Application of Nerve Growth Factor in Alzheimer’s Disease

Abstract

Alzheimer's Disease (AD) is the most common form of dementia, which is characterized by a progressive decline in memory and cognitive function, accompanied with behavioral changes such as confusion, irritability and aggression, mood swings, language breakdown and eventually long-term memory loss. The most significant pathological findings in the brain affected by AD are senile plaques, neurofibrillary tangles, neuron loss or degeneration, particularly in the areas connected to the cerebral cortex and hippocampus, one of the most prominent among the regions being the basal forebrain cholinergic neurons. Although many basic and clinical studies have shown that drug treatment could improve the cognitive function and memory of AD patient, it is still a considerable challenge to delay and/or stop the neuron loss and degeneration.Previous studies showed that imbalance of neurotrophic factors in the brain and lack of neurotrophic support causes neuronal atrophy and death. Among the neurotrophic factors, Nerve Growth Factor (NGF) is the best characterized one. Knockout of NGF in adult transgenic mice leads to severe neuronal death in basal forebrain cholinergic neurons. Several in vivo and in vitro studies have demonstrated that Intra Cerebro Ventricular (ICV) NGF administration completely prevents the retrograde degeneration of cholinergic neurons and increases learning and memory in the animal model of AD [1]. However, NGF is a large molecular protein that does not easily cross the blood-brain barrier. The delivery of NGF to the brain poses a major challenge for clinical application. Here, we will focus on the delivery strategies of NGF on brain and beneficial effects of delivered NGF on cholinergic neurons and functional recovery of AD. ICV NGF AdministrationThe beneficial effects of ICV NGF administration in the AD model with fimbria-fornix transection have been studies nearly 30 years ago. Studies performed in aged animals showed that ICV NGF administration could reverse age-associated basal forebrain cholinergic neuronal degeneration and improve the learning and memory. Furthermore, in non-human primate brain, the ability of NGF could also prevent basal forebrain cholinergic neuronal degeneration and correct the learning and memory. One clinical trial was reported in 1998. In this study, three AD patients were treated with murine ICV NGF injection and showed certain beneficial effects. Two negative side effects occurred after NGF treatment, back pain and weight reduction [2]. Scientists keep seeking options to deliver NGF into the brain.