Deletion of endogenous Tau proteins is not detrimental in Drosophila

Human Tau (hTau) is a highly soluble and natively unfolded protein that binds to microtubules within neurons. Its dysfunction and aggregation into insoluble paired helical filaments is involved in the pathogenesis of Alzheimer’s disease (AD), constituting, together with accumulated β-amyloid (Aβ) peptides, a hallmark of the disease. Deciphering both the loss-of-function and toxic gain-of-function of hTau proteins is crucial to further understand the mechanisms leading to neurodegeneration in AD. As the fruit fly Drosophila melanogaster expresses Tau proteins (dTau) that are homologous to hTau, we aimed to better comprehend dTau functions by generating a specific tau knock-out (KO) fly line using homologous recombination. We observed that the specific removal of endogenous dTau proteins did not lead to overt, macroscopic phenotypes in flies. Indeed, survival, climbing ability and neuronal function were unchanged in tau KO flies. In addition, we did not find any overt positive or negative effect of dTau removal on human Aβ-induced toxicity. Altogether, our results indicate that the absence of dTau proteins has no major functional impact on flies, and suggests that our tau KO strain is a relevant model to further investigate the role of dTau proteins in vivo, thereby giving additional insights into hTau functions

NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model.

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies

Rescue of impaired late-phase long-term depression in a tau transgenic mouse model

Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.publisher: Elsevier articletitle: Rescue of impaired late–phase long-term depression in a tau transgenic mouse model journaltitle: Neurobiology of Aging articlelink: http://dx.doi.org/10.1016/j.neurobiolaging.2014.09.015 content_type: article copyright: Copyright © 2015 Elsevier Inc. All rights reserved.status: publishe

Adenosine receptors in Huntington's disease

Huntington's disease is a devastating hereditary neurodegenerative disorder caused by CAG mutation within the IT15 gene encoding Huntingtin protein. Even though mutant and normal Huntingtin are ubiquitously expressed, the degenerative processes primarily occur within the striatum and particularly hit the GABAergic enkephalin neuronal subpopulation of medium spiny neurons particularly enriched with adenosine A2ARs, suggesting that the latter might play a role in HD. In agreement, variants in the ADORA2A gene influence the age at onset in HD and A2AR dynamics is largely altered by mutated Huntingtin. Adenosine receptors are involved in a number of processes critical for neuronal function and homeostasis, such as modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions as well as the regulation of protein degradation mechanisms. In the present review, we critically reviewed the current knowledge involving adenosine receptors in HD and discussed whether they represent a suitable therapeutic target.SCOPUS: ch.binfo:eu-repo/semantics/publishe

Early Tau pathology involving the septo-hippocampal pathway in a Tau transgenic model: relevance to Alzheimer's disease.

International audienceAlzheimer's disease is a neurodegenerative disorder characterized by amyloid deposits and neurofibrillary tangles. Cholinergic dysfunction is also a main pathological feature of the disease. Nevertheless, the links between cholinergic dysfunction and neuropathological hallmarks of Alzheimer's are still unknown. In the present study, we aimed to further investigate Tau aggregation in cholinergic systems, in a Tau transgenic mouse model. THY-Tau22 mice have recently been described as a novel model of Alzheimer-like Tau pathology without motor deficits. This strain presents an age-dependent development of Tau pathology leading to synaptic dysfunctions as well as learning and memory impairments. In the present work, we observed that Tau pathology differentially affects cerebral structures. Interestingly, early Tau pathology was observed in both hippocampus and basal forebrain. Moreover, some morphological as well as functional alterations of the septohippocampal pathway suggest a disconnection between these two key brain regions in Alzheimer's disease. Finally, these data suggest that Tau pathology may participate in cholinergic degeneration

Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach.: Active Tau immunotherapy

International audienceRecent data indicate that Tau immunotherapy may be relevant for interfering with neurofibrillary degeneration in Alzheimer disease and related disorders referred to as Tauopathies. The key question for immunotherapy is the choice of the epitope to target. Abnormal phosphorylation is a well-described post-translational modification of Tau proteins and may be a good target. In the present study, we investigated the effects of active immunization against the pathological epitope phospho-Ser422 in the THY-Tau22 transgenic mouse model. Starting from 3-6 months of age, THY-Tau22 mice develop hippocampal neurofibrillary tangle-like inclusions and exhibit phosphorylation of Tau on several AD-relevant Tau epitopes. Three month-old THY-Tau22 mice were immunized with a peptide including the phosphoserine 422 residue while control mice received the adjuvant alone. A specific antibody response against the phospho-Ser422 epitope was observed. We noticed a decrease in insoluble Tau species (AT100- and pS422 immunoreactive) by both biochemical and immunohistochemical means correlated with a significant cognitive improvement using the Y-maze. This Tau immunotherapy may facilitate Tau clearance from the brain toward the periphery since, following immunization, an increase in Tau concentrations was observed in blood. Overall, the present work is, to our knowledge, the first one to demonstrate that active immunotherapy targeting a real pathological epitope such as phospho-Ser422 epitope is efficient. This immunotherapy allows for Tau clearance and improves cognitive deficits promoted by Tau pathology in a well-defined Tau transgenic model

From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease?

© The Authors Journal compilation © 2014 Biochemical SocietyAD (Alzheimer's disease) is the most prevalent form of dementia in the aged population. Definitive diagnosis of AD is based on the presence of senile plaques and neurofibrillary tangles that are identified in post-mortem brain specimens. A third pathological component is inflammation. AD results from multiple genetic and environmental risk factors. Among other factors, epidemiological studies report beneficial effects of caffeine, a non-selective antagonist of adenosine receptors. In the present review, we discuss the impact of caffeine and the adenosinergic system in AD pathology as well as consequences in terms of pathology and therapeutics.D.Bl. and L.B. are supported by France Alzheimer, La Ligue Européenne Contre la Maladie d’Alzheimer (LECMA)/Alzheimer Forschung Initiative, LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Inserm, Centre National de la Recherche Scientifique (CNRS), Université Lille 2, Région Nord/Pas-de-Calais, Agence Nationale de la Recherche (ADORATAU), ERA-Net (ABeta-ID) and Fonds Unique Interministériel MEDIALZ. V.F. holds a grant from Inserm/Region Nord pas de Calais. C.L. holds a doctoral grant from Lille 2 University. D.Bo. is supported through grants from the National Institutes of Health [grant numbers NS065957, MH083973 and NS061844], the U.S. Department of the Army [grant number W81XWH-12-1-0283] and the Legacy Good Samaritan Foundation. L.V.L. is an FCT Investigator (iFCT). Her laboratory has support from Fritz-Thyssen Foundation, Bial and Fundação para a Ciência e a Tecnologia (FCT) (Portugal). D.B. is an Inserm investigator.info:eu-repo/semantics/publishedVersio

Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy

International audienc