YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer's disease and other tauopathies.

BACKGROUND: The innate immune system is known to be involved early in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. The inflammatory response in the central nervous system can be measured postmortem or through a series of inflammatory mediator surrogates. YKL-40 (also named Chitinase-3-like I) has been frequently investigated in body fluids as a surrogate marker of neuroinflammation in AD and other neurological disorders. However, the expression pattern of YKL-40 in the human brain with neurodegenerative pathology remains poorly investigated. Our aim was to study the cellular expression pattern of YKL-40 in the brain of patients with clinical and neuropathological criteria for AD (n = 11); three non-AD tauopathies: Pick's disease (PiD; n = 8), corticobasal degeneration (CBD; n = 8) and progressive supranuclear palsy (PSP; n = 9) and a group of neurologically healthy controls (n = 6). METHODS: Semiquantitative neuropathological evaluation and quantitative confocal triple immunofluorescence studies were performed. An in-house algorithm was used to detect and quantify pathology burden of random regions of interest on a full tissue-section scan. Kruskal-Wallis and Dunn's multiple comparison tests were performed for colocalization and quantification analyses. RESULTS: We found that brain YKL-40 immunoreactivity was observed in a subset of astrocytes in all four diseases and in controls. There was a strong colocalization between YKL-40 and the astroglial marker GFAP but not with neuronal nor microglial markers. Intriguingly, YKL-40-positive astrocytes were tau-negative in PSP, CBD and PiD. The number of YKL-40-positive astrocytes was increased in tauopathies compared with that in controls. A positive correlation was found between YKL-40 and tau immunoreactivities. CONCLUSIONS: This study confirms that YKL-40 is expressed by a subset of astrocytes in AD and other tauopathies. YKL-40 expression is elevated in several neurodegenerative conditions and correlates with tau pathology.

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy.

Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for l-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV-tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.

Phosphorylation of protein Tau by GSK3ß prolongs survival of bigenic Tau.P301L×GSK3ß mice by delaying brainstem tauopathy.

Tau.P301L transgenic mice suffer precocious mortality between ages 8 and 11 months, resulting from upper airway defects caused by tauopathy in autonomic brainstem circuits that control breathing (Dutschmann et al., 2010). In individual mice, the clinical phenotype evolves progressively and rapidly (3-6weeks) from clasping, over general motor impairment to severe reduction in body-weight into the terminal phase that announces imminent death (<3days). Surprisingly, co-expression of GSK3ß with Tau.P301L significantly prolonged survival of bigenic biGT mice (Terwel et al., 2008), which we here assign to delayed development of brainstem tauopathy. Eventually, brainstem tauopathy became as prominent in old biGT mice in the specified brainstem nuclei as in the parental Tau.P301L mice, resulting in similar clinical deterioration and terminal phase preceding death, although at later age. Biochemically, in both genotypes the pathway to neurofibrillary tangles and neuropil threads was similar: phosphorylation of protein Tau and formation of soluble oligomers and insoluble aggregates, ending in the typical tangles and threads of tauopathy. The extra GSK3ß activity led to expected increased phosphorylation of protein Tau, particularly at residues S262 and S396, which we must conclude to delay the aggregation of protein Tau in the brainstem of aging biGT mice. The unexpected, paradoxical alleviation of the brainstem problems in biGT mice allowed them to grow older and thereby develop more severe tauopathy in forebrain than Tau.P301L mice, which succumb at younger age.

NMNAT suppresses tau-induced neurodegeneration by promoting clearance of hyperphosphorylated tau oligomers in a Drosophila model of tauopathy.

Tauopathies, including Alzheimer's disease, are a group of neurodegenerative diseases characterized by abnormal tau hyperphosphorylation that leads to formation of neurofibrillary tangles. Drosophila models of tauopathy display prominent features of the human disease including compromised lifespan, impairments of learning, memory and locomotor functions and age-dependent neurodegeneration visible as vacuolization. Here, we use a Drosophila model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), in order to study the neuroprotective capacity of a recently identified neuronal maintenance factor, nicotinamide mononucleotide (NAD) adenylyl transferase (NMNAT), a protein that has both NAD synthase and chaperone function. NMNAT is essential for maintaining neuronal integrity under normal conditions and has been shown to protect against several neurodegenerative conditions. However, its protective role in tauopathy has not been examined. Here, we show that overexpression of NMNAT significantly suppresses both behavioral and morphological deficits associated with tauopathy by means of reducing the levels of hyperphosphorylated tau oligomers. Importantly, the protective activity of NMNAT protein is independent of its NAD synthesis activity, indicating a role for direct protein-protein interaction. Next, we show that NMNAT interacts with phosphorylated tau in vivo and promotes the ubiquitination and clearance of toxic tau species. Consequently, apoptosis activation was significantly reduced in brains overexpressing NMNAT, and neurodegeneration was suppressed. Our report on the molecular basis of NMNAT-mediated neuroprotection in tauopathies opens future investigation of this factor in other protein foldopathies.

Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3beta.

Functional diversity of protein phosphatase 2A (PP2A) enzymes mainly results from their association with distinct regulatory subunits. To analyze the functions of one such holoenzyme in vivo, we generated mice lacking PR61/B'δ (B56δ), a subunit highly expressed in neural tissues. In PR61/B'δ-null mice the microtubule-associated protein tau becomes progressively phosphorylated at pathological epitopes in restricted brain areas, with marked immunoreactivity for the misfolded MC1-conformation but without neurofibrillary tangle formation. Behavioral tests indicated impaired sensorimotor but normal cognitive functions. These phenotypical characteristics were further underscored in PR61/B'δ-null mice mildly overexpressing human tau. PR61/B'δ-containing PP2A (PP2A(T61δ)) poorly dephosphorylates tau in vitro, arguing against a direct dephosphorylation defect. Rather, the activity of glycogen synthase kinase-3ß, a major tau kinase, was found increased, with decreased phosphorylation of Ser-9, a putative cyclin-dependent kinase 5 (CDK5) target. Accordingly, CDK5 activity is decreased, and its cellular activator p35, strikingly absent in the affected brain areas. As opposed to tau, p35 is an excellent PP2A(T61δ) substrate. Our data imply a nonredundant function for PR61/B'δ in phospho-tau homeostasis via an unexpected spatially restricted mechanism preventing p35 hyperphosphorylation and its subsequent degradation.

Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates.

Protective proteases are key elements of protein quality control pathways that are up-regulated, for example, under various protein folding stresses. These proteases are employed to prevent the accumulation and aggregation of misfolded proteins that can impose severe damage to cells. The high temperature requirement A (HtrA) family of serine proteases has evolved to perform important aspects of ATP-independent protein quality control. So far, however, no HtrA protease is known that degrades protein aggregates. We show here that human HTRA1 degrades aggregated and fibrillar tau, a protein that is critically involved in various neurological disorders. Neuronal cells and patient brains accumulate less tau, neurofibrillary tangles, and neuritic plaques, respectively, when HTRA1 is expressed at elevated levels. Furthermore, HTRA1 mRNA and HTRA1 activity are up-regulated in response to elevated tau concentrations. These data suggest that HTRA1 is performing regulated proteolysis during protein quality control, the implications of which are discussed.

Histone deacetylase-1 (HDAC1) is a molecular switch between neuronal survival and death.

Both neuroprotective and neurotoxic roles have previously been described for histone deacetylase-1 (HDAC1). Here we report that HDAC1 expression is elevated in vulnerable brain regions of two mouse models of neurodegeneration, the R6/2 model of Huntington disease and the Ca(2+)/calmodulin-dependent protein kinase (CaMK)/p25 double-transgenic model of tauopathic degeneration, suggesting a role in promoting neuronal death. Indeed, elevating HDAC1 expression by ectopic expression promotes the death of otherwise healthy cerebellar granule neurons and cortical neurons in culture. The neurotoxic effect of HDAC1 requires interaction and cooperation with HDAC3, which has previously been shown to selectively induce the death of neurons. HDAC1-HDAC3 interaction is greatly elevated under conditions of neurodegeneration both in vitro and in vivo. Furthermore, the knockdown of HDAC3 suppresses HDAC1-induced neurotoxicity, and the knockdown of HDAC1 suppresses HDAC3 neurotoxicity. As described previously for HDAC3, the neurotoxic effect of HDAC1 is inhibited by treatment with IGF-1, the expression of Akt, or the inhibition of glycogen synthase kinase 3ß (GSK3ß). In addition to HDAC3, HDAC1 has been shown to interact with histone deacetylase-related protein (HDRP), a truncated form of HDAC9, whose expression is down-regulated during neuronal death. In contrast to HDAC3, the interaction between HDRP and HDAC1 protects neurons from death, an effect involving acquisition of the deacetylase activity of HDAC1 by HDRP. We find that elevated HDRP inhibits HDAC1-HDAC3 interaction and prevents the neurotoxic effect of either of these two proteins. Together, our results suggest that HDAC1 is a molecular switch between neuronal survival and death. Its interaction with HDRP promotes neuronal survival, whereas interaction with HDAC3 results in neuronal death.

Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

A subset of neurodegenerative tauopathies is characterized by abundant filamentous inclusions of hyperphosphorylated tau in both neurons and glia. Although the contribution of neuronal tau to behavioral changes and neuronal loss in neurodegenerative diseases has been studied extensively, the functional consequences of tau deposition in glial cells have been less well characterized. To investigate the role of abnormal tau accumulation and aggregation in glial cells, we created a Drosophila model of glial tauopathy by expressing human wild-type tau in adult fly glial cells. Glial expression of tau resulted in robust aggregation of phosphorylated tau into fibrillary inclusions similar to human glial tangles. Tangle formation was accompanied by shortened lifespan and age-dependent apoptotic cell death of both glia and neurons. Genetic manipulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling modified toxicity of glial tau. We also identified a synergistic interaction of combined tau expression in neurons and glial cells. In summary, we present a genetically tractable model of glial fibrillary tau tangle formation and identify JAK/STAT signaling as mediating the death of both glia and neurons in this model.

Cognitive effects of the GSK-3 inhibitor "lithium" in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy.

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration.

Neurofibrillary tangles (NFT) containing tau are a hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). NFT burden correlates with cognitive decline and neurodegeneration in AD. However, little is known about mechanisms that protect against tau-induced neurodegeneration. We used a cross species functional genomic approach to analyze gene expression in multiple brain regions in mouse, in parallel with validation in Drosophila, to identify tau modifiers, including the highly conserved protein puromycin-sensitive aminopeptidase (PSA/Npepps). PSA protected against tau-induced neurodegeneration in vivo, whereas PSA loss of function exacerbated neurodegeneration. We further show that human PSA directly proteolyzes tau in vitro. These data highlight the utility of using both evolutionarily distant species for genetic screening and functional assessment to identify modifiers of neurodegeneration. Further investigation is warranted in defining the role of PSA and other genes identified here as potential therapeutic targets in tauopathy.

Role of the prolyl isomerase Pin1 in protecting against age-dependent 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.

Role of caspase-3 in tau truncation at D421 is restricted in transgenic mouse models for tauopathies.

Truncated tau is widely detected in Alzheimer's disease brain, and caspase-3 has been considered as a major executioner for tau truncation at aspartate421 (D421), according to its capability of cleaving recombinant tau in vitro. Here we investigated the relationship between D421 truncated tau and caspase-3 in two transgenic mouse models for tauopathies. In adult transgenic mice, activated caspase-3 could not be detected in neurons containing truncated tau, with the exception of a few glia-like cells or neurons in postnatal mice. Caspase-3 expression exhibited a dramatic decrease at the early development stage, and kept at constantly low levels during adult stages in both wild type and transgenic mice. On the other hand, co-incubating brain homogenates from adult tau transgenic mice and ethanol-treated postnatal mice promoted tau truncation at D421, which was mildly reduced by caspase inhibitor, but completely suppressed by phosphatase inhibitor, indicating that hyperphosphorylated tau becomes a poor substrate for truncation at D421. Taken together, our study shows that insufficient caspase-3 expression and hyperphosphorylated status of tau in the adult transgenic mouse brain restrict caspase-3 as an efficient enzyme for tau truncation in vivo. Clearly, there is a caspase-3 independent mechanism responsible for tau truncation at D421 in these models.

Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies.

The present study was undertaken to investigate whether chronic endurance exercise affects tau phosphorylation levels in the brain with Alzheimer's disease (AD)-like pathology. To address this, the transgenic (Tg) mouse model of tauopathies, Tg-NSE/htau23, which expresses human tau23 in the brain, was chosen. Animals were subjected to chronic exercise for 3 months from 16 months of age. The exercised Tg mouse groups were treadmill run at speeds of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1 hr/day, 5 days/week, during the 3-month period. Chronic endurance exercise in Tg mice increased the expression of Cu/Zn-superoxide dismutase (SOD) and catalase, and also their enzymatic activities in the brain. In parallel, chronic exercise in Tg mice up-regulated the expression of phospho-PKCalpha, phospho-AKT, and phospho-PI3K, and down-regulated the expressions of phospho-PKA, phosphor-p38, phospho-JNK, and phospho-ERK. Moreover, chronic exercise up-regulated both cytosolic and nuclear levels of beta-catenin, and the expression of T-cell factor-4 (Tcf-4) and cyclin D1 in the brain. As a consequence of such changes, the levels of phospho-tau in the brain of Tg mice were markedly decreased after exercise. Immunohistochemical analysis showed an exercised-induced decrease of the phospho-tau levels in the CA3 subregion of the hippocampus. These results suggest that chronic endurance exercise may provide a therapeutic potential to alleviate the tau pathology.

Spermidine/spermine-N1-acetyltransferase ablation impacts tauopathy-induced polyamine stress response.

BACKGROUND: Tau stabilizes microtubules; however, in Alzheimer's disease (AD) and tauopathies, tau becomes hyperphosphorylated, aggregates, and results in neuronal death. Our group recently uncovered a unique interaction between polyamine metabolism and tau fate. Polyamines exert an array of physiological effects that support neuronal function and cognitive processing. Specific stimuli can elicit a polyamine stress response (PSR), resulting in altered central polyamine homeostasis. Evidence suggests that elevations in polyamines following a short-term stressor are beneficial; however, persistent stress and subsequent PSR activation may lead to maladaptive polyamine dysregulation, which is observed in AD, and may contribute to neuropathology and disease progression. METHODS: Male and female mice harboring tau P301L mutation (rTg4510) were examined for a tau-induced central polyamine stress response (tau-PSR). The direct effect of tau-PSR byproducts on tau fibrillization and oligomerization were measured using a thioflavin T assay and a N2a split superfolder GFP-Tau (N2a-ssGT) cell line, respectively. To therapeutically target the tau-PSR, we bilaterally injected caspase 3-cleaved tau truncated at aspartate 421 (AAV9 Tau ΔD421) into the hippocampus and cortex of spermidine/spermine-N1-acetyltransferase (SSAT), a key regulator of the tau-PSR, knock out (SSAT-/-), and wild type littermates, and the effects on tau neuropathology, polyamine dysregulation, and behavior were measured. Lastly, cellular models were employed to further examine how SSAT repression impacted tau biology. RESULTS: Tau induced a unique tau-PSR signature in rTg4510 mice, notably in the accumulation of acetylated spermidine. In vitro, higher-order polyamines prevented tau fibrillization but acetylated spermidine failed to mimic this effect and even promoted fibrillization and oligomerization. AAV9 Tau ΔD421 also elicited a unique tau-PSR in vivo, and targeted disruption of SSAT prevented the accumulation of acetylated polyamines and impacted several tau phospho-epitopes. Interestingly, SSAT knockout mice presented with altered behavior in the rotarod task, the elevated plus maze, and marble burying task, thus highlighting the impact of polyamine homeostasis within the brain. CONCLUSION: These data represent a novel paradigm linking tau pathology and polyamine dysfunction and that targeting specific arms within the polyamine pathway may serve as new targets to mitigate certain components of the tau phenotype.

Glycogen synthase kinase-3ß suppresses the expression of protein phosphatase methylesterase-1 through ß-catenin.

Protein phosphatase 2A (PP2A) is the major tau phosphatase. Its activity toward tau is regulated by the methylation of PP2A catalytic subunit (PP2Ac) at Leu309. Protein phosphatase methylesterase-1 (PME-1) demethylates PP2Ac and suppresses its activity. We previously found that glycogen synthase kinase-3ß (GSK-3ß) suppresses PME-1 expression. However, the underlying molecular mechanism is unknown. In the present study, we analyzed the promoter of PME-1 gene and found that human PME-1 promoter contains two lymphoid enhancer binding factor-1/T-cell factor (LEF1/TCF) cis-elements in which ß-catenin serves as a co-activator. ß-catenin acted on these two cis-elements and promoted PME-1 expression. GSK-3ß phosphorylated ß-catenin and suppressed its function in promoting PME-1 expression. Inhibition and activation of GSK-3ß by PI3K-AKT pathway promoted and suppressed, respectively, PME-1 expression in primary cultured neurons, SH-SY5Y cells and in the mouse brain. These findings suggest that GSK-3ß phosphorylates ß-catenin and suppresses its function on PME-1 expression, resulting in an increase of PP2Ac methylation.

Activation of PAR-1 kinase and stimulation of tau phosphorylation by diverse signals require the tumor suppressor protein LKB1.

Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human beta-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.

Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism?

Presence of neuritic plaques and neurofibrillary tangles in the brain are two neuropathological hallmarks of Alzheimer's disease (AD), although the molecular basis of their coexistence remains elusive. The neurofibrillary tangles are composed of microtubule binding protein Tau, whereas neuritic plaques consist of amyloid-beta peptides derived from amyloid precursor protein (APP). Recently, the peptidyl-prolyl cis/trans isomerase Pin1 has been identified to regulate the function of certain proteins after phosphorylation and to play an important role in cell cycle regulation and cancer development. New data indicate that Pin1 also regulates the function and processing of Tau and APP, respectively, and is important for protecting against age-dependent neurodegeneration. Furthermore, Pin1 is the only gene known so far that, when deleted in mice, can cause both Tau and Abeta-related pathologies in an age-dependent manner, resembling many aspects of human Alzheimer's disease. Moreover, in the human AD brain Pin1 is downregulated or inhibited by oxidative modifications and/or genetic changes. These results suggest that Pin1 deregulation may provide a link between formation of tangles and plaques in AD.

Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro.

The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasing evidence in recent years supports the notion that Tau pathology spreading throughout the brain in AD and other Tauopathies is the consequence of the propagation of specific Tau species along neuroanatomically connected brain regions in a so-called "prion-like" manner. A number of steps are assumed to be involved in this process, including secretion, cellular uptake, transcellular transfer and/or seeding, although the precise mechanisms underlying propagation of Tau pathology are not fully understood yet. This review summarizes recent evidence on the nature of the specific Tau species that are propagated and the different mechanisms of Tau pathology spreading.

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase.

Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.

Overexpression of 5-Lipoxygenase Worsens the Phenotype of a Mouse Model of Tauopathy.

Brain accumulation of increasing amount of phosphorylated microtubule associated tau protein is one the major hallmark lesions of Alzheimer's disease (AD) and related tauopathies. Consistent evidence from clinical and animal studies has shown that neuroinflammation characterizes these diseases. The 5-lipoxygenase (5LO) is an enzyme protein whose metabolic products are lipids with potent inflammatory actions. Previously, we showed that blockade of 5LO activation ameliorates the phenotype of the htau transgenic mice. Here, by employing a vector system to overexpress 5LO in the brain of the same mouse model, we investigated its role and contribution to their behavioral deficits and development of tau neuropathology. Compared with controls, 5LO gene targeted mice manifested significant impairments in their memory and learning ability. On the other hand, brain tissues of the same mice had higher 5LO protein level and activity which resulted in intense neuroinflammation and synaptic pathology. Further, the same mice had a significant elevation of tau phosphorylation, which associated with the activation of the cdk5 kinase and an accumulation of insoluble tau. The functional involvement of this kinase in the 5LO-dependent tau phosphorylation was confirmed in neuronal cells. Taken together, our findings demonstrate that neuronal 5LO is directly involved in tau phosphorylation and tau neuropathology, and for this reason, it should be considered a good therapeutic target for tauopathies.