γ-Secretase component presenilin is important for microglia β-amyloid clearance.

Objective: The cleavage of amyloid precursor protein by c-secretase is an important aspect of the pathogenesis of Alzheimer’s disease. c-Secretase also cleaves other membrane proteins (eg, Notch), which control cell development and homeostasis. Presenilin 1 and 2 are considered important determinants of the c-secretase catalytic site. Our aim was to investigate whether c-secretase can be important for microglial phagocytosis of Alzheimer’s disease b-amyloid. Methods: We investigated the role of c-secretase in microglia activity toward b-amyloid phagocytosis in cell culture using c-secretase inhibitors and small hairpin RNA and presenilin-deficient mice. Results: We found that c-secretase inhibitors impair microglial activity as measured in gene expression, protein levels, and migration ability, which resulted in a reduction of soluble b-amyloid phagocytosis. Moreover, microglia deficient in presenilin 1 and 2 showed impairment in phagocytosis of soluble b-amyloid. Dysfunction in the csecretase catalytic site led to an impairment in clearing insoluble b-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 c-secretase in Alzheimer’s disease. One role is the cleavage of the amyloid precursor protein for pathologic b-amyloid production and the other is to regulate microglia activity that is important for clearing neurotoxic b-amyloid deposits. Further studies of c-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. ANN NEUROL 2011;69:170–180