Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.

In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPTP301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPTP301L mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young MAPTP301L/P301L knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPTP301L/P3101L impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.This work was supported by Alzheimer’s Research UK (ART/PG2009/2 to R.A.), MRC project grant (MR/L003813/1 to R.A., S.G.), Medical Research Council studentship (S.M.), Alzheimer’s Research UK studentship (ARUKPhD2013-13 to C.D.), Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant (M.P.C.), the Foundation for Alzheimer Research (FRA/SAO) (JPB) and the Belgian F.N.R.S. (K.A and JPB)

Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.

Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies

Downregulation of hsa-miR-132 and hsa-miR-129: non-coding RNA molecular signatures of Alzheimer’s disease

Alzheimer’s disease (AD) affects the elderly population by causing memory impairments, cognitive and behavioral abnormalities. Currently, no curative treatments exist, emphasizing the need to explore therapeutic options that modify the progression of the disease. MicroRNAs (miRNAs), as non-coding RNAs, demonstrate multifaceted targeting potential and are known to be dysregulated in AD pathology. This mini review focuses on two promising miRNAs, hsa-miR-132 and hsa-miR-129, which consistently exhibit differential regulation in AD. By employing computational predictions and referencing published RNA sequencing dataset, we elucidate the intricate miRNA-mRNA target relationships associated with hsa-miR-132 and hsa-miR-129. Our review consistently identifies the downregulation of hsa-miR-132 and hsa-miR-129 in AD brains as a non-coding RNA molecular signature across studies conducted over the past 15 years in AD research

Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients

International audienceIdentification of blood-based biomarkers of Alzheimer’s disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C11]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker

Role of p73 in Alzheimer disease: lack of association in mouse models or in human cohorts.

BACKGROUND: P73 belongs to the p53 family of cell survival regulators with the corresponding locus Trp73 producing the N-terminally distinct isoforms, TAp73 and DeltaNp73. Recently, two studies have implicated the murine Trp73 in the modulation in phospho-tau accumulation in aged wild type mice and in young mice modeling Alzheimer's disease (AD) suggesting that Trp73, particularly the DeltaNp73 isoform, links the accumulation of amyloid peptides to the creation of neurofibrillary tangles (NFTs). Here, we reevaluated tau pathologies in the same TgCRND8 mouse model as the previous studies. RESULTS: Despite the use of the same animal models, our in vivo studies failed to demonstrate biochemical or histological evidence for misprocessing of tau in young compound Trp73+/- + TgCRND8 mice or in aged Trp73+/- mice analyzed at the ages reported previously, or older. Secondly, we analyzed an additional mouse model where the DeltaNp73 was specifically deleted and confirmed a lack of impact of the DeltaNp73 allele, either in heterozygous or homozygous form, upon tau pathology in aged mice. Lastly, we also examined human TP73 for single nucleotide polymorphisms (SNPs) and/or copy number variants in a meta-analysis of 10 AD genome-wide association datasets. No SNPs reached significance after correction for multiple testing and no duplications/deletions in TP73 were found in 549 cases of AD and 544 non-demented controls. CONCLUSION: Our results fail to support P73 as a contributor to AD pathogenesis.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

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

Alzheimer risk factor, PICALM is involved in tau pathology in Alzheimer and other tauopathies.

info:eu-repo/semantics/publishe

Prolyl isomerase Pin1 et la maladie d'Alzheimer

La maladie d'Alzheimer (MA) est une démence neurodégénérative caractérisée neuropathologiquement par une Dégénérescence Neurofibrillaire (DNF) et des dépôts amyloïdes. La DNF est constituée de protéines Tau hyper- et anormalement phosphorylées, alors que dépôts amyloïdes sont constitués par des peptides Amyloid Beta qui sont les produits de clivages successifs du précurseur du peptide amyloïde (APP). Actuellement, les mécanismes qui conduisent à la DNF et aux dépôts amyloïdes sont encore mal connus. Récemment, Pin1 a été retrouvée dans les deux lésions de la MA. Pin1 est une peptidyl prolyl cis/trans isomérase qui régule ses cibles par isomérisation de sites phospho Serine / phospho Thréonine suivis d'une Proline (pSer/Thr-Pro). Pin1 elle-même est régulée par certaines modifications post-traductionnelles comme oxydation ou phosphorylation. De plus, des travaux récents sur un modèle de souris invalidées (KO) pour le gène PIN1 ont montré qu'une absence de Pin1 était associée au développement d'une DNF. Enfin, Pin1 KO et Pin1 KO en combinaison avec surexpression de APP mutée montraient une augmentation de Amyloid Beta insoluble dans les cerveaux de souris. Nous avons cherché à étudier la présence d'éventuelles variations des modifications post-traductionnelles de Pin1 qui seraient associées à la maladie d'Alzheimer en analysant des cerveaux de patients atteints de MA, de souris transgéniques pour tau et des cellules SY5Y qui surexpriment la tau humaine. Par ces travaux, nous mettons en évidence que la protéine Pin1 est régulée par phosphorylation. Il existe au moins 5 sites de phosphorylation comme cela est suggéré par nos analyses en électrophorèse bidimensionnelle. Par ailleurs, la progression de la pathologie tau peut moduler l'état de phosphorylation de Pin1. Notre étude, pour la première fois, montre la relation entre la pathologie tau et la phosphorylation de Pin1 dans la progression de la MA.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

The role of PICALM in tau pathology progression

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Vaccines: why and how do we need to improve vaccine coverage?

Vaccines: why and how do we need to improve vaccine coverage