Cerebral Innate Immunity: A New Conceptual Framework for Alzheimer's Disease

Alzheimer's disease (AD) is pathologically defined by the presence of extracellular amyloid plaques comprised of amyloid-β (Aβ) peptides, formation of neurofibrillary tangles, and low-level, chronic neuroinflammation. These pathological hallmarks are posited to work in a concerted manner according to the "amyloid cascade hypothesis," which purports that Aβ deposition as "senile" amyloid plaques is the principal etiopathological event in AD. Despite local recruitment of brain microglia to sites of Aβ deposition, the brain's innate immune system ultimately fails at restricting Aβ plaque formation. It is becoming increasingly clear that inhibitory mechanisms exist to restrict amyloid clearance by both brain-resident and peripheral monocytes, and that innate immune genes can be targeted to reduce AD-like pathology in rodent models of cerebral amyloidosis. This chapter explores the preclinical science behind the expanding field of Aβ immunotherapy and the potential for a new generation of pharmacotherapeutics that promote a beneficial innate immune response in the AD brain.