The Brain NGF Metabolic Pathway in Health and in Alzheimer’s Pathology

Abstract

Emerging research has re-emphasized the role of the cortical cholinergic system in the symptomology and progression of Alzheimer’s disease (AD). Basal forebrain (BF) cholinergic nuclei depend on target-derived NGF for survival during development and for the maintenance of a classical cholinergic phenotype during adulthood. In AD, BF cholinergic neurons lose their cholinergic phenotype and function, suggesting an impairment in NGF-mediated trophic support. We propose that alterations to the enzymatic pathway that controls the maturation of proNGF to mature NGF and the latter’s ulterior degradation underlie this pathological process. Indeed, the NGF metabolic pathway has been demonstrated to be impaired in AD and other amyloid pathologies, and pharmacological manipulation of NGF metabolism has consequences in vivo for both levels of proNGF/NGF and the phenotype of BF cholinergic neurons. The NGF pathway may also have potential as a biomarker of cognitive decline in AD, as its changes can predict future cognitive decline in patients with Down syndrome as they develop preclinical Alzheimer’s pathology. New evidence suggests that the cholinergic system, and by extension NGF, may have a greater role in the progression of AD than previously realized, as changes to the BF precede and predict changes to the entorhinal cortex, as anticholinergic drugs increase odds of developing AD, and as the use of donepezil can reduce rates of hippocampal and cortical thinning. These findings suggest that new, more sophisticated cholinergic therapies should be capable of preserving the basal forebrain thus having profound positive effects as treatments for AD.

Muscle Injury Induces Postoperative Cognitive Dysfunction

“…NGF is an essential neurotrophin for survival and regulation of basal forebrain cholinergic neuron (BFCN) function. Its decrease was shown to affect BFCN functions, resulting in memory issues in Alzheimer's disease 38 . Impaired NGF signaling pathway is also described in mild cognitive impairment resulting to aging 38 or sepsis 23 , and recent therapeutic approaches in secondary cognitive impairments are aiming to restore normal expression or/and level of NGF 49 .…”

“…Its decrease was shown to affect BFCN functions, resulting in memory issues in Alzheimer's disease 38 . Impaired NGF signaling pathway is also described in mild cognitive impairment resulting to aging 38 or sepsis 23 , and recent therapeutic approaches in secondary cognitive impairments are aiming to restore normal expression or/and level of NGF 49 . We hypothesize that the decrease in brain NGF levels observed in FI mice 28 days after surgery, more than a marker of memory dysfunction, plays an active role in the processes leading to cognitive impairment after surgical intervention.…”

“…Mouse drawing by Clker-Free-Vector-Images from Pixabay. (2020) 10:2768 | https://doi.org/10.1038/s41598-020-59639-3 www.nature.com/scientificreports www.nature.com/scientificreports/ in neuronal function and synaptic plasticity 38,39 and their potential implication in POCD has recently been described 13,15 .…”

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

“…Finally, neuroinflammation can exert a primary function in AD pathophysiology by interfering with nerve growth factor (NGF) maturation and function. NGF is a neurotrophic factor essential for the survival and homeostasis of basal forebrain cholinergic neurons whose selective degeneration critically contributes to cognitive decline in AD patients (132,133). Studies in transgenic animal models of AD indicate that the proinflammatory process-initiated before plaque deposition and promoted by soluble Aβ oligomers-leads to an impairment of NGF metabolic pathway characterized by a reduced conversion of the precursor proNGF to the mature NGF (mNGF) as well as by an increased deprivation of mNGF (18,132,134).…”

Sesamin Promotes Neurite Outgrowth under Insufficient Nerve Growth Factor Condition in PC12 Cells through ERK1/2 Pathway and SIRT1 Modulation

“…e binding of NGF and tropomyosin-receptor-kinase A (TrkA) receptor stimulates downstream signaling pathways, resulting in expression of genes essential for neuronal differentiation such as growth-associated protein-43 (GAP43) and synaptophysin (SYP) via the extracellular signal-regulated kinase (ERK1/2-MAPK) signaling pathway [2]. However, the mature NGF level is reduced in neurodegenerative diseases, especially AD, leading to NGF insufficiency in patients [3]. Currently, NGF supplementation becomes to be an interesting option to restore neuronal function.…”