p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease

Background Ribosomal protein S6 kinase 1(S6K1)is a serine-threonine kinase that has two main isoforms:p70S6K(70-kDa isoform)and p85S6K(85-kDa isoform).p70S6K,with its upstream mammalian target of rapamycin(mTOR),has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s dis-ease(AD).However,the function of p85S6K has long been neglected due to its high similarity to p70S6k.The role of p85S6K in learning and memory is still largely unknown.Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K.Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor.The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence,Western blot,in situ proximity ligation assay,morphological staining and behavioral examination.Further,the expression level of p85S6K was measured in brains from AD patients and AD model mice.Results p85S6K,but not p70S6K,was enriched in the postsynaptic densities.Moreover,knockdown of p85S6K resulted in defective spatial and recognition memory.In addition,p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150.Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in syn-apses,thus sustaining synaptic function and spine densities.Moreover,p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice.Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice.Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1.The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer’s disease mice

Background Neuropsychiatric symptoms(NPS)such as depression,anxiety,apathy,and irritability occur in prodromal phases of clinical Alzheimer’s disease(AD),which might be an increased risk for later developing AD.Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor(SSRI)paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress.Methods To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress,we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age.Next,we tested the cognitive,biochemical and pathological,effects of long term administration of paroxetine at 6 months old.Results Our results showed that AD mice displayed emotional dysfunction in the early stage.Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice.Conclusion Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice.These neuroprotective effects are attributable to functional restoration of glutamate receptor(GluN2A)in AD mice.

Targeting neuroplasticity in neurodegenerative diseases stimulation techniques

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer's disease(AD)and Parkinson's disease(PD).Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity,which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers.In this review,we discuss several brain stimulation techniques,with a special emphasis on transcranial magnetic stimulation and deep brain stimulation(DBS),and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD.The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases.However,current brain stimulation techniques,with a notable exception of DBS for PD treatment,cannot serve as adequate clinical tools to assist in the diagnosis,treatment,or prognosis of individual patients with AD or PD.Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.

Postsynaptic Targeting and Mobility of Membrane Surface-Localized hASIC1a

Acid-sensing ion channels(ASICs),the main H^(+)receptors in the central nervous system,sense extracellular pH fluctuations and mediate cation influx.ASIC1a,the major subunit responsible for acid-activated current,is widely expressed in brain neurons,where it plays pivotal roles in diverse functions including synaptic transmission and plasticity.However,the underlying molecular mechanisms for these functions remain mysterious.Using extracellular epitope tagging and a novel antibody recognizing the hASIC1a ectodomain,we examined the membrane targeting and dynamic trafficking of hASIC1a in cultured cortical neurons.Surface hASIC1a was distributed throughout somata and dendrites,clustered in spine heads,and co-localized with postsynaptic markers.By extracellular pHluorin tagging and fluorescence recovery after photobleaching,we detected movement of hASIC1a in synaptic spine heads.Single-particle tracking along with use of the anti-hASIC1a ectodomain antibody revealed long-distance migration and local movement of surface hASIC1a puncta on dendrites.Importantly,enhancing synaptic activity with brain-derived neurotrophic factor accelerated the trafficking and lateral mobility of hASIC1a.With this newly-developed toolbox,our data demonstrate the synaptic location and high dynamics of functionallyrelevant hASIC1a on the surface of excitatory synapses,supporting its involvement in synaptic functions.