Hiding in plain sight: Do recruited dendritic cells surround amyloid plaques in Alzheimer's disease?

Over the past decade, human genome-wide association and expression studies have strongly implicated dysregulation of the innate immune system in the pathogenesis of Alzheimer's disease (AD). Single cell mRNA sequencing studies have identified innate immune cell subtypes that are minimally present in normal healthy brain, but whose numbers greatly increase in association with AD pathology. These AD pathology-associated immune cells are putatively the locus for the immune-related AD risk. While the prevailing view is that these immune cells arise from transformation of resident brain microglia, studies across several decades and using multiple techniques and strategies suggest instead that the pathology-associated immune cells are bone-marrow derived hematopoietic cells that are recruited into brain. We critically review this translational literature, emphasizing the strengths and limitations of techniques used to address recruitment and the experimental designs employed. We conclude that the aggregate evidence points toward recruitment into brain of innate immune cells of the myeloid dendritic cell lineage. Recruitment of dendritic cells and their role in AD pathogenesis has broad implications for our understanding of the etiology and pathobiology of AD that impact the strategies to develop new, immune system-targeted therapeutics for this devastating disease.