Cholinergic Involvement in Alzheimer’s Disease. A Link with NGF Maturation and Degradation

Abstract

Basal forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) supply for the maintenance of their cholinergic phenotype as well as their cholinergic synaptic integrity. The precursor form of NGF, proNGF, abounds in the CNS and is highly elevated in Alzheimer's disease. In order to obtain a deeper understanding of the NGF biology in the CNS, we have performed a series of ex vivo and in vivo investigations to elucidate the mechanisms of release, maturation and degradation of this neurotrophin. In this short review, we describe this NGF metabolic pathway, its significance for the maintenance of basal cholinergic neurons, and its dysregulation in Alzheimer's disease. We are proposing that the conversion of proNGF to mature NGF occurs in the extracellular space by the coordinated action of zymogens, convertases, and endogenous regulators, which are released in the extracellular space in an activity-dependent fashion. We further discuss our findings of a diminished conversion of the NGF precursor molecule to its mature form in Alzheimer's disease as well as an augmented degradation of mature NGF. These combined effects on NGF metabolism would explain the well-known cholinergic atrophy found in Alzheimer's disease and would offer new therapeutic opportunities aimed at correcting the NGF dysmetabolism along with Abeta-induced inflammatory responses.

Association between Nerve Growth Factor Gene Polymorphism and Executive Dysfunction in Japanese Patients with Early-Stage Alzheimer’s Disease and Amnestic Mild Cognitive Impairment

“…Maturation failure or increased degradation of NGF might be responsible for the vulnerability of cholinergic neurons in the medial frontal cortex of patients with AD [18,19,46]. Since cholinergic neurons influence the neurocognitive attentional function of rodents and humans, cholinergic drugs (acetylcholine esterase inhibitors) or NGF gene injection into BCNs have improved attention deficits and cerebral metabolism in early-stage AD [5,7,46,47,48,49].…”

“…The hypothesis was advanced that NGF reduction led to vulnerabilities in the cholinergic system including associated enzymes, such as choline-acetyl transferase and acetylcholine esterase [14,15]. Moreover, some previous reports have supported a ‘neurotrophic deficit’ hypothesis, in which a reduction in NGF would cause the deterioration of basal forebrain cholinergic neurons (BCNs) and an NGF/tropomyosin-related kinase A signaling system dysregulation, resulting in the neuropathological changes of AD including amyloid-β accumulation and cognitive impairments [16,17,18,19,20]. While a regional increase in proNGF levels was shown in the frontal, hippocampus and parietal cortex of patients with MCI, early-stage AD and late-stage AD, the mature NGF levels were not reduced in the frontal and hippocampus cortex of postmortem brain tissue in patients with AD [21,22,23,24].…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…Recently, evidence has been provided to support a model in which the formation of an inter-protomer disulfide bond in p75 allows a scissoring (or snail-tong) action upon NGF binding that promotes binding of intracellular adaptor proteins (Simi & Ibanez, 2010;Vilar et al, 2009). As mentioned above (Section 2.2), proneurotrophins may play significant role in AD, due to their ability to stimulate p75 in the absence of positive Trk signals thereby promoting apoptosis and death of neurons or glia (Cuello et al, 2010;Fahnestock et al, 2001;Teng, et al 2010). These effects are thought to be mediated by the same pathways ( Fig.…”

The role of nerve growth factor and its receptors in tumorigenesis and cancer pain

“…However, recent studies showed that proNGF, the precursor form of NGF, is really largely exist in central nervous system tissues, and has biological functions exceeding its role as a precursor (17,28,29). ProNGF could induce cell death by binding to p75NTR with high affinity (30)(31)(32).…”