Nerve Growth Factor Pathobiology During the Progression of Alzheimer’s Disease

Abstract

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75 NTR -mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75 NTR death receptor for the treatment of AD.

Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease

“…Cerebellar PCs are also characterized by the expression of the neurotrophin protein NGF (Shelton and Reichardt, 1986) and its cognate low affinity p75 NTR and high affinity TrkA receptors (Cohen-Cory et al, 1991;Mufson et al, 1991;Hock et al, 1998;Triaca et al, 2016). NGF binds to its TrkA receptor, activating signal transduction pathways key for neuronal survival (Kaplan and Miller, 2004), while p75 NTR , a modulator of NGF/TrkA binding (Kaplan and Miller, 2004), is associated with cell death (Mufson et al, 2019). Our quantitative analysis revealed a significant reduction in the number of TrkA-ir PCs in AD compared to HC but not DS.…”

“…Used with permission from Barrow Neurological Institute, Phoenix, Arizona. 2014) and AD (Mufson et al, 2019) are required to decipher the molecular mechanisms underlying the role that NGF and its receptors play in PC dysfunction in DS.…”

“…Although these receptors are constitutively expressed during early cerebellar development through adulthood (Muragaki et al, 1995;Roux and Barker, 2002;Quartu et al, 2003a,b;Florez-McClure et al, 2004;Schor, 2005;Lotta et al, 2014), their role in PC pathology in DS is poorly defined. Numerous studies indicate that NGF receptors play a key role in cholinergic basal forebrain neuron dysfunction in AD and DS (Sendera et al, 2000;Mufson et al, 2019). However, the effect of trisomy upon TrkA and p75 NTR and their relationship with CBPs in PCs in DS remains to be investigated.…”

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

“…Likewise, KLK6 can release enkephalin from pro-enkephalin precursors, similarly to the canonical processing performed by the enzyme furin (Silva et al, 2017). It has been proposed that alterations in the enzymatic pathway that controls the maturation of pro-nerve growth factor (NGF) to NGF and its subsequent degradation could be relevant in neurodegenerative processes such as Alzheimer's disease that affect the activity of basal cholinergic neurons of the forebrain (Fahnestock and Shekari, 2019;Mitra et al, 2019;Mufson et al, 2019). A role for KLK8 in the expression of NGF at the skin has been described, but studies directed to show whether that KLK8 or other KLKs influence the bioavailability of NGF in the CNS have not yet been explored (Shingaki et al, 2012).…”

Small molecule activation of the neurotrophin hepatocyte growth factor to treat Alzheimer disease

“…He went on to conclude that even though the presence of senile plaques and neurofibrillary tangles were observed, "the plaques are not the cause of senile dementia, but only an accompanying feature of senile involution of the central nervous system" [7] . Despite this warning research regarding AD has long been focused on the "amyloid cascade hypothesis" and strategies to prevent and/or remove plaques [2,8] . Unfortunately, the results seen from anti-amyloid (plaque buster) clinical trials have been disappointing [9] .…”