Gene deletion of Pregnancy-associated Plasma Protein-A (PAPP-A) improves pathology and cognition in an Alzheimer's disease mouse model

Alzheimer's disease (AD) is a progressive neurodegenerative disease of age with no effective preventative or treatment approaches. Deeper understanding of the mechanisms underlying the accumulation of toxic β-amyloid oligopeptides and the formation of amyloid plaque in AD has the potential to identify new therapeutic targets. Prior research links the insulin-like growth factor (IGF) system to pathologic mechanisms underlying AD. Suppression of local IGF-I receptor (IGFIR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGFIR signaling are not a viable treatment option for AD due to the essentiality of the IGFIR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGFIR signaling through inhibition of PAPP-A, a novel zinc metalloprotease that regulates local IGF-I bioavailability through cleavage of inhibitory IGF binding proteins. Here we tested if deletion of PAPP-A in a mouse model of AD provides protection against pathology and behavioral changes. We show that compared to AD mice, AD/PAPP-A KO mice had significantly less plaque burden, reduced astrocytic activation, decreased IGF-IR activity, and improved cognition. Human senile AD plaques showed specific immunostaining for PAPP-A. Thus, inhibition of PAPP-A expression or activity may represent a novel treatment strategy for AD.