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Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

The microtubule-associated protein tau (MAPT, tau) forms neurotoxic aggregates that promote cognitive deficits in tauopathies, the most common of which is Alzheimer’s disease (AD). The 90-kDa heat shock protein (Hsp90) chaperone system affects the accumulation of these toxic tau species, which can be modulated with Hsp90 inhibitors. However, many Hsp90 inhibitors are not blood–brain barrier-permeable, and several present associated toxicities. Here, we find that the cochaperone, activator of Hsp90 ATPase homolog 1 (Aha1), dramatically increased the production of aggregated tau. Treatment with an Aha1 inhibitor, KU-177, dramatically reduced the accumulation of insoluble tau. Aha1 colocalized with tau pathology in human brain tissue, and this association positively correlated with AD progression. Aha1 overexpression in the rTg4510 tau transgenic mouse model promoted insoluble and oligomeric tau accumulation leading to a physiological deficit in cognitive function. Overall, these data demonstrate that Aha1 contributes to tau fibril formation and neurotoxicity through Hsp90. This suggests that therapeutics targeting Aha1 may reduce toxic tau oligomers and slow or prevent neurodegenerative disease progression.

Although previous studies have demonstrated the effects of concussions do not accumulate as the time interval between injuries increases, little is known about the relationship between this interval and the effects of repetitive concussions. The objective of this study is to explore the relationship between the time interval and changes in behavior and histology following repetitive concussions. Male adolescent rats received concussions by weight drop and were randomly assigned to one of five experimental groups, receiving concussions three times either daily, every other day, once per week, once every 2 weeks, or receiving sham procedures. Only rats that received daily concussions exhibited cognitive impairment, while the other groups did not. No groups showed motor or anxiety-like impairments. Histological analysis revealed accumulation of microglia, as well as astrogliosis, in the prefrontal cortex, corpus callosum, dentate gyrus, and cornu Ammonis 1 region of the hippocampus in rats subjected to daily concussions. Accumulation of phosphorylated tau was also observed in the prefrontal cortex and cornu Ammonis 1. Longer intervals between concussions may reduce the risk of cognitive impairment and limit microglial activation, astrogliosis, and phosphorylated tau accumulation. These findings may help guide decisions on the appropriate timing for return to play in humans.

In Alzheimer’s disease (AD), and other tauopathies, microtubule destabilization compromises axonal and synaptic integrity contributing to neurodegeneration. These diseases are characterized by the intracellular accumulation of hyperphosphorylated tau leading to neurofibrillary pathology. AD brains also accumulate amyloid-beta (Aβ) deposits. However, the effect of microtubule stabilizing agents on Aβ pathology has not been assessed so far. Here we have evaluated the impact of the brain-penetrant microtubule-stabilizing agent Epothilone D (EpoD) in an amyloidogenic model of AD. Three-month-old APP/PS1 mice, before the pathology onset, were weekly injected with EpoD for 3 months. Treated mice showed significant decrease in the phospho-tau levels and, more interesting, in the intracellular and extracellular hippocampal Aβ accumulation, including the soluble oligomeric forms. Moreover, a significant cognitive improvement and amelioration of the synaptic and neuritic pathology was found. Remarkably, EpoD exerted a neuroprotective effect on SOM-interneurons, a highly AD-vulnerable GABAergic subpopulation. Therefore, our results suggested that EpoD improved microtubule dynamics and axonal transport in an AD-like context, reducing tau and Aβ levels and promoting neuronal and cognitive protection. These results underline the existence of a crosstalk between cytoskeleton pathology and the two major AD protein lesions. Therefore, microtubule stabilizers could be considered therapeutic agents to slow the progression of both tau and Aβ pathology.

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro , neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. Here the cis form of tau protein, which disrupts axonal microtubules and transport, spreads to other neurons, and leads to apoptosis in vitro and in vivo , is found to be produced by neurons immediately after traumatic brain injury (TBI); treating TBI mice with cis antibody blocks early production of cis tau, prevents tauopathy and spread and restores brain structural and functional outcomes, and may be further developed to treat TBI and to prevent neurodegeneration after injury. cis P-tau tauopathy in traumatic brain injury The symptoms of traumatic brain injury (TBI), a common condition in players of contact sports and in the military, are associated with acute neurological dysfunction and TBI is a major risk factor for Alzheimer's disease. Tauopathy associated with the aggregation of phosphorylated tau protein (P-tau) in the brain is a defining feature of the neurodegeneration associated with chronic traumatic encephalopathy and Alzheimer's but it has not been observed in the early stages of TBI. Here Kun Ping Lu and colleagues show that tauopathy caused by cis P-tau, but not trans P-tau, is an early driver of brain injury in patients with TBI and in mouse models. Treating TBI mice with cis antibody blocks early production of cis P-tau and prevents further tauopathy and spread, and may be further developed to treat TBI after injury.

Significance The transcription factor p53 plays a critical role in the cellular response to DNA damage and has thus been studied intensively in oncogenesis research. However, the role that p53 plays in the response of postmitotic neurons to cellular stress has received less attention. Here we describe an unexpected neuroprotective role for p53 in an in vivo model of tau-mediated neurodegeneration relevant to Alzheimer's disease and related disorders. Further, we identify synaptic function as a novel target pathway for p53 in aging neurons, consistent with the growing evidence for synaptic pathology as an early event in neurodegenerative disease. Our study defines mechanistically a new, conserved role for p53 in protecting postmitotic neurons from degeneration during aging and disease. DNA damage has been implicated in neurodegenerative disorders, including Alzheimer’s disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis, we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration.

The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles. Although mouse models have been created by overexpressing specific proteins including beta-amyloid precursor protein, presenilin and tau, no model has been generated by gene knockout. Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer's disease. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase. Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration; however, genetic evidence is lacking. Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioural deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.

Misfolded tau proteins induce accumulation of free radicals and promote neuroinflammation by activating microglia-releasing proinflammatory cytokines, leading to neuronal cell death. Traditional Chinese herbal medicines (CHMs) have been widely used in clinical practice to treat neurodegenerative diseases associated with oxidative stress and neuroinflammation. This study examined the neuroprotection effects of formulated CHMs Bai-Shao (made of Paeonia lactiflora), Gan-Cao (made of Glycyrrhiza uralensis), and Shaoyao Gancao Tang (SG-Tang, made of P. lactiflora and G. uralensis at 1 : 1 ratio) in cell model of tauopathy. Our results showed that SG-Tang displayed a greater antioxidative and antiaggregation effect than Bai-Shao and Gan-Cao and a stronger anti-inflammatory activity than Bai-Shao but similar to Gan-Cao. In inducible 293/SH-SY5Y cells expressing proaggregant human tau repeat domain (ΔK280 tauRD), SG-Tang reduced tau misfolding and reactive oxygen species (ROS) level in ΔK280 tauRD 293 cells and promoted neurite outgrowth in ΔK280 tauRD SH-SY5Y cells. Furthermore, SG-Tang displayed anti-inflammatory effects by reducing nitric oxide (NO) production in mouse BV-2 microglia and increased cell viability of ΔK280 tauRD-expressing SH-SY5Y cells inflamed by BV-2 conditioned medium. To uncover the neuroprotective mechanisms of SG-Tang, apoptosis protein array analysis of inflamed tau expressing SH-SY5Y cells was conducted and the suppression of proapoptotic proteins was confirmed. In conclusion, SG-Tang displays neuroprotection by exerting antioxidative and anti-inflammatory activities to suppress neuronal apoptosis in human tau cell models. The study results lay the base for future applications of SG-Tang on tau animal models to validate its effect of reducing tau misfolding and potential disease modification.

Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1β expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.