Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

Kailainathan, Sumangali; Piers, Thomas M.; Yi, Jee Hyun; Choi, Seong-Min; Fahey, Mark; Borger, Eva; Gunn-Moore, Frank J.; O'Neill, Laurie; Lever, Michael B; Whitcomb, Daniel J.; Cho, Kwangwook; Allen, Shelley J

doi:10.1016/j.phrs.2015.12.008

Cited by 32 publications

(34 citation statements)

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“…Our data are consistent with a serial synaptic weakening mechanism in which the activation of caspase-3 leads to cleavage of Akt1, removing the tonic inhibition of GSK-3, which subsequently increases pTau and causes inhibition of LTP. Caspase-3, GSK-3 and pTau are all critically involved in LTD, and aberrant LTD expression by these molecules has been implicated in the pathophysiology of synapse weakening and neurodegeneration [18,19,21,[32][33][34][35]. Interestingly, LTP induction can inhibit LTD signalling cascades [17] and, conversely, aberrant activation of LTD and/or synapse weakening signalling cascades inhibits LTP expression [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…A given stimuli (i.e., GCs), therefore, could tip this balance in favor of LTP or LTD by acting as a catalyst for signalling mechanisms associated with one or the other form of plasticity. Previous studies have demonstrated that the inhibition of aberrantly expressed LTD and synapse weakening signalling molecules restores LTP expression ordinarily inhibited in an Aβ neurotoxicity model [19,35].…”

Section: Discussionmentioning

confidence: 99%

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Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Brown

Whitehead

et al. 2017

Pharmacological Research

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Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Brown

Whitehead

et al. 2017

Pharmacological Research

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“…Instead, proBDNF binds to the pan-neurotrophin receptor p75 Neurotrophin Receptor (p75NTR; Lee et al, 2001 ), to promote cell death (Frade et al, 1996 ; Kuan et al, 1999 , 2003 ), to inhibit neurite outgrowth (Yamashita et al, 1999 ) by modulating RhoA GTPase activity (Yamashita and Tohyama, 2003 ), and to determine presynaptic terminal retraction (Nakayama et al, 2000 ; Yang et al, 2009 ). ProBDNF and p75NTR negatively regulate synaptic transmission and plasticity (Yang et al, 2014 ; Kailainathan et al, 2015 ) and are linked to NMDAR-dependent LTD (Nakayama et al, 2000 ; Rösch et al, 2005 ; Woo et al, 2005 ; Yang et al, 2009 ; Michaelsen et al, 2010 ). A recently generated cleavage-resistant proBDNF knockin mouse (Yang et al, 2014 ) revealed that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75NTR.…”

Section: Introductionmentioning

confidence: 99%

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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“…We have recently identified the activation of caspase-3 and glycogen synthase kinase 3 (GSK3β), and phosphorylation of the microtubule associated protein tau (pTau), as being pivotal and necessary end-point signals in synapse weakening (Kimura et al, 2014, Regan et al, 2016. Critically, aberrantly enhanced pTau is a common factor to synapse dysregulation and weakening induced by a variety of factors, including Aβ, stress and neurotrophins (Sotiropoulos et al, 2011, Pooler et al, 2014, Kailainathan et al, 2016. Given the aforementioned importance of CP-AMPAR expression to the initial synaptic alterations induced by stress and Aβ (Whitehead et al, 2013, one favourable hypothesis is that CP-AMPAR expression leads to aberrant synapse weakening via the activation of signaling pathways culminating in tau phosphorylation.…”

Section: Potential Role Of Ca 2+ -Permeable Ampa Receptors In Alzheimmentioning

confidence: 99%

Ca2+-permeable AMPA receptor: A new perspective on amyloid-beta mediated pathophysiology of Alzheimer's disease

Whitehead

Regan²,

Whitcomb³

et al. 2017

Neuropharmacology

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α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the primary conduits of excitatory synaptic transmission. AMPARs are predominantly Ca-impermeable in the matured excitatory synapse, except under certain circumstances. Growing evidence implicates the Ca permeability of AMPARs in the regulation of long-term synaptic plasticity and in the pathophysiology of several neurological disorders. Therefore, the Ca conductance of AMPARs may have both physiological and pathological roles at synapses. However, our understanding of the role of Ca permeable AMPARs (CP-AMPARs) in Alzheimer's disease is limited. Here we discuss insights into the potential CP-AMPAR mediated pathophysiology of Alzheimer's disease, including: 1. Ca-mediated aberrant regulation of synapse weakening mechanisms, and 2. neuronal network dysfunction in the brain. Consideration of CP-AMPARs as primary drivers of pathophysiology could help in understanding synaptopathologies, and highlights the potential of CP-AMPARs as therapeutic targets in Alzheimer's disease. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.

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Activation of a synapse weakening pathway by human Val66 but not Met66 pro-brain-derived neurotrophic factor (proBDNF)

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Cited by 32 publications

References 50 publications

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Increased Hippocampal ProBDNF Contributes to Memory Impairments in Aged Mice

Ca2+-permeable AMPA receptor: A new perspective on amyloid-beta mediated pathophysiology of Alzheimer's disease

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