Dysmetabolism of the nerve growth factor pathway in the aging brain plays a pivotal role in cognitive decline

Nerve growth factor (NGF) is one of several neurotrophic proteins necessary for normal development and function of the mammalian nervous system. Nerve growth factor is necessary for normal brain cholinergic function, and reduced brain cholinergic activity is a hallmark pathological feature of human Alzheimer’s disease (AD). In both aging humans and transgenic rodent models, disruption of the normal NGF metabolic pathway (NGF dysmetabolism) leads to brain neuronal damage, loss of synaptic plasticity, and cognitive decline. Nerve growth factor dysmetabolism in AD patients is a gradual process, beginning years prior to the development of mild cognitive impairment. In addition to changes in the levels of specific molecular regulators of the NGF pathway, there are changes in the proportions of the 2 major receptors for NGF and its precursor (proNGF) in the brain: the tropomyosin kinase A (TrkA) receptor and the p75 neurotrophin (p75 NTR ) receptor. Nerve growth factor has high affinity for TrkA receptors, the stimulation of which has neuroprotective effects. The precursor of NGF has higher affinity than NGF for p75 NTR receptors; stimulation of p75 NTR receptors by proNGF has deleterious effects on neurons. With NGF dysmetabolism, the respective ratios of available NGF/proNGF and TrkA/p75 NTR receptors are decreased, favoring neuronal damage. In rodent models genetically engineered to produce monoclonal antibodies against NGF, neuronal damage and cognitive decline occur, even when the antibodies are targeted specifically against peripheral (ie, not CNS) NGF. Because canine cognitive dysfunction is a naturally occurring model of human AD, NGF dysmetabolism may be relevant to aging dogs. This article will review details of NGF dysmetabolism and how this aberrant pathway contributes to cognitive decline.