Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease

Murphy, Mark; Wilson, Yvette; Vargas, Ernesto; Munro, Kathryn M.; Smith, B.; Huang, Mengjie; Li, Qiao‐Xin; Xiao, Junhua; Masters, Colin L.; Reid, Christopher A.; Barrett, Graham L.

doi:10.1016/j.neurobiolaging.2014.09.014

Cited by 26 publications

(17 citation statements)

References 63 publications

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“…Indeed, we have reported previously (Fortress et al, 2011 ) that a single intra-hippocampal proNGF injection in aged rats induces morphological changes in basal forebrain cholinergic neurons, with dendritic retraction and atrophy of cell bodies. Recent studies also showed that a reduction of p75NTR expression ameliorates the cognitive deficits (Murphy et al, 2015 ) and increases cholinergic innervation in the dentate gyrus (Dokter et al, 2015 ), basolateral amygdala (Busch et al, 2017 ) and visual cortex (Von Bohlen und Halbach and Von Bohlen und Halbach, 2016 ); moreover, a small molecule ligand of p75NTR (LM11A-31) reverses cholinergic neurite dystrophy in Alzheimer’s Disease mouse models (Simmons et al, 2014 ). Therefore, we cannot exclude that the improvement of spatial learning and memory in TAT-Pep5 infused mice reflects positive effects on basal forebrain cholinergic neurons and their hippocampal projections.…”

Section: Discussionmentioning

confidence: 98%

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice

Buhusi

Etheredge

Granholm

et al. 2017

Front. Aging Neurosci.

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Memory decline during aging or accompanying neurodegenerative diseases, represents a major health problem. Neurotrophins have long been considered relevant to the mechanisms of aging-associated cognitive decline and neurodegeneration. Mature Brain-Derived Neurotrophic Factor (BDNF) and its precursor (proBDNF) can both be secreted in response to neuronal activity and exert opposing effects on neuronal physiology and plasticity. In this study, biochemical analyses revealed that increased levels of proBDNF are present in the aged mouse hippocampus relative to young and that the level of hippocampal proBDNF inversely correlates with the ability to perform in a spatial memory task, the water radial arm maze (WRAM). To ascertain the role of increased proBDNF levels on hippocampal function and memory we performed infusions of proBDNF into the CA1 region of the dorsal hippocampus in male mice trained in the WRAM paradigm: In well-performing aged mice, intra-hippocampal proBDNF infusions resulted in a progressive and significant impairment of memory performance. This impairment was associated with increased p-cofilin levels, an important regulator of dendritic spines and synapse physiology. On the other hand, in poor performers, intra-hippocampal infusions of TAT-Pep5, a peptide which blocks the interaction between the p75 Neurotrophin Receptor (p75NTR) and RhoGDI, significantly improved learning and memory, while saline infusions had no effect. Our results support a role for proBDNF and its receptor p75NTR in aging-related memory impairments.

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Section: Discussionmentioning

confidence: 98%

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice

Buhusi

Etheredge

Granholm

et al. 2017

Front. Aging Neurosci.

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“…Through either its constitutive activity in the unliganded state, or via that stimulated by its proneurotropin (proNT) ligands, p75 NTR promotes degenerative signaling mechanisms including activation of JNK, caspase, and RhoA (Casaccia-Bonnefil et al, 1996; Harrington et al, 2002; Troy et al, 2002; Ibanez and Simi, 2012; Coulson and Nykjaer, 2013) each of which likely contributes to AD-related degeneration (Figure 12). Crossing various AD mouse models with a p75 NTR knockout mouse construct results in reduced neuronal degeneration (Sotthibundhu et al, 2008; Knowles et al, 2009; Murphy et al, 2015). Multiple studies have identified genetic polymorphisms in the genes encoding p75 NTR , proNGF, proBDNF, or p75 NTR co-receptors including sortilin and SorCS2 that mediate proNT binding associated with increased AD risk (Cozza et al, 2008; Di Maria et al, 2012; Anastasia et al, 2013; Reitz et al, 2013; Andersson et al, 2016; Matyi et al, 2017).…”

Section: Small Molecule Neurotrophin Compounds For Treatment Of Admentioning

confidence: 99%

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

et al. 2019

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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.

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“…In vivo knock down of p75 NTR increased ChAT activity in aging rats ( Barrett et al, 2016 ). The reduction of p75 NTR expression ameliorated cognitive and cholinergic deficits in Tg2576 mice ( Murphy et al, 2015 ).…”

Section: Acetyl-coa Levels In the Brainmentioning

confidence: 99%

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Ronowska

Szutowicz

Bielarczyk

et al. 2018

Front. Cell. Neurosci.

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Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders.

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Reduction of p75 neurotrophin receptor ameliorates the cognitive deficits in a model of Alzheimer's disease

Cited by 26 publications

References 63 publications

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice

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

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

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