proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice

Background: Alzheimer's disease (AD) is pathologically known for the amyloid-beta (A beta) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear. Objective: To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain A beta production in a transgenic AD mouse model (APPswePS1dE9). Methods: We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and A beta deposition in the brains of the AD mice. Results: The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance A beta levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR. Conclusions: Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis and progression.