APP regulates microglial phenotype in a mouse model of alzheimer’s disease

Abstract

Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer’s disease. Although fibrillar amyloidβ (Aβ)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP-/-) microglial cultures, oligomeric Aβ was unable to stimulate increased secretion from mAPP-/- cells. This was consistent with an ability of oligomeric Aβ to bind APP. Similarly, intracerebroventricular infusions of oligomeric Aβ produced less microgliosis in mAPP-/- mice compared with wild-type mice. The mAPP-/- mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Aβ plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease.