Gene deletion of Pregnancy-associated Plasma Protein-A (PAPP-A) improves pathology and cognition in an Alzheimer's disease mouse model
Year: 2024
Type: article
Abstract: 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 (IGF IR) signaling in AD mice has been shown to reduce plaque formation in the brain and delay neurodegeneration and behavioral changes. However, direct inhibitors of IGF IR signaling are not a viable treatment option for AD due to the essentiality of the IGF IR in physiological growth and metabolism. We have previously demonstrated a more selective means to reduce local IGF IR 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. • Generations of an AD mouse model of amyloid plaque accumulation with the PAPP-A gene knocked out. • Compared to AD mice, AD/PAPP-A KO mice had reduced plaque number and size, reduced astrocytosis, and reduced brain IGF activity. • Compared to AD mice, AD/PAPP-A KO mice had improved cognitive behavior. • Human amyloid plaque immunostained for PAPP-A.
Source: Experimental Neurology
Institutions: Mayo Clinic, Mayo Clinic in Arizona
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,810
OpenAlex ID: W4402945561