Atypical, non-standard functions of the microtubule associated Tau protein.

Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau's role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplastic and neuropathological implications of Tau in both the central and the peripheral nervous system

Associatioin of Plasma Aβ Peptides with Blood Pressure in the Elderly

Background Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). Methodology/Principal Findings Plasma Aß1-40 and Aß1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß1-42/ Aß1-40 ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß1-42/Aß1-40 ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß1-42/ Aß1-40 ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß1-40. Conclusion The plasma Aß1-42/Aß1-40 ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer\u27s disease, in which a high Aß1-42/Aß1-40 plasma ratio is reportedly associated with a decreased risk of incident disease

A walk through tau therapeutic strategies.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade

Dementia beyond 2025: knowledge and uncertainties

International audienceGiven that there may well be no significant advances in drug development before 2025, prevention of dementia/AD through the management of vascular and lifestyle-related risk factors may be a more realistic goal than treatment. Level of education and cognitive reserve assessment in neuropsychological testing deserve attention, as well as cultural, social and economic aspects of caregiving. Assistive technologies for dementia care remain complex. Serious games are emerging as virtual educational and pleasurable tools, designed for individual and cooperative skill-building. Public policies are likely to pursue improving awareness and understanding of dementia; providing good quality early diagnosis and intervention for all; improving quality of care from diagnosis to the end of life, using clinical and economic endpoints; delivering dementia strategies quicker, with an impact on more people. Dementia should remain presented as a stand-alone concept, distinct from frailty or loss of autonomy. The basic science of sensory impairment and social engagement in people with dementia needs to be developed. E-learning and serious games programmes may enhance public and professional education. Faced with funding shortage, new professional dynamics and economic models may emerge through coordinated, flexible research networks. Psychosocial research could be viewed as an investment in quality of care, rather than an academic achievement in a few centres of excellence. This would help provide a competitive advantage to the best operators. Stemming from care needs, a logical, systems approach to dementia care environment through organizational, architectural and psychosocial interventions may be developed, to help reduce symptoms in people with dementia and enhance quality of life. Dementia-friendly environments, culture and domesticity are key factors for such interventions

Two-Dimensional Electrophoresis of Tau Mutants Reveals Specific Phosphorylation Pattern Likely Linked to Early Tau Conformational Changes

The role of Tau phosphorylation in neurofibrillary degeneration linked to Alzheimer's disease remains to be established. While transgenic mice based on FTDP-17 Tau mutations recapitulate hallmarks of neurofibrillary degeneration, cell models could be helpful for exploratory studies on molecular mechanisms underlying Tau pathology. Here, “human neuronal cell lines” overexpressing Wild Type or mutated Tau were established. Two-dimensional electrophoresis highlights that mutated Tau displayed a specific phosphorylation pattern, which occurs in parallel to the formation of Tau clusters as visualized by electron microscopy. In fact, this pattern is also displayed before Tau pathology onset in a well established mouse model relevant to Tau aggregation in Alzheimer's disease. This study suggests first that pathological Tau mutations may change the distribution of phosphate groups. Secondly, it is possible that this molecular event could be one of the first Tau modifications in the neurofibrillary degenerative process, as this phenomenon appears prior to Tau pathology in an in vivo model and is linked to early steps of Tau nucleation in Tau mutants cell lines. Such cell lines consist in suitable and evolving models to investigate additional factors involved in molecular pathways leading to whole Tau aggregation

Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants

INTRODUCTION: There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. RESULTS: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aβ1-42 and Aβ1-42/Aβ1-40 ratio, and BACE1 for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. DISCUSSION: Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels as an endophenotype of AD

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD

La phosphorylation des isoformes de protéines tau (marqueurs de sous-populations neuronales vulnérables dans les maladies neurodégénératives de l'ischémie cérébrale)

La degenerescence neuronale est un processus commun aux maladies neurodegeneratives (mnd) et a l'ischemie cerebrale. Dans de nombreuses mnd, les proteines tau anormalement phosphorylees s'agregent en filaments intracellulaires insolubles. Ces proteines font partie de la famille des proteines associees aux microtubules. Elles sont principalement exprimees dans le tissu nerveux et interviennent dans la stabilite et le maintien de l'architecture neuronale. Leur etat de phosphorylation regule leur liaison aux microtubules. Recemment, des mutations du gene codant les proteines tau ont ete identifiees dans certaines formes de demences frontotemporales (dftp-17), dont plusieurs ont pour consequence d'augmenter la quantite intracellulaire de certaines isoformes de proteines tau. Dans le cadre de notre these, nous avons etudie l'etat de phosphorylation des proteines tau dans differents modeles in vitro et in vivo.LILLE1-BU (590092102) / SudocSudocFranceF

Modélisation cellulaire de la dégénérescence neurofibrillaire (étude du rôle et des modifications des protéines Tau)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Caractérisation d'un modèle murin de dégénérescence neurofibrillaire (étude de conséquences fonctionnelles de la pathologie tau potentiellement impliquées dans les phases précoces de la maladie d'Alzheimer)

La maladie d'Alzheimer (MA) sporadique est une maladie d'origine multifactorielle caractérisée par la perte progressive et irréversible de nombreuses fonctions cognitives. L'autopsie de cerveaux de patients atteints révèle l'accumulation de deux lésions caractéristiques : les dépôts amyloïdes et les dégénérescences neurofibrillaires. Un déficit cholinergique majeur est également associé à la pathologie et participerait aux altérations cognitives. Les dégénérescences neurofibrillaires correspondent à une agrégation intraneuronale de protéines tau hyperphosphorylées et anormalement phosphorylées. Dans la MA, elles apparaissent dans la structure hippocampique avant l'apparition des manifestations cliniques de la maladie puis s'étendent de manière stéréotypée à l'ensemble du cortex cérébral. Les travaux présentés dans cette thèse ont pour objectif de mieux comprendre les conséquences de la pathologie tau potentiellement impliquées dans les phases précoces de la MA. Les souris transgéniques THY-Tau22 surexpriment une isoforme humaine de tau comportant deux mutations et visent à modéliser la pathologie tau retrouvée dans la MA. Par une approche biochimique et immunohistochimique, nous montrons que la pathologie tau affecte différentiellement les structures cérébrales et principalement la structure hippocampique des souris transgéniques. Nous mettons de plus en évidence chez les souris transgéniques des altérations de plasticité synaptique associées à des troubles mnésiques majeurs à un stade encore dépourvu de mort neuronale hippocampique importante. Ces résultats suggèrent que la pathologie tau aurait un impact réel et délétère sur la fonctionnalité neuronale dès les stades précoces de la MA. Nous montrons également chez les souris transgéniques de douze mois un envahissement de l'axe septohippocampique par la pathologie tau et une dégénérescence des neurones cholinergiques du medial septum. De nombreuses études suggèrent que la pratique d'une activité physique préviendrait le risque de survenue de la MA. Afin d'étudier les effets de l'activité physique volontaire à long terme sur le phénotype des souris THY-Tau22, des souris transgéniques et sauvages âgées de trois mois ont été placées dans des cages avec ou sans libre accès à une roue pendant neuf mois. Les résultats présentés montrent que l'activité physique peut prévenir l'altération de mémoire spatiale à court terme causée par la pathologie tau dans notre modèle. Cette diminution de l'atteinte cognitive est associée à une diminution de la phosphorylation anormale de tau au niveau de l'hippocampe et à une prévention de la dégénérescence des neurones cholinergiques du medial septum. En conclusion, nos travaux montrent que la lignée THY-Tau22 présente un intérêt majeur dans l'étude des effets de la pathologie tau sur la fonctionnalité neuronale et les capacités mnésiques, mais également dans l'étude des liens entre la pathologie tau et d'autres facteurs possiblement impliqués dans la physiopathologie de la MA. Nos résultats confèrent également au modèle THY-Tau22 un intérêt majeur dans l'évaluation du potentiel thérapeutique d'agents pharmacologiques, notamment ceux ciblant la pathologie tau ou visant à stimuler le système cholinergiqueLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF