Abstract
Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology. This is mainly based on the finding that TrkA receptor binding to APP depends on a minimal stretch of ~20 amino acids located in the juxtamembrane/extracellular domain of APP that carries the α- and β-secretase cleavage sites. Here, we provide evidence that: (i) NGF could be one of the “routing” proteins responsible for modulating the metabolism of APP from amyloidogenic towards non-amyloidogenic processing via binding to the TrkA receptor; (ii) the loss of NGF/TrkA signaling could be linked to sporadic AD contributing to the classical hallmarks of the neuropathology, such as synaptic loss, β-amyloid peptide (Aβ) deposition and tau abnormalities. These findings will hopefully help to design therapeutic strategies for AD treatment aimed at preserving cholinergic function and anti-amyloidogenic activity of the physiological NGF/TrkA pathway in the septo-hippocampal system.
Highlights
Alzheimer s disease (AD), a progressive and multifactorial neurodegenerative disease with both genetic and environmental causes, represents the most common form of dementia among the elderly (50–70% of late-life cases)
The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between nerve growth factor (NGF)/Tropomyosin receptor kinase A (TrkA) signaling and amyloid precursor protein (APP) metabolism within the context of Alzheimer's disease (AD) neuropathology
We focus on the control of cholinergic neurons metabolism by the NGF/TrkA system, with the long-term goal of identifying new approaches to improve the resilience of the cholinergic system to ageing and age-related neurodegeneration
Summary
Alzheimer s disease (AD), a progressive and multifactorial neurodegenerative disease with both genetic and environmental causes, represents the most common form of dementia among the elderly (50–70% of late-life cases). The so-called “neurotrophic model” hypothesizes that reduced availability of NGF and/or increased level of Pro-NGF, drives sporadic AD by linking the characteristic histopathological signs—such as synaptic pathology, cerebral Aβ deposits, neurofibrillary tangles, and memory loss—into a common neurodegenerative cascade [8] In support of this hypothesis, initial results on the effects of imbalanced NGF/TrkA signaling on pathological amyloid precursor protein (APP) metabolism [39,40,41] were subsequently extended at the molecular level. These agents cause the dissociation of APP/TrkA complexes and increase the production of a C-terminal fragment of APP (CTFβ) [45] Taken together, these results and observations suggest a model in which a deficit in NGF support leads to the first steps in degeneration of the BFCN. With other findings from other laboratories add further support to a unifying hypothesis linking NGF pathophysiology with cholinergic degeneration, tau, and Aβ misfolding in the onset of SAD [55,59]
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