Knut Biber, Research Fellow & Head of Glial Biology Team, AbbVie, explained that microglia are not passive bystanders but active participants in AD progression. Genetic studies (GWAS) show that many AD-associated genes are highly or exclusively expressed in microglia, implicating them in the spread of tau pathology and the development of full-blown AD.
Biber stressed that microglial response to amyloid plaque is complex and context-dependent. For instance, in elderly patients with amyloid pathology but no dementia, microglial clustering is rare.
The responses vary depending on the presence of tau and amyloid, which differ between AD patients and healthy controls. This implies that microglial activation is not a uniform or inevitable process, making it quite puzzling.
Biber and his colleagues used single-nucleus RNA-seq to identify multiple microglial clusters with distinct transcriptomic profiles across different brain regions and disease stages. These clusters show varied inflammatory tones and correlate differently with tau and amyloid loads, thus revealing specific trajectories of microglial transformation during disease progression.
To dig a little deeper into physiology, the team began selectively targeting microglia subtypes. More precisely, they selected those with an interferon signature. From this procedure, the researchers were able to unpack that using a variety of pathways could produce a shift in the overall microglia population, meaning they have a solid understanding of what kind of microglia population one needs to target to bring down the AD population.
Biber explained that modulating just a small fraction (5–6%) of microglia can significantly impact AD pathology without harming beneficial microglial functions. He concluded his presentation with a word of caution against the broad-spectrum inhibition of microglia. Since microglia have both protective and detrimental roles, indiscriminate suppression could worsen outcomes. Therefore, precision targeting of specific dysfunctional microglial populations is essential for safe therapeutic strategies.
