Filamentous Tau Inclusions Research Articles

Novel tau filament folds in individuals with MAPT mutations P301L and P301T.

Mutations in MAPT, the microtubule-associated protein tau gene, give rise to cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with abundant filamentous tau inclusions in brain cells. Individuals with pathological MAPT variants exhibit behavioural changes, cognitive impairment and signs of parkinsonism. Missense mutations of residue P301, which are the most common MAPT mutations associated with FTDP-17, give rise to the assembly of mutant four-repeat tau into filamentous inclusions, in the absence of extracellular deposits. Here we report the cryo-EM structures of tau filaments from five individuals belonging to three unrelated families with mutation P301L and from one individual belonging to a family with mutation P301T. A novel three-lobed tau fold resembling the two-layered tau fold of Pick's disease was present in all cases with the P301L tau mutation. Two different tau folds were found in the case with mutation P301T, the less abundant of which was a variant of the three-lobed fold. The major P301T tau fold was V-shaped, with partial similarity to the four-layered tau folds of corticobasal degeneration and argyrophilic grain disease. These findings suggest that FTDP-17 with mutations in P301 should be considered distinct inherited tauopathies and that model systems with these mutations should be used with caution in the study of sporadic tauopathies.

Corticobasal degeneration: An update

Corticobasal degeneration (CBD) is one of the primary tauopathies with a disease onset in the 5th to 7th decade. CBD is a progressive condition of unknown aetiology, which is characterised neuropathologically by neuronal loss, astrogliosis and deposition of filamentous tau inclusions, composed entirely of 4-repeat tau isoforms, in neurons and glial cells in cerebral cortical areas, basal ganglia, brainstem and cerebellar nuclei. The term CBD is now a neuropathological diagnostic one and for the canonical clinical syndrome associated with CBD neuropathological changes, the corticobasal syndrome (CBS) term is used. In addition to CBS, the clinical spectrum also includes a behavioural variant of frontotemporal dementia syndrome, speech disorders, Richardson’s syndrome and, rarely, posterior cortical syndrome. In addition to CBD, CBS can also be caused by other pathologies. A number of genetic risk factors of CBD have been identified. As specific biomarkers confirming CBD as the underlying pathology responsible for CBS or other clinical manifestations are still lacking, for a definitive diagnosis of CBD neuropathological investigation is required. Recent cryo-electron microscopic studies have proven that CBD is a distinct tauopathy associated with a unique molecular structure of the tau filaments, which firmly differentiates it from other primary tauopathies.

Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold.

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.

Tau and neurodegeneration.

First identified in 1975, tau was implicated in Alzheimer's disease 10 years later. Filamentous tangle inclusions were known to be made of hyperphosphorylated tau by 1991, with similar inclusions gaining recognition for being associated with other neurodegenerative diseases. In 1998, mutations in MAPT, the gene that encodes tau, were identified as the cause of a dominantly inherited form of frontotemporal dementia with abundant filamentous tau inclusions. While this result indicated that assembly of tau into aberrant filaments is sufficient to drive neurodegeneration and dementia, most cases of tauopathy are sporadic. More recent work in experimental systems showed that filamentous assemblies of tau may first form in one brain area, and then spread to others in a prion-like fashion. Beginning in 2017, work on human brains using high-resolution techniques has led to a structure-based classification of tauopathies, which has opened the door to a better understanding of the significance of tau filament formation.

Neurodegeneration: 2021 update.

This article reviews a collection of manuscripts in the field of neurodegenerative disease chosen from what are considered by the author to be among the 10 most important and potentially impactful topics or research trends of 2020 relevant to the field of experimental and diagnostic neuropathology. A deliberate effort was made to provide balance among disease categories covered. The result is a varied selection that includes not just individual papers but also research topics and trends. The association of COVID-19 with longer-term neurological symptoms has launched a research trend fueled by speculation that the SARS-CoV-2 might trigger neurodegenerative changes. The onslaught of transcriptomic studies has begun to give way to proteomics, with three transformative studies published examining glial contributions to Alzheimer disease, cerebral atherosclerosis in cognitive decline, and the complex sequence of post-translational modifications of the tau protein. Plasma biomarkers for Alzheimer disease have continued to make rapid advances, especially around highly sensitive assays capable of detecting different forms of abnormal hyperphosphorylated tau in peripheral blood. Two studies using cryo-electron microscopy showed the power of the approach by continuing to elucidate the diversity of filamentous tau inclusions, and a third study gave the first glimpse of α-synuclein aggregates at near atomic resolution. Another study continued to delineate how different α-synuclein conformers ("strains") target specific brain regions and lead to neurodegeneration. In Huntington's disease, we saw compelling molecular data showing how cells adapt to endoplasmic reticulum stress through the unfolded protein response. Finally, the role of astrocytes in chronic traumatic encephalopathy has emerged as a critical area of interest.

Pathological Alterations of Tau in Alzheimer's Disease and 3xTg-AD Mouse Brains.

Microtubule-associated protein tau in Alzheimer's disease (AD) brain is hyperphosphorylated, truncated, and aggregated into neurofibrillary tangles. Oligomeric and hyperphosphorylated tau (Oligo-tau) isolated from AD brain captures and templates normal tau into filaments both in vitro and in vivo; this prion-like activity is believed to be responsible for the progression of neurofibrillary pathology in AD. The 3xTg-AD mouse model develops both Aβ and tau pathologies and thus gains popularity in preclinical studies of AD. Despite the histopathological similarity of the 3xTg-AD model to AD, biochemical authenticity of tau alterations in this model remains elusive. To investigate the biochemical basis of tau pathology in 3xTg-AD brain, we here compared pathological alterations of tau in the aged 3xTg-AD brain to those in AD brain. We found that in contrast to substantial high molecular weight smear tau (HMW-tau) lacking the N-terminal portion and hyperphosphorylated at multiple sites in AD brain, tau in 3xTg-AD mouse brain showed no detectable HMW-tau or truncation but slightly increased phosphorylation when normalized with total tau. In addition, AT8 immunostaining exhibited filamentous tau inclusions in AD brain, but predominantly truffle-like morphology in aged 3xTg-AD mouse brain. Further, Oligo-tau isolated from 3xTg-AD mice showed minimal potency in capturing tau in vitro and seeding tau aggregation in cultured cells when compared to AD Oligo-tau. These findings suggest that the alterations of tau in 3xTg-AD mouse brain differ from those in AD brain. In 3xTg-AD mice, the lack of N-terminal truncation, scarce SDS/reducing reagent-resistant HMW-tau, and minimal hyperphosphorylation may collectively result in low potency in prion-like activityofthe Oligo-tau.

Ordered Assembly of Tau Protein and Neurodegeneration.

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. Their formation is important, because dominantly inherited mutations in MAPT, the tau gene, cause frontotemporal dementia with abundant filamentous tau inclusions. Assembly of tau may begin in a specific region of the brain, from where it spreads to other areas. It remains to be seen if the molecular species underlying tau aggregate-mediated neurodegeneration and propagation are the same or different. In the brains of mice transgenic for human mutant P301S tau, small tau filaments are the predominant seed-competent species. It has been suggested that different conformers of assembled tau may give rise to different human tauopathies, but until recently, it was not possible to study this directly. Electron cryo-microscopy can now be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer's disease are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304-E380 (in the numbering of the 441 amino acid isoform of human tau), which adopt a combined cross-β/β-helix structure. They comprise the ends of the first or second microtubule-binding repeat (R1 or R2), the whole of R3 and R4, as well as 12 amino acids after R4. By contrast, the core of the narrow filament of Pick's disease consists of a single protofilament extending from K254-F378 of 3R tau, which adopts a cross-β structure. It comprises the last 21 amino acids of R1, all of R3 and R4, as well as 10 amino acids after R4. Wide tau filaments of Pick's disease, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of Alzheimer's and Pick's diseases appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in Alzheimer's disease and a different fold in Pick's disease, establishing the existence of distinct conformers.

Imbalanced Expression of Tau and Tubulin Induces Neuronal Dysfunction in C. elegans Models of Tauopathy.

Tauopathy is a type of dementia defined by the accumulation of filamentous tau inclusions in neural cells. Most types of dementia in the elderly, including Alzheimer’s disease, are tauopathies. Although it is believed that tau protein abnormalities and/or the loss of its functions results in neurodegeneration and dementia, the mechanism of tauopathy remains obscure. Loss of microtubules and/or tubulin is a known consequence of tau accumulating in neurons in Alzheimer’s disease. In other words, there is an excess level of tau relative to tubulin in tauopathy neurons. To test whether this imbalance of tau and tubulin expression results in the neurotoxicity of tau, we developed several transgenic C. elegans lines that express human tau at various levels in pan-neurons. These worms showed behavioral abnormalities in a tau expression-dependent manner. The knockdown of a tubulin-specific chaperon, or a subset of tubulin, led to enhanced tau toxicity even in low-expressing tau-transgenic worms that showed no abnormal behaviors. In addition, the suppression of tau expression in tubulin knockdown worms rescued neuronal dysfunction. Thus, not only the overexpression of tau but also a reduction in tubulin can trigger the neurotoxicity of tau. Tau expressed in worms was also highly phosphorylated and largely bound to tubulin dimers rather than microtubules. Relative amount of tubulin-unbound tau was increased in high-expressing tau-transgenic worms showing tau toxicity. We further demonstrated that tau aggregation was inhibited by co-incubation of purified tubulin in vitro, meaning sufficient amounts of tubulin can protect against the formation of tau inclusions. These results suggest that the expression ratio of tau to tubulin may be a determinant of the tauopathy cascade.

Tau Fibril Formation in Cultured Cells Compatible with a Mouse Model of Tauopathy.

Neurofibrillary tangles composed of hyperphosphorylated tau protein are primarily neuropathological features of a number of neurodegenerative diseases collectively termed tauopathy. To understand the mechanisms underlying the cause of tauopathy, precise cellular and animal models are required. Recent data suggest that the transient introduction of exogenous tau can accelerate the development of tauopathy in the brains of non-transgenic and transgenic mice expressing wild-type human tau. However, the transmission mechanism leading to tauopathy is not fully understood. In this study, we developed cultured-cell models of tauopathy representing a human tauopathy. Neuro2a (N2a) cells containing propagative tau filaments were generated by introducing purified tau fibrils. These cell lines expressed full-length (2N4R) human tau and the green fluorescent protein (GFP)-fused repeat domain of tau with P301L mutation. Immunocytochemistry and super-resolution microscopic imaging revealed that tau inclusions exhibited filamentous morphology and were composed of both full-length and repeat domain fragment tau. Live-cell imaging analysis revealed that filamentous tau inclusions are transmitted to daughter cells, resulting in yeast-prion-like propagation. By a standard method of tau preparation, both full-length tau and repeat domain fragments were recovered in sarkosyl insoluble fraction. Hyperphosphorylation of full-length tau was confirmed by the immunoreactivity of phospho-Tau antibodies and mobility shifts by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). These properties were similar to the biochemical features of P301L mutated human tau in a mouse model of tauopathy. In addition, filamentous tau aggregates in cells barely co-localized with ubiquitins, suggesting that most tau aggregates were excluded from protein degradation systems, and thus propagated to daughter cells. The present cellular model of tauopathy will provide an advantage for dissecting the mechanisms of tau aggregation and degradation and be a powerful tool for drug screening to prevent tauopathy.

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1483-3) contains supplementary material, which is available to authorized users.

Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections.

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024-1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6-12months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.

Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity.

The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present in a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To gain more insights into the pathomechanism of tauopathies, we performed an RNAi-based large-scale screen in Drosophila melanogaster to identify genetic modifiers of Tau[R406W]-induced toxicity. A collection of RNAi lines, putatively silencing more than 7000 genes, was screened for the ability to modify Tau[R406W]-induced toxicity in vivo. This collection covered more than 50% of all protein coding fly genes and more than 90% of all fly genes known to have a human ortholog. Hereby, we identified 62 genes that, when silenced by RNAi, modified Tau-induced toxicity specifically. Among these 62 modifiers were three subunits of the Dynein/Dynactin complex. Analysis on segmental nerves of fly larvae showed that pan neural Tau[R406W] expression and concomitant silencing of Dynein/Dynactin complex members synergistically caused strong pathological changes within the axonal compartment, but only minor changes at synapses. At the larval stage, these alterations did not cause locomotion deficits, but became evident in adult flies. Our data suggest that Tau-induced detrimental effects most likely originate from axonal rather than synaptic dysfunction and that impaired retrograde transport intensifies detrimental effects of Tau in axons. In conclusion, our findings contribute to the elucidation of disease mechanisms in tauopathies like FTDP-17 or AD.

TARGETING THE SHARED PATHOLOGICAL CONFORMERS OF BOTH Aβ AND HYPERPHOSPHYLATED TAU WITH A CONFORMATIONALLY SELECTIVE MONOCLONAL ANTIBODY

Background: Pathological tau aggregation leading to filamentous tau inclusions characterizes neurodegenerative tauopathies such as Alzheimer’s Disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Tau aggregation is linked with clinical symptoms and probably represents the mediator of neurodegeneration. At the moment there is no cure for these diseases and existing treatments are only of palliative nature. Methods: Transgenic mice that overexpress human P301S tau mutation resemble many neuropathological features of human tauopathies in combination with behavioral deficits and increased mortality. We tested the effect of the small molecule anle138b as an anti-aggregative drug on the neuropathology and behavioral deficits in P301S mice. The compound was administered from weaning until death. Results: Here we show that reducing the amount of tau aggregates using the compound anle138b ameliorates disease symptoms in a mousemodel for tauopathies. Treatment with anle138b significantly prolonged the survival of transgenic mice and rescued behavioral deficits as well as synapse and neuron loss in the CA3 region and stratum lucidum of the hippocampus. Our results indicate that reducing tau pathology with the anti-aggregative compound anle138b represents a clinically effective and promising approach for the treatment of human tauopathies. Conclusions: In conclusion, anle138b mitigate tau pathology and may represent a new lead compound for developing a therapy for human tauopathies.

Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy

The Tau protein is the major component of intracellular filaments observed in a number of neurodegenerative diseases known as tauopathies. The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) leads to severe human tauopathy. Here, we assess the impact of FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52), an immunophilin protein that interacts with physiological Tau, on Tau-P301L activity. We identify a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrate FKBP52's ability to induce the formation of Tau-P301L oligomers. EM analysis shows that Tau-P301L oligomers, induced by FKBP52, can assemble into filaments. In the transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons. This result correlates with a significant reduction of pT181 pathological phosphorylated Tau and with recovery of the stereotypic escape response behavior. Collectively, FKBP52 appears to be an endogenous candidate that directly interacts with the pathogenic Tau-P301L and modulates its function in vitro and in vivo.

Blocking Effects of Human Tau on Squid Giant Synapse Transmission and Its Prevention by T-817 MA

Filamentous tau inclusions are hallmarks of Alzheimer's disease and related neurodegenerative tauopathies, but the molecular mechanisms involved in tau-mediated changes in neuronal function and their possible effects on synaptic transmission are unknown. We have evaluated the effects of human tau protein injected directly into the presynaptic terminal axon of the squid giant synapse, which affords functional, structural, and biochemical analysis of its action on the synaptic release process. Indeed, we have found that at physiological concentration recombinant human tau (h-tau42) becomes phosphorylated, produces a rapid synaptic transmission block, and induces the formation of clusters of aggregated synaptic vesicles in the vicinity of the active zone. Presynaptic voltage clamp recordings demonstrate that h-tau42 does not modify the presynaptic calcium current amplitude or kinetics. Analysis of synaptic noise at the post-synaptic axon following presynaptic h-tau42 microinjection revealed an initial phase of increase spontaneous transmitter release followed by a marked reduction in noise. Finally, systemic administration of T-817MA, a proposed neuro-protective agent, rescued tau-induced synaptic abnormalities. Our results show novel mechanisms of h-tau42 mediated synaptic transmission failure and identify a potential therapeutic agent to treat tau-related neurotoxicity.

Improved behavioral response as a valid biomarker for drug screening program in transgenic rodent models of tauopathies.

Neurodegenerative tauopathies are defined as a group of dementia and movement disorders characterized by prominent filamentous tau inclusions and degeneration located within certain brain regions. Their common sign is a presence of proteinaceous aggregates composed of hyperphosphorylated and truncated tau proteins. The molecular mechanisms of the disease still remain unresolved, therefore transgenic organisms displaying tau-related neurodegenerative cascade have been created to allow decoding of individual pathways involved in human pathological conditions. Moreover, use of transgenic model organisms enables the application of potential therapeutic approaches. The expression of mutated or misfolded tau as a transgene in vivo leads to significant alteration of neurobehavioral features of experimental animal, therefore detailed classification of behavioral phenotype become one of the first crucial analyses, while it functionally correlates with central nervous system impairment. Currently, two major types of behavioral impairment have been described in transgenic rodent models of tauopathies, (1) progressive motor impairment associated with muscular weakness and premature death and (2) age-related impairment of cognitive functions attended with unaffected motor status. Up to the present, only transgenic models displaying motor impairment were successfully applied into the drug trials targeting misfolded tau protein, despite their behavioral inconsistence with clinical profile of progressive human tauopathy. The aim of this study was, therefore, to summarize the pros and cons of used transgenic rodent models mimicking human tauopathies in connection with development of therapeutic strategies.

Detection of filamentous tau inclusions by the fluorescent Congo red derivative FSB [(trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene

Filamentous inclusions made of the microtubule-associated protein tau in a hyperphosphorylated state are a defining feature of a large number of human neurodegenerative diseases. Here we show that (trans,trans)-1-fluoro-2,5-bis(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), a fluorescent Congo red derivative, labels tau inclusions in tissue sections from a mouse line transgenic for human P301S tau and in cases of familial frontotemporal dementia and sporadic Pick’s disease. Labelling by FSB required the presence of tau filaments. More importantly, tau inclusions in the spinal cord of human P301S tau transgenic mice were labelled following a single intravenous injection of FSB. These findings indicate that FSB can be used to detect filamentous tau in vivo.

シンポジウム２‐４ 神経変性疾患研究の焦点‐新たな病的因子の登場と臨床への展望‐ 神経変性と炎症：ＦＴＤＰ−１７モデルマウスをもちいて

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, and the discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. To investigate the pathomechanism of tauopathies, we generated and studied P301S mutant human tau transgenic mice (line PS19). Filamentous tau lesions developed in PS19 mice at 6-months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old PS19 mice before fibrillary tau tangles emerged. Prominent microglial activation and proinflammatory cytokine expressions in neurons also preceded tangle formation. Importantly, immunosuppression of young PS19 mice with FK506 attenuated tau pathology, thereby linking neuroinflammation to early progression of tauopathies. Recently, an anti-inflammatory function of acetylcholine (ACh) has been reported, suggesting that synaptic dysfunction might accelerate neuroinflammatory reaction by depletion of ACH. To investigate this, we administered donepezil (DZ), an ACh-esterase inhibitor, and trihexiphenidyl (TP), an anti-cholinergic agent to PS19 mice. Interestingly, DZ ameliorated but TP deteriorated microglial activation, tau pathology and neuronal loss, indicating the ACh level in the brain might play roles in not only neurotransmission, but also suppressing neuroinflammation in the brain.

Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.

Frontotemporal Lobar Degeneration: Current Concepts in the Light of Recent Advances

Work done over the past decade has led to a molecular understanding of frontotemporal lobar degeneration (FTLD), a deadly disease that afflicts patients in mid-life. It is a common cause of dementia, second only to Alzheimer's disease in the population below 65 years of age. Neuroanatomical and neurobiological substrates have been identified for the three major subtypes of FTLD and these discoveries have broadened the FTLD spectrum to include amyotrophic lateral sclerosis (ALS). Mutations in MAPT were found to cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), a familial disorder with filamentous tau inclusions in nerve cells and glial cells. FTDP-17 can result in clinical syndromes that closely resemble progressive supranuclear palsy, corticobasal degeneration and Pick's disease. More recently, mutations in three genes (VCP, CHMP2B and PGRN) have been found to cause FTLD with ubiquitin-positive, tau-negative neuronal inclusions (FTLD-U). They explain a large proportion of inherited FTLD-U. It remains to be seen whether dementia lacking distinctive histopathology (DLDH) constitutes a third disease category, as many of these cases are now being reclassified as FTLD-U. Recently, TAR DNA-binding protein-43 (TDP-43) has been identified as a key protein of the ubiquitin inclusions of FTLD-U and ALS. Thus, for familial forms of FTLD and related disorders, we now know the primary etiologies and accumulating proteins. These findings are pivotal for dissecting the pathways by which different etiologies lead to the varied clinicopathological presentations of FTLD.