Tau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice.

BACKGROUND: Tau protein serves a pro-inflammatory function in neuroinflammation. However, the role of tau in other inflammatory disorders such as rheumatoid arthritis (RA) is less explored. This study is to investigate the role of endogenous tau and the potential mechanisms in the pathogenesis of inflammatory arthritis. METHODS: We established collagen-induced arthritis (CIA) model in wild-type and Tau-/- mice to compare the clinical score and arthritis incidence. Micro-CT analysis was used to evaluate bone erosion of ankle joints. Histological analysis was performed to assess inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Serum levels of pro-inflammatory cytokines were measured by ELISA. The expression levels of macrophage markers were determined by immunohistochemistry staining and quantitative real-time PCR. RESULTS: Tau expression was upregulated in joints under inflammatory condition. Tau deletion in mice exhibited milder inflammation and protected against the progression of CIA, evidenced by reduced serum levels of pro-inflammatory cytokines and attenuated bone loss, inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Furthermore, tau deficiency led to the inhibition of classically activated type 1 (M1) macrophage polarization in the synovium. CONCLUSION: Tau is a previously unrecognized critical regulator in the pathogenesis of RA and may provide a potential therapeutic target for autoimmune and inflammatory joint diseases.

Evaluation of heptelidic acid as a potential inhibitor for tau aggregation-induced Alzheimer's disease and associated neurotoxicity.

Tau is a major component of protein plaques in tauopathies, especially Alzheimer's disease (AD). The purpose of the present study is to explore the inhibitory effects of heptelidic acid as a bioactive compound from fungus T. koningii on tau fibrillization and associated neurotoxicity. The influences of various concentrations of heptelidic acid on tau fibrillization and underlying neurotoxicity were explored by assessment of the biophysical (ThT/Nile red fluorescence, CR absorbance, CD, and TEM) and cellular (MTT, LDH, and caspase-3) assays. It was shown that heptelidic acid inhibited tau fibrillization in a concentration-dependent manner. On the other hand, cellular assays indicated that the viability, LDH release, and caspase-3 activity were regulated when neurons were exposed to tau samples co-incubated with heptelidic acid. In conclusion, it may be indicated that heptelidic acid inhibited tau fibrillization which was accompanied by formation of amorphous aggregated species of tau with much less neurotoxicity than tau amyloid alone. Thus, heptelidic acid can be considered as a potential candidate in preventive care studies to inhibit the formation of tau plaques as neurotoxic species.

Transcriptional Signatures of Tau and Amyloid Neuropathology.

Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of ß-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.

Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau.

To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Some homeostatic mechanisms act in a subcellular compartment-specific manner, but others exhibit trans-compartmental mechanisms of proteostasis. To identify pathways protecting neurons from pathological tau protein, we employed a transgenic Caenorhabditis elegans model of human tauopathy exhibiting proteostatic disruption. We show normal functioning of the endoplasmic reticulum unfolded protein response (UPRER) promotes clearance of pathological tau, and loss of the three UPRER branches differentially affects tauopathy phenotypes. Loss of function of xbp-1 and atf-6 genes, the two main UPRER transcription factors, exacerbates tau toxicity. Furthermore, constitutive activation of master transcription factor XBP-1 ameliorates tauopathy phenotypes. However, both ATF6 and PERK branches of the UPRER participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD). Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms.

Tau protein in neurodegenerative diseases - a review.

The study of rare, inherited forms of different diseases resulted in the discovery of gene defects that cause inherited variants of the respective diseases. The defective genes were found to encode major molecular players leading to the neuropathological lesions or factors that characterize these diseases. The exact role of the tau protein in the neurodegenerative process is still under debate. It is very important to understand the normal biological roles of tau and the specific events that induce tau to become neurotoxic. Tau is the major microtubule-associated protein (MAP) of a mature neuron. The other neuronal MAPs are MAP1 and MAP2. These three MAPs perform similar function, promoting assembly and stability of microtubules. Tau protein was isolated as a microtubule-associated factor in the porcine brain. It was isolated as a protein that co-purified with tubulin and had the ability to promote microtubule assembly in vitro. Normal adult human brain tau contains 2-3 moles phosphate÷mole of tau protein. Hyperphosphorylation of tau depress this biological activity of tau. Almost 80 diseases caused by missense mutations and intronic mutations in the tau gene have been found in familial cases of frontotemporal dementia (FTD). In Alzheimer's disease (AD), there are intraneuronal neurofibrillary tangles composed of the microtubule-associated protein tau (MAPT). In other neurodegenerative diseases, there are similar deposits of tau, in the absence of extracellular deposits (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, etc.). Tau pathology is also often seen in some forms of Parkinson's disease (PD) and prion diseases. In genetic forms of FTD, mutations in tau implicate abnormal tau as the initiation of neurodegeneration. In FTD, there are deposits especially in temporal and frontal lobes, regions that are very important for behavior and executive function. It is critical to understand how tau becomes pathogenic, in order to consider developing any strategies for treatment.

Role of insulin resistance in Alzheimer's disease.

A critical role of insulin resistance (IR) in Alzheimer's disease (AD) includes beta-amyloid (Aß) production and accumulation, the formation of neurofibrillary tangles (NFTs), failure of synaptic transmission and neuronal degeneration. Aß is sequentially cleavaged from APP by two proteolytic enzymes: ß-secretase and γ-secretase. IR could regulate Aß production via enhancing ß- and γ-secretase activity. Meanwhile, IR induces oxidative stress and inflammation in the brain which contributes to Aß and tau pathology. Aß accumulation can enhance IR through Aß-mediated inflammation and oxidative stress. IR is a possible linking between amyloid plaques and NFTs pathology via oxidative stress and neuroinflammation. Additionally, IR could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that insulin could be useful in the treatment of AD. Thus, an effective measure to inhibit IR may be a novel drug target in AD.

Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-ß oligomer-treated hippocampal neurons.

Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AßOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3ß. By this mechanism, AßOs may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in AßO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3ß rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in AßO-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression.

p53 prevents neurodegeneration by regulating synaptic genes.

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.

Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease.

The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aß) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of Aß deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aß oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for Aß in AD. We conclude it is essential to expand our view of pathogenesis beyond Aß and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.

Amyloid-ß and tau: the trigger and bullet in Alzheimer disease pathogenesis.

The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-ß (Aß) peptides for plaques and tau for tangles. Amyloid-ß peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aß and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aß require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aß species and depend on soluble, cytoplasmic tau. Therefore, Aß is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aß toxicity via a feedback loop. Because soluble toxic aggregates of both Aß and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.

Of rodents and men: the mysterious interneuronal pilgrimage of misfolded protein tau in Alzheimer's disease.

Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimer's disease brains that would allow stratification of Alzheimer's disease patients.

Intravenous immunoglobulin reduces ß amyloid and abnormal tau formation caused by herpes simplex virus type 1.

Intravenous immunoglobulin (IVIG) treatment of Alzheimer's disease (AD) has been encouraging. Its mechanism of action might be via anti-ß-amyloid (Aß) antibodies which facilitate Aß clearance. However, IVIG's benefits might result from its antiviral activity, particularly against herpes simplex virus type 1 (HSV1), a virus implicated in AD. We investigated IVIG's effect on HSV1, specifically on the accumulation of Aß and abnormally phosphorylated tau which it causes. We show that IVIG is effective at reducing the accumulation of these abnormal molecules and that it acts synergistically with the antiviral acyclovir, suggesting that their combined use would be beneficial for treating AD.

A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) involves progressive accumulation of amyloid ß-peptide (Aß) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Aß deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model.

Widespread τ and amyloid-ß pathology many years after a single traumatic brain injury in humans.

While a history of a single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment such as Alzheimer's disease, the long-term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive/mild head injury. Here, post-mortem brains from long-term survivors of just a single TBI (1-47 years survival; n=39) vs. uninjured, age-matched controls (n=47) were examined for neurofibrillary tangles (NFTs) and amyloid-ß (Aß) plaques using immunohistochemistry and thioflavine-S staining. Detailed maps of findings permitted classification of pathology using semiquantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases. In addition, Aß-plaques were found in a greater density following TBI vs. controls. Moreover, thioflavine-S staining revealed that while all plaque-positive control cases displayed predominantly diffuse plaques, 64% of plaque-positive TBI cases displayed predominantly thioflavine-S-positive plaques or a mixed thioflavine-S-positive/diffuse pattern. These data demonstrate that widespread NFT and Aß plaque pathologies are present in up to a third of patients following survival of a year or more from a single TBI. This suggests that a single TBI induces long-term neuropathological changes akin to those found in neurodegenerative disease.

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology.

Tau pathology is encountered in many neurodegenerative disorders known as tauopathies, including Alzheimer's disease. Physical activity is a lifestyle factor affecting processes crucial for memory and synaptic plasticity. Whether long-term voluntary exercise has an impact on Tau pathology and its pathophysiological consequences is currently unknown. To address this question, we investigated the effects of long-term voluntary exercise in the THY-Tau22 transgenic model of Alzheimer's disease-like Tau pathology, characterized by the progressive development of Tau pathology, cholinergic alterations and subsequent memory impairments. Three-month-old THY-Tau22 mice and wild-type littermates were assigned to standard housing or housing supplemented with a running wheel. After 9 months of exercise, mice were evaluated for memory performance and examined for hippocampal Tau pathology, cholinergic defects, inflammation and genes related to cholesterol metabolism. Exercise prevented memory alterations in THY-Tau22 mice. This was accompanied by a decrease in hippocampal Tau pathology and a prevention of the loss of expression of choline acetyltransferase within the medial septum. Whereas the expression of most cholesterol-related genes remained unchanged in the hippocampus of running THY-Tau22 mice, we observed a significant upregulation in mRNA levels of NPC1 and NPC2, genes involved in cholesterol trafficking from the lysosomes. Our data support the view that long-term voluntary physical exercise is an effective strategy capable of mitigating Tau pathology and its pathophysiological consequences.

Alzheimer's pathogenesis: is there neuron-to-neuron propagation?

There is increasing interest in the early phase of Alzheimer's disease before severe neuronal dysfunction occurs, but it is still not known when or where in the central nervous system the underlying pathological process begins. In this review, we discuss the idea of possible disease progression from the locus coeruleus to the transentorhinal region of the cerebral cortex via neuron-to-neuron transmission and transsynaptic transport of tau protein aggregates, and we speculate that such a mechanism together with the very long prodromal period that characterizes Alzheimer's disease may be indicative of a prion-like pathogenesis for this tauopathy. The fact that AT8-immunoreactive abnormal tau aggregates (pretangles) develop within proximal axons of noradrenergic coeruleus projection neurons in the absence of both tau lesions (pretangles, NFTs/NTs) in the transentorhinal region as well as cortical amyloid-ß pathology means that currently used neuropathological stages for Alzheimer's disease will have to be reclassified.

Rescue of neurons from undergoing hallmark tau-induced Alzheimer's disease cell pathologies by the antimitotic drug paclitaxel.

Through the use of live confocal imaging, electron microscopy, and the novel cell biological platform of cultured Aplysia neurons we show that unfolding of the hallmark cell pathologies induced by mutant-human-tau (mt-human-tau) expression is rescued by 10 nM paclitaxel. At this concentration paclitaxel prevents mt-human-tau-induced swelling of axonal segments, translocation of tau and microtubules (MT) to submembrane domains, reduction in the number of MTs along the axon, reversal of the MT polar orientation, impaired organelle transport, accumulation of macro-autophagosomes and lysosomes, compromised neurite morphology and degeneration. Unexpectedly, higher paclitaxel concentrations (100 nM) do not prevent these events from occurring and in fact facilitate them. We conclude that antimitotic MT-stabilizing reagents have the potential to serve as drugs to prevent or slow down the unfolding of tauopathies.

Evidence for participation of aluminum in neurofibrillary tangle formation and growth in Alzheimer's disease.

This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease.