Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2-promotor, displaying tau pathology in the absence of any motor dysfunction. THY-Tau22 shows hyperphosphorylation of tau on several Alzheimer's disease-relevant tau epitopes (AT8, AT100, AT180, AT270, 12E8, taupSer396, and AP422), neurofibrillary tangle-like inclusions (Gallyas and MC1-positive) with rare ghost tangles and PHF-like filaments, as well as mild astrogliosis. These mice also display deficits in hippocampal synaptic transmission and impaired behavior characterized by increased anxiety, delayed learning from 3 months, and reduced spatial memory at 10 months. There are no signs of motor deficits or changes in motor activity at any age investigated. This mouse model therefore displays the main features of tau pathology and several of the pathophysiological disturbances observed during neurofibrillary degeneration. This model will serve as an experimental tool in future studies to investigate mechanisms underlying cognitive deficits during pathogenic tau aggregation. Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized neuropathologically by the presence of intracellular neurofibrillary tangles (NFTs) and senile plaques in the brain and by a major loss of synaptic connections. NFTs are neuronal inclusions of the microtubule-associated tau protein and are composed of aggregated phosphorylated tau. In AD, NFTs occur in the hippocampus, the entorhinal and polymodal association cortices, and in the basal forebrain. These brain areas are also severely affected by neuronal and synaptic loss. The loss of neurites, synapses, and neurons represent one of the reasons for the cognitive deficits and dementia of AD.

Tau, a neuronal protein involved in neurodegenerative disorders such as Alzheimer disease, which is primarily described as a microtubule-associated protein, has also been observed in the nuclei of neuronal and non-neuronal cells. However, the function of the nuclear form of Tau in neurons has not yet been elucidated. In this work, we demonstrate that acute oxidative stress and mild heat stress (HS) induce the accumulation of dephosphorylated Tau in neuronal nuclei. Using chromatin immunoprecipitation assays, we demonstrate that the capacity of endogenous Tau to interact with neuronal DNA increased following HS. Comet assays performed on both wildtype and Tau-deficient neuronal cultures showed that Tau fully protected neuronal genomic DNA against HS-induced damage. Interestingly, HS-induced DNA damage observed in Tau-deficient cells was completely rescued after the overexpression of human Tau targeted to the nucleus. These results highlight a novel role for nuclear Tau as a key player in early stress response.

Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.

A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer’s disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0386-4) contains supplementary material, which is available to authorized users.

BackgroundIn sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer’s disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau.ResultsUsing a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one.ConclusionTaken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.

Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by ␥-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. Amyloid precursor protein (APP)3 metabolism is central to Alzheimer disease etiopathogenesis. Extracellular amyloid deposits, a neuropathological hallmark of Alzheimer disease, are composed of amyloid-␤ (A␤) peptides that derive from APP catabolism. APP is a type I transmembrane glycoprotein processed by an ␣-or a ␤-secretase to produce C-terminal fragments (CTFs) (for review, see Ref. 1). ␥-Secretase further processes APP-CTFs (2, 3), releasing A␤ from ␤-CTF and the amyloid intracellular domain (AICD or ⑀-CTF) from all APP-CTFs (2, 4 -8). Several lines of evidence suggest that AICD is a trans-regulating factor of gene expression (neprilysin, KAI1, APP, and glycogen synthase kinase-3␤) (9 -12). However, AICD is rapidly degraded and thus seldom detected (13). We showed recently that AICD is strongly increased upon treatment with alkalizing drugs, suggesting that the endosomal/lysosomal pathway regulates AICD degradation (14).The endosomal/lysosomal pathway is essential for A␤ production and APP catabolism. For instance, BACE-1 (beta-site APP-cleaving enzyme 1) resides within endosomes, and endocytosis of BACE-1 and APP is a prerequisite for generating A␤ (15-17). An acidic pH is necessary for optimal BACE-1 protease activity (18), and BACE-1 is degraded in lysosomes (19). The ␥-secretase activity has been localized at the endosomal/ lysosomal membrane (20 -23). Treatment with drugs that prevent endosomal/lysosomal acidification (24 -26) or deletion of the APP internalization motif (27, 28) dramatically reduces A␤ secretion.The endosomal/lysosomal system is likely to be altered in Alzheimer disease (for review, see Ref. 29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30, 31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs. 34 -36). More recently, exosomes were demonstrated to contain A␤ peptides (37). Taken together, a growing body of evidence suggests that APP processing takes place mainly between the plasma membrane and late endosomal compartments such as multivesicular endosomes. Herein, we studied the localization of APP and its derivatives in SY5Y neuroblastoma cells stably overexpressing human APP and demonstrate that APP, APP-CTFs, and AICD accumulate in the luminal vesicles of multivesicular endosomes and are also found in exosomes.

Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of AD patients. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses, and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in astrocytes of the hilus of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.

Pericentromeric heterochromatin (PCH) gives rise to highly dense chromatin sub-structures rich in the epigenetic mark corresponding to the trimethylated form of lysine 9 of histone H3 (H3K9me3) and in heterochromatin protein 1α (HP1α), which regulate genome expression and stability. We demonstrate that Tau, a protein involved in a number of neurodegenerative diseases including Alzheimer’s disease (AD), binds to and localizes within or next to neuronal PCH in primary neuronal cultures from wild-type mice. Concomitantly, we show that the clustered distribution of H3K9me3 and HP1α, two hallmarks of PCH, is disrupted in neurons from Tau-deficient mice (KOTau). Such altered distribution of H3K9me3 that could be rescued by overexpressing nuclear Tau protein was also observed in neurons from AD brains. Moreover, the expression of PCH non-coding RNAs, involved in PCH organization, was disrupted in KOTau neurons that displayed an abnormal accumulation of stress-induced PCH DNA breaks. Altogether, our results demonstrate a new physiological function of Tau in directly regulating neuronal PCH integrity that appears disrupted in AD neurons.