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Neuronal p38? mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling ?-amyloid production.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38? to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38? signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38? only in neurons (5XFAD/p38??-N). We found that the neuronal-specific deletion of p38? improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38??-N mice display reduced amyloid-? accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38? signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-? deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.

SUBMITTER: Colie S

PROVIDER: S-EPMC5374488 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling β-amyloid production.

Colié Sandra S Sarroca Sara S Palenzuela Rocío R Garcia Idoia I Matheu Ander A Corpas Rubén R Dotti Carlos G CG Esteban José A JA Sanfeliu Coral C Nebreda Angel R AR

Scientific reports 20170331

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptom ...[more]

PMID: 28361984

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Project description:Introduction: β-Amyloid protein (Aβ) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aβ, it is known that Aβ oligomers (AβOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AβOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AβOs attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AβOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AβOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AβOs was developed and used to block the toxicity of AβOs. The data were analyzed with one-way analysis of variance. Results: AβOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aβ inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aβ. α3-Na/K-ATPase protein and synaptic β-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aβ oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three AβO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aβ oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

Dataset Information

Neuronal p38? mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling ?-amyloid production.

Publications

Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling β-amyloid production.

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