Different tau species lead to heterogeneous tau pathology propagation and misfolding.

Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species

Hippocampal Microbleed on a Post-Mortem T2*-Weighted Gradient-Echo 7.0-Tesla Magnetic Resonance Imaging

The present post-mortem study of a brain from an Alzheimer patient showed on a T2*-weighted gradient-echo 7.0-T MRI of a coronal brain section a hyposignal in the hippocampus, suggesting a microbleed. On the corresponding histological examination, only iron deposits around the granular cellular layer and in blood vessel walls of the hippocampus were observed without evidence of a bleeding. This case report illustrates that the detection of microbleeds on MRI has to be interpreted with caution

Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: possible implication for Alzheimer's disease.

Multiple lines of evidence have linked oxidative stress, tau pathology and neuronal cell cycle re-activation to Alzheimer's disease (AD). While a prevailing idea is that oxidative stress-induced neuronal cell cycle reactivation acts as an upstream trigger for pathological tau phosphorylation, others have identified tau as an inducer of cell cycle abnormalities in both mitotic and postmitotic conditions. In addition, nuclear hypophosphorylated tau has been identified as a key player in the DNA damage response to oxidative stress. Whether and to what extent these observations are causally linked remains unclear. Using immunofluorescence, fluorescence-activated nucleus sorting and single-nucleus sequencing, we report an oxidative stress-associated accumulation of nuclear hypophosphorylated tau in a subpopulation of cycling neurons confined in S phase in AD brains, near amyloid plaques. Tau downregulation in murine neurons revealed an essential role for tau to promote cell cycle progression to S phase and prevent apoptosis in response to oxidative stress. Our results suggest that tau holds oxidative stress-associated cycling neurons in S phase to escape cell death. Together, this study proposes a tau-dependent protective effect of neuronal cell cycle reactivation in AD brains and challenges the current view that the neuronal cell cycle is an early mediator of tau pathology

Mis-splicing of Tau exon 10 in myotonic dystrophy type I is reproduced by overexpression of CELF2 but not by MBNL1 silencing

International audienceTau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type I (DM1). In DM1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the RNA level is a major etiological factor responsible for the mis-splicing of several transcripts in DM1. These are probably the consequence of a loss of MBNL1 function or gain of CELF1 splicing function. Whether these two dysfunctions occur together or separately, and whether all mis-splicing events in DM1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of DM1 patients. Two DM1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all DM1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors MBNL1, CELF1, CELF2 and CELF4 or a dominant-negative CELF factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CELF2 whereas it is insensitive to the loss-of-function of MBNL1, CELF1 gain-of-function or a dominant-negative of CELF factor. Moreover, we observed an increased expression of CELF2 only in the brain of DM1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in DM1 that is neither induced by a loss of MBNL1 function nor a gain of CELF1 function, but is rather associated to CELF2 gain-of-function

[Management of muscle and nerve biopsies: expert guidelines from two French professional societies, Société française de myologie et de l'Association française contre les myopathies] : Prise en charge des biopsies musculaires et nerveuses. Recommandations formalisées d'experts sous l'égide de la Société française de neuropathologie, de la Société française de myologie et de l'Association française contre les myopathies

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Biomechanical wall properties of human intracranial aneurysms resected following surgical clipping (IRRAs Project)

Background and purpose: Individual rupture risk assessment of intracranial aneurysms is a major issue in the clinical management of asymptomatic aneurysms. Aneurysm rupture occurs when wall tension exceeds the strength limit of the wall tissue. At present, aneurysmal wall mechanics are poorly understood and thus, risk assessment involving mechanical properties is inexistent. Aneurysm computational hemodynamics studies make the assumption of rigid walls, an arguable simplification. We therefore aim to assess mechanical properties of ruptured and unruptured intracranial aneurysms in order to provide the foundation for future patient-specific aneurysmal risk assessment. This work also challenges some of the currently held hypotheses in computational flow hemodynamics research. Methods: A specific conservation protocol was applied to aneurysmal tissues following clipping and resection in order to preserve their mechanical properties. Sixteen intracranial aneurysms (11 female, 5 male) underwent mechanical uniaxial stress tests under physiological conditions, temperature, and saline isotonic solution. These represented 11 unruptured and 5 ruptured aneurysms. Stress/strain curves were then obtained for each sample, and a fitting algorithm was applied following a 3-parameter (C(10), C(01), C(11)) Mooney-Rivlin hyperelastic model. Each aneurysm was classified according to its biomechanical properties and (un)rupture status./nResults: Tissue testing demonstrated three main tissue classes: Soft, Rigid, and Intermediate. All unruptured aneurysms presented a more Rigid tissue than ruptured or pre-ruptured aneurysms within each gender subgroup. Wall thickness was not correlated to aneurysmal status (ruptured/unruptured). An Intermediate subgroup of unruptured aneurysms with softer tissue characteristic was identified and correlated with multiple documented risk factors of rupture. Conclusion: There is a significant modification in biomechanical properties between ruptured aneurysm, presenting a soft tissue and unruptured aneurysms, presenting a rigid material. This finding strongly supports the idea that a biomechanical risk factor based assessment should be utilized in the to improve the therapeutic decision making