The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer’s Cholinergic Atrophy

Abstract

The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer’s disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer’s disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.

Rita Levi-Montalcini: the neurologist who challenged fascism

“…Evidence towards the importance of the nerve growth factor, particularly in neurodegenerative diseases, piled on mainly after the 1970s, resulting in the researchers only receiving the due accolades with the Nobel in 1986. 7,[16][17][18] HER POLITICAL AND SOCIAL WORK Throughout her life, Rita was very politically active. In 2001, she was made senator for life, and although she considered it a very stressful experience, she never lost a session.…”

“…Her discovery of the nerve growth factor paved the way for our current comprehension of neurodegeneration. [16][17][18]…”

Modes of Acetylcholine Signaling in the Prefrontal Cortex: Implications for Cholinergic Dysfunction and Disorders

“…Recent data from preclinical studies demonstrate that the consequences of adult or developmental EtOH exposure resemble advanced brain aging or produces accelerated AD-related pathology in transgenic models with AD-related transgenes [80][81][82][83]. Advanced aging, AD, and AUD have some overlapping neuropathological sequelae: upregulation of proinflammatory markers, suppressed hippocampal neurogenesis, suppression of basal forebrain cholinergic phenotype, and altered pro-and mature NT levels-as well as a change in the ratio of Trk to p75 NTRs [84][85][86][87][88]. A common pathway for cholinergic dysfunction in AD and AUD is the disruption of neurotrophins and their receptors (see Figure 2), which may drive additive effects of AD and AUD pathology.…”

The Role of Neurotrophin Signaling in Age-Related Cognitive Decline and Cognitive Diseases

“…Because of the severe neurodegeneration of the cholinergic neurons in the basal forebrain and linkage with cholinergic input and cognitive function in AD, NGF signaling has been indicated as a key modulator of AD pathology [ 81 ]. Meta-analysis of 98 articles investigating neurotrophic factor levels in CSF and the blood of AD patients showed increased NGF levels in CSF of AD patients [ 82 ].…”

“…A systematic review covering 23 post-mortem studies of AD patients showed that most studies suggested increased proNGF levels in the hippocampus and neocortex of patients with AD [82]. As a mechanism of proNGF accumulation in the AD brain, it has been proposed that there are disturbances in the conversion of proNGF to NGF [81]. Bruno et al (2006) demonstrated that NGF is produced in the synaptic cleft via a coordinated release of proNGF, zymogens, convertases, and endogenous regulators in an activity-dependent manner [83].…”