Analysis of the effect of adult onset increase of neurotrophic factor GDNF expression in APP‐NL‐G‐F AD mouse model

Abstract

AbstractBackgroundGradual decline in cholinergic transmission and cognitive function occurs during normal aging, whereas pathological loss of cholinergic function is a hallmark of different types of dementia, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease dementia (PDD). Glial cell line‐derived neurotrophic factor (GDNF) is known to modulate and enhance the dopamine system. However, how endogenous GDNF influences brain cholinergic transmission has remained elusive.MethodRecently we showed that two fold increase in endogenous GDNF expression in Gdnf hypermorphic mice, Gdnf wt/hyper, attenuated age‐associated decline in the cholinergic index and cognitive function observed in Gdnf wt/wt animals. Biochemical analysis revealed that the level of nerve growth factor (NGF), which is important for survival and function of central cholinergic neurons, was significantly increased in several brain areas of old Gdnf wt/hyper miceResultOur results identified endogenous GDNF as a potential enhancer of cholinergic transmission upon aging (11). Here we propose to follow up those results by analyzing the effect of adult onset increase in endogenous GDNF expression on cholinergic index, A‐beta load, NGF expression and cognition in APP‐NLGF mouse model of AD. To accelerate AD onset and to facilitate future studies we have also generated and propose characterization of APP‐NLGF conditional Hypermorph mouse model.ConclusionOur goal is to conclude therapeutic potential of enhanced endogenous GDNF signaling on AD associated cholinergic and cognitive decline to pave way to new dementia treatments based on GDNF mimetics currently under development by several academic and industrial laboratories.