Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons

Allard, S.T.M.; Jacobs, Marie L.; Carmo, Sonia Do; Cuello, A. Claudio

doi:10.1016/j.neurobiolaging.2018.03.002

Cited by 29 publications

(23 citation statements)

References 76 publications

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“…Cholinergic neurons are distributed in the nervous system of all vertebrates and are involved in the control of motor functions as well as in complex cognitive functions and behaviors. Cholinergic systems are also associated to age-dependent neurodegeneration [ 58 , 59 , 60 ], also caused by an imbalance of neurotrophins and related receptors [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Cholinergic System and NGF Receptors: Insights from the Brain of the Short-Lived Fish Nothobranchius furzeri

et al. 2020

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Nerve growth factor (NGF) receptors are evolutionary conserved molecules, and in mammals are considered necessary for ensuring the survival of cholinergic neurons. The age-dependent regulation of NTRK1/NTRKA and p75/NGFR in mammalian brain results in a reduced response of the cholinergic neurons to neurotrophic factors and is thought to play a role in the pathogenesis of neurodegenerative diseases. Here, we study the age-dependent expression of NGF receptors (NTRK1/NTRKA and p75/NGFR) in the brain of the short-lived teleost fish Nothobranchius furzeri. We observed that NTRK1/NTRKA is more expressed than p75/NGFR in young and old animals, although both receptors do not show a significant age-dependent change. We then study the neuroanatomical organization of the cholinergic system, observing that cholinergic fibers project over the entire neuroaxis while cholinergic neurons appear restricted to few nuclei situated in the equivalent of mammalian subpallium, preoptic area and rostral reticular formation. Finally, our experiments do not confirm that NTRK1/NTRKA and p75/NGFR are expressed in cholinergic neuronal populations in the adult brain of N. furzeri. To our knowledge, this is the first study where NGF receptors have been analyzed in relation to the cholinergic system in a fish species along with their age-dependent modulation. We observed differences between mammals and fish, which make the African turquoise killifish an attractive model to further investigate the fish specific NGF receptors regulation.

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Section: Discussionmentioning

confidence: 99%

Cholinergic System and NGF Receptors: Insights from the Brain of the Short-Lived Fish Nothobranchius furzeri

et al. 2020

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“…Simultaneous evaluation demonstrated hampered plasmin machinery along with increased MMP9 activity, culminating in elevated levels of proNGF in the brain tissue (Fahnestock et al, 2001; Peng et al, 2004; Fabbro and Seeds, 2009; Mroczko et al, 2013). Higher proNGF levels not only induce pro-apoptotic signaling, but are also found to affect the receptor binding of mNGF and its axonal trafficking and result in retrograde atrophy of cholinergic neurons in the basal forebrain (Sobottka et al, 2008; Ioannou and Fahnestock, 2017; Allard et al, 2018). The apoptotic signaling induced by pro-NGF is dependent on the relative expression of TrkA and p75, and is favored by a decreased ratio of TrkA/p75 that is also evident in AD (Counts et al, 2004; Ginsberg et al, 2006; Masoudi et al, 2009).…”

Section: What Goes Wrong In Ad In Relation To Ngf?mentioning

confidence: 99%

Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF

2019

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

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“…In a further study, impaired proNGF cortical maturation following infusion of α2-antiplasmin was sufficient to alter BFCN phenotype. In particular, there was a significant atrophy of cell bodies as well as a downregulation of p75NTR and TrkA, and a reduction in the expression of ChAT protein, further validating the importance of the extracellular NGF metabolic pathway for the phenotypic maintenance of BFCN (Allard et al, 2018).…”

Section: A Novel Ngf Metabolic Pathway and Its Pharmacological Validamentioning

confidence: 68%

“…We further validated this pathway by demonstrating that pharmacological inhibition of the maturation or degradation enzymatic pathway can trigger proNGF/mNGF imbalances (Allard et al, 2012, 2018). In particular, continuous infusion of α2-antiplasmin, the endogenous inhibitor of plasmin, in the cerebral cortex of rats led to reduced levels of mNGF, which further led to cortical cholinergic synaptic atrophy.…”

Section: A Novel Ngf Metabolic Pathway and Its Pharmacological Validamentioning

confidence: 82%

“…Our lab introduced the concept that the day-to-day expression of endogenous mNGF regulates the steady-state number of cortical cholinergic synapses (Debeir et al, 1999) and, in consequence, the maintenance of the “cholinergic tone.” This is in line with the classical Hebbian notion that synaptic growth is a brain activity-dependent phenomenon (Hebb, 1949). Indeed, altering the availability of endogenous NGF by pharmacologically blocking its conversion from proNGF to mNGF or by preventing its degradation does lead to notable changes in the density of cortical cholinergic terminals (Allard et al, 2012) as well as in the size and phenotype of BF cholinergic cell bodies (Allard et al, 2018).…”

Section: Ngf Is Responsible For the Maintenance Of The Cholinergic Phmentioning

confidence: 99%

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

2019

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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.

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Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons

Cited by 29 publications

References 76 publications

Cholinergic System and NGF Receptors: Insights from the Brain of the Short-Lived Fish Nothobranchius furzeri

Cholinergic System and NGF Receptors: Insights from the Brain of the Short-Lived Fish Nothobranchius furzeri

Innovative Therapy for Alzheimer’s Disease-With Focus on Biodelivery of NGF

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

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