Chapter 8: Microglial Blockade of the Amyloid Cascade: A New Therapeutic Frontier Check Access

Microglia, the brain's resident immune cells, have long been presumed to play detrimental roles in neurodegenerative diseases including Alzheimer's disease (AD). However, studies of TREM2 mutations and other human genetic variants have recently flipped the script for AD, revealing a fundamental role for microglia in preventing AD pathogenesis. Validation of this role in animal models has both substantiated the β-amyloid hypothesis and necessitated its revision, with microglial activation opposing, not promoting, the amyloid-tau pathogenic cascade. In this chapter we will focus our attention on this newly minted understanding of microglial function, from its basis in human genetics to its validation in preclinical models, and from its molecular mechanisms of protection to the emerging drug development efforts seeking to promote those mechanisms. We include discussion of how microglial neuroprotection involves apoE, and how the recent FDA approval of the anti-β-amyloid drug aducanumab may complicate future studies of microglia-directed AD therapeutics. With similarities to immune checkpoint inhibitors for cancer or statins for cardiovascular disease, drugs that promote TREM2-related microglial activation are poised to revolutionize the landscape of AD therapeutics by slowing AD pathogenesis or preventing it altogether.