Farfara_2011_Ann.Neurol_69_170

OBJECTIVE: The cleavage of amyloid precursor protein by gamma-secretase is an important aspect of the pathogenesis of Alzheimer's disease. gamma-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the gamma-secretase catalytic site. Our aim was to investigate whether gamma-secretase can be important for microglial phagocytosis of Alzheimer's disease beta-amyloid.
METHODS: We investigated the role of gamma-secretase in microglia activity toward beta-amyloid phagocytosis in cell culture using gamma-secretase inhibitors and small hairpin RNA and presenilin-deficient mice.
RESULTS: We found that gamma-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble beta-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble beta-amyloid. Dysfunction in the gamma-secretase catalytic site led to an impairment in clearing insoluble beta-amyloid from brain sections taken from an Alzheimer's disease mouse model when compared to microglia from wild-type mice. INTERPRETATION: We suggest for the first time, a dual role for gamma-secretase in Alzheimer's disease. One role is the cleavage of the amyloid precursor protein for pathologic beta-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic beta-amyloid deposits. Further studies of gamma-secretase-mediated cellular pathways in microglia may provide useful insights into the development of Alzheimer's disease and other neurodegenerative diseases, providing future avenues for therapeutic intervention.