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 amyloid β (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.
The Journal of Neuroscience
Manocha, Gunjan; Floden, Angela; Rausch, Keiko; Kulas, Joshua; McGregor, Brett; Rojanathammanee, Lalida; Puig, Kelley; Puig, Kendra; Karki, Sanjib; Nichols, Michael; Darland, Diane; Porter, James; and Combs, Colin, "APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease" (2016). Chemistry & Biochemistry Faculty Works. 31.