more coverage of AAIC 2024.

REFERENCE
1. Onos K, Keezer K, Perkins B, et al. Deciphering microglial contributions to amyloid and tau pathology in diverse genetic contexts. Presented at: AAIC; July 28-August 1, 2024; Philadelphia, PA. Abstract 92886