Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Brito, Verónica; Giralt, Albert; Enriquez-Barreto, Lilian; Puigdellívol, Mar; Suelves, Núria; Zamora‐Moratalla, Alfonsa; Ballesteros, Jesús J.; Martı́n, Eduardo D.; Domínguez-Iturza, Nuria; Morales, Miguel; Alberch, Jordi; Ginés, Sílvia

doi:10.1172/jci74809

Cited by 103 publications

(133 citation statements)

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“…We demonstrated up-regulation of p75 NTR in the hippocampus of distinct HD mouse models and in human brain without evident changes in the cortex, which extends our previous data showing increased p75 NTR expression in the HD striatum [4]. In agreement with a critical role of aberrant p75 NTR expression in hippocampal dysfunction we found preserved spatial, recognition and associative memories in new double-mutant mice expressing mutant huntingtin but "physiological" levels of p75 NTR levels (Hdh…”

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confidence: 88%

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2016

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Huntington's disease (HD) is a fatal neurodegenerative disorder with a characteristic phenotype including chorea and dystonia, uncoordinated fine movements, cognitive decline and psychiatric disturbances. Even though the clinical diagnosis of HD relies on the manifestation of motor abnormalities, the associated memory impairments have been growing in prominence. Indeed, cognitive deficits are evident along all the disease process even in the prodrome before any motor diagnosis is given.These clinical signs have been mainly attributed to corticostriatal dysfunction being deficits of neurotrophic support, caused by either reduced levels of brain-derived neurotrophic factor (BDNF) [1] or decreased TrkB and aberrant p75 NTR signalling [2, 3], one of the major pathogenic mechanism involved. However, in recent years has emerged the idea that cognitive decline in HD is likely a reflection of a widespread brain circuitry defect rather than a basal ganglia dysfunction per se. In this regard, in our recent studies we shed new light on the contribution of the hippocampal circuitry to synaptic and memory decline in HD. We demonstrated hippocampal dysfunction in a precise genetic HD mouse model that expresses endogenous levels of mutant huntingtin, Hdh Q7/ Q111 mice, manifested as alterations in spatial, recognition and associative memories.To get insight into the molecular mechanisms underlying such defects, we focused on p75 NTR since growing evidence indicate that p75 NTR plays an antagonistic role in synaptic plasticity. We demonstrated up-regulation of p75 NTR in the hippocampus of distinct HD mouse models and in human brain without evident changes in the cortex, which extends our previous data showing increased p75 NTR expression in the HD striatum [4]. In agreement with a critical role of aberrant p75 NTR expression in hippocampal dysfunction we found preserved spatial, recognition and associative memories in new double-mutant mice expressing mutant huntingtin but "physiological" levels of p75 NTR levels (Hdh:p75+/-mice).How aberrant p75 NTR levels may mediate synaptic and memory deficits in HD is an intriguing question. On one hand, our results indicated that p75 NTR directly or indirectly regulate the expression of different synapticrelated proteins previously implicated in HD synaptic and/or cognitive deficits, such as CBP, CamKII, GluA1 or BDNF since memory improvements in double mutant :p75 +/-mice correlated with a recovery of the expression and/or phosphorylation of these molecules. On the other, the loss of dendritic spines in CA1 pyramidal neurons exhibited by Hdh Q7/Q111 mutant mice was also prevented by normalization of p75 NTR levels. Altogether, these data suggest that synaptic and memory deficits in HD could be related with a reduction in proteins involved in synaptic function and in the number and complexity of hippocampal dendritic spines in agreement with a role of p75 NTR as a negative regulator of dendritic spine dynamics and synaptic activity.We further built on work showing that p75 NTR contribute...

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confidence: 88%

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2016

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“…Thus, the synaptic dysfunction of MSNs early in HD is attributable to enhanced p75 NTR signalling through PTEN (phosphatase and tensin homolog) resulting in suppression of Akt signalling [117,119]. Likewise, striatal activation of TrkB-FL and ERK1/2 is attenuated at early disease stages when total receptor and ligand levels are still normal [118].…”

Section: Defective Expression and Stability Of Bdnf And Trkb In Nementioning

confidence: 99%

Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

Tejeda

Dı́az-Guerra

2017

IJMS

104

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Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling.

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“…Other non-neuronal cell types present in the striatum, such as astrocytes, microglia, and oligodendrocytes could express p75 and provide some type of extrinsic support for the MSNs. Some expression of p75 in MSNs has been reported previously (Brito et al, 2014). A recent study, however, indicates that the majority of p75 in the striatum is expressed in immature oligodendrocytes, suggesting at least some p75 signaling is non-cell autonomous (Ma et al, 2015).…”

Section: Discussionmentioning

confidence: 54%

“…The BACHD model used in this study differs substantially from the Hdh +/ Q175 mice used in this study, both in symptom onset and disease course, and this paper was examining a specific type of synaptic plasticity, while we focused on biochemical and histological changes. In addition, Brito et al reported rescued learning and memory deficits in Q111 mice by decreasing the level of p75 expression in the hippocampus (2014). These two studies suggest a potentially pathogenic role for p75 in HD at symptomatic disease stages and/or possibly in a regionally specific, or animal model-specific fashion.…”

Section: Discussionmentioning

confidence: 99%

“…R6/1 is more rapidly progressive, and the truncated mutation is transgenically expressed rather than being expressed from the endogenous locus (Brooks et al, 2011; Pouladi et al, 2013). We were unable to achieve specific labeling with the p75 antibody used in the Q111 and human post-mortem studies, and therefore a direct comparison with these studies is difficult (Brito et al, 2013, 2014). Interestingly, in the same Q175 model of HD used in this study, p75 levels were reported to be decreased at 12 months of age in both the heterozygous and homozygous mutants when compared to WT animals (Ma et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

et al. 2016

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Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a constellation of motor, cognitive, and psychiatric features. Striatal medium spiny neurons, one of the most affected populations, are dependent on brain-derived neurotrophic factor (BDNF) anterogradely transported from the cortex for proper function and survival. Recent studies suggest both receptors for BDNF, TrkB and p75 neurotrophin receptor (p75), are improperly regulated in the striata of HD patients and mouse models of HD. While BDNF–TrkB signaling almost exclusively promotes survival and metabolic function, p75 signaling is able to induce survival or apoptosis depending on the available ligand and associated co-receptor. We investigated the role of p75 in the Q175 knock-in mouse model of HD by examining the levels and activation of downstream signaling molecules, and subsequently examining Hdh+/Q175;p75−/− mice to determine if p75 represents a promising therapeutic target. In Hdh+/Q175;p75+/+ mice, we observed enhanced survival signaling as evidenced by an increase in phosphorylation and activation of Akt and the p65 subunit of NFκB in the striatum at 5 months of age and an increase in XIAP expression compared to Hdh+/+;p75+/+ mice; this increase was lost in Hdh+/Q175;p75−/− mice. Hdh+/Q175;p75−/− mice also showed a decrease in Bcl-XL expression by immunoblotting compared to Hdh+/Q175;p75+/+ and Hdh+/+;p75+/+ littermates. Consistent with diminished survival signaling, DARPP-32 expression decreased both by immunoblotting and by immunohistochemistry in Hdh+/Q175;p75−/− mice compared to Hdh+/+;p75+/+, Hdh+/Q175;p75+/+, and Hdh+/+;p75−/− littermates. Additionally, striatal volume declined to a greater extent in Hdh+/Q175;p75−/− when compared to Hdh+/Q175;p75+/+ littermates at 12 months, indicating a more aggressive onset of degeneration. These data suggest that p75 signaling plays an early role in augmenting pro-survival signaling in the striatum and that disruption of p75 signaling at a pre-symptomatic age may exacerbate pathologic changes in Hdh+/Q175 mice.

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Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

Cited by 103 publications

References 104 publications

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Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

The p75 neurotrophin receptor augments survival signaling in the striatum of pre-symptomatic Q175 mice

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