Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mouse model of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

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Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau−/−) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau−/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

Frontotemporal dementia (FTD) presents clinically with behavioral changes including disinhibition. Mutations in the tau-encoding MAPT gene identified in familial cases of FTD have been used to generate transgenic mouse models of the human condition. Here, we report behavioral changes in a recently developed P301S mutant tau transgenic mouse, including disinhibition-like behavior in the elevated plus maze and hyperactivity in the open field arena. Furthermore, histological analysis revealed the amygdala as a primary and early site of pathological tau deposition in these mice. Taken together, neuropathological and behavioral changes in P301S tau transgenic mice resemble features of human FTD. Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication DetailsPrzybyla, M., Stevens, C. H., van der Hoven, J., Harasta, A., Bi, M., Ittner, A., van Hummel, A., Hodges, J. R., Piguet, O., Karl, T., Kassiou, M., Housley, G. Approximately one third of FTD cases are familial with the most frequent mutations found in the tau-encoding MAPT 13 gene with tau pathology, and in GRN and C9ORF72 associated with TDP-43 deposition [10]. Interestingly, behavioral 14 disinhibition is more frequent amongst MAPT, than GRN and C9ORF72 mutation carriers with familial FTD [21]. 15 16 Tau is an unstructured multi-domain protein that binds to microtubules to regulate their dynamics and intracellular 17 transport processes [2]. Tau is predominantly found in the axon of neurons, although small amounts localize to the post -18 synapse to regulate excitatory signaling [15]. Tau harbors over 80 potential phosphorylation sites, and in disease, it 19 becomes aberrantly phosphorylated at many sites, which coined the term 'hyperphosphorylated tau' [11]. 20Hyperphosphorylation of tau compromises its binding to microtubules, resulting in accumulation of tau in the soma and 21 dendrites of neurons [13]. Hyperphosphorylated tau is prone to oligomerize and form insoluble fibrillar aggregates that 22 present as neurofibrillary tangles (NFTs), a common feature of FTD with tau pathology [5]. 23 24 The identification of MAPT mutations in familial FTD has been instrumental in the generation of a significant number 25 of transgenic mouse lines that develop functional deficits and NFT pathology (reviewed by [12]). We have recently 26 reported TAU58/2 mice with neuronal expression of P301S mutant tau [24]. TAU58/2 mice present with motor deficits , 27 and tau and neurofillament pathology reminiscent of human FTD with tau pathology. In the present study, we show that 28 TAU58/2 mice develop early-onset disinhibition-like behavior and increased motor activity together with early NFT 29 pathology in the amygdala, reminiscent of bvFTD. Open Field 5Activity, anxiety and exploration pattern were tested in 3, 6 and 10 month-old male TAU58/2 mice (n=6-17) and non-6 transgenic littermates (n=6-13) in an open field arena. Mice were individually placed at the periphery of a box (40cm x 7 40cm) in an enclosed cupboard and their movement ...