PAPP-A as a Potential Target in Alzheimer's Disease

PROJECT SUMMARY Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease of age that is associated with formation of plaques and destruction of neurons in the brain, leading to severe memory loss and behavioral changes. Unfortunately and despite intensive research, there is no effective treatment for AD. A better understanding of the cellular mechanisms underlying the accumulation of toxic β-amyloid peptides and formation of amyloid plaque in AD is likely to identify potential new therapeutic targets. Rigorous prior research links the insulin-like growth factor (IGF) system to the accelerated progression of AD. Experimental AD in mice responds positively to reduction of IGF signaling through genetic means. Thus, deletion or knock-down of IGF-I receptors or intracellular mediators of receptor-mediated signal transduction in AD mice has been shown to reduce plaque formation in the brain and prevent/delay neurodegeneration and associated behavioral changes. We hypothesize that deletion of a novel proteolytic enzyme (PAPP-A), which enhances IGF action through cleavage of inhibitory IGF binding proteins, protects against AD-like pathology and behavior in mouse models of AD. For this proposal, we will generate AD mice combined with PAPP-A gene deletion. ATTPswe/PS1dE9 transgenic (AD) mice express mutations associated with early-onset AD, and develop β- amyloid deposits in brain by 6 to 7 months of age. Our established PAPP-A knock-out (KO) mice are crossed with the AD mice to get mice heterozygous for PAPP-A with or without AD transgenes. These mice are then crossed to get four genotypes for the study: Wild-type (WT), AD, PAPP-A KO, and AD/PAPP-A KO mice. Our preliminary data establish feasibility. Specific Aim 1. Determine the consequences of PAPP-A gene deletion on brain pathology in AD mice. At 6, 12, and 18 months of age, brains from WT, AD, PAPP-A KO and AD/PAPP-A KO mice will be analyzed for amyloid plaque, β-amyloid oligopeptides, and reactive astrocytes and activated microglia. In addition, brain IGF-I receptor activation and circulating PAPP-A in extracellular vesicles will be assessed. Specific Aim 2. Assess how PAPP-A gene deletion impacts cognitive function in AD mice. At 6, 12, and 18 months of age, WT, AD, PAPP-A KO, and AD/PAPP-A KO mice will undergo behavioral testing using novel object recognition and the Stone T-maze. The proposed studies would be the first to generate and characterize a mouse model to study the role of PAPP-A in AD. Demonstration that loss of PAPP-A expression impacts pathological changes and behavioral consequences would support the development of novel neurodegenerative therapies based on targeted inhibition of PAPP-A.