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Pathological tau accumulates in the brain in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration, and forms amyloid-like filaments incorporating various post-translational modifications (PTMs). Cryo-electron microscopic (cryo-EM) studies have demonstrated that tau filaments extracted from tauopathy brains are characteristic of the disease and share a common fold(s) in the same disease group. Furthermore, the tau PTM profile changes during tau pathology formation and disease progression, and disease-specific PTMs are detected in and around the filament core. In addition, templated seeding has been suggested to trigger pathological tau amplification and spreading in vitro and in vivo , although the molecular mechanisms are not fully understood. Recently, we reported that the cryo-EM structures of tau protofilaments in SH-SY5Y cells seeded with patient-derived tau filaments show a core structure(s) resembling that of the original seeds. Here, we investigated PTMs of tau filaments accumulated in the seeded cells by liquid chromatography/tandem mass spectrometry and compared them with the PTMs of patient-derived tau filaments. Examination of insoluble tau extracted from SH-SY5Y cells showed that numerous phosphorylation, deamidation and oxidation sites detected in the fuzzy coat in the original seeds were well reproduced in SH-SY5Y cells. Moreover, templated tau filament formation preceded both truncation of the N-/C-terminals of tau and PTMs in and around the filament core, indicating these PTMs may predominantly be introduced after the degradation of the fuzzy coat. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative condition that presents with several neurological symptoms, such as cerebellar ataxia, parkinsonism, and cognitive impairment. It is caused by a CTA/CTG repeat expansion on chromosome 13q21 (ataxin 8 opposite strand [ATXN8OS]). However, the pathological significance of this expansion remains unclear. Moreover, abnormal CTA/CTG repeat expansions in ATXN8OS have also been reported in other neurodegenerative diseases, including progressive supranuclear palsy. In this study, we analyzed all available autopsy cases in Japan to investigate common pathological features and profiles of tau pathology in each case. Severe neuronal loss in the substantia nigra and prominent loss of Purkinje cells, atrophy of the molecular layer, and proliferation of Bergmann glia in the cerebellum were common features. Regarding tauopathy, one case presented with progressive supranuclear palsy‐like 4‐repeat tauopathy in addition to mild Alzheimer‐type 3‐ and 4‐repeat tauopathy. Another case showed 3‐ and 4‐repeat tauopathy accentuated in the brainstem. The other two cases lacked tauopathy after extensive immunohistochemical studies. The present study confirmed common pathological features of SCA8 as degeneration of the substantia nigra in addition to the cerebellum. Our study also confirmed unique tauopathy in two of four cases, indicating the necessity to further collect autopsy cases. [ABSTRACT FROM AUTHOR]

The formation of amyloid filaments through templated seeding is believed to underlie the propagation of pathology in most human neurodegenerative diseases. A widely used model system to study this process is to seed amyloid filament formation in cultured cells using human brain extracts. Here, we report the electron cryo‐microscopy structures of tau filaments from undifferentiated seeded SH‐SY5Y cells that transiently expressed N‐terminally HA‐tagged 1N3R or 1N4R human tau, using brain extracts from individuals with Alzheimer's disease or corticobasal degeneration. Although the resulting filament structures differed from those of the brain seeds, some degrees of structural templating were observed. Studying templated seeding in cultured cells, and determining the structures of the resulting filaments, can thus provide insights into the cellular aspects underlying neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

We report an autopsy case of progressive supranuclear palsy (PSP‐Richardson syndrome). The individual had been enrolled in a phase 2 trial and received a monoclonal tau antibody (tilavonemab, ABBV‐8E12); he died of intrahepatic cholangiocarcinoma and gastrointestinal bleeding during the clinical trial. Neuropathological examination demonstrated neuronal loss, gliosis, and widespread deposits of phosphorylated tau in the neurofibrillary tangles, tufted astrocytes, coiled bodies, and threads, which mainly occurred in the inferior olive nucleus, dentate nucleus of the cerebellum, substantia nigra, midbrain tegmentum, subthalamic nuclei, globus pallidus, putamen, and precentral gyrus, confirming typical PSP pathology. Phosphorylated tau was also found to accumulate in Betz cells, Purkinje cells, and pencil fibers in the basal ganglia. In conclusion, no additional changes or pathological modifications, which were expected from immunotherapy targeting tau, were visible in the present case. [ABSTRACT FROM AUTHOR]

Subacute sclerotic panencephalitis (SSPE) is a refractory neurological disorder after exposure to measles virus. Recently, SSPE cases have been treated with antiviral therapies, but data on the efficacy are inconclusive. Abnormal tau accumulation has been reported in the brain tissue of SSPE cases, but there are few reports in which this is amply discussed. Five autopsied cases diagnosed as definite SSPE were included in this study. The subject age or disease duration ranged from 7.6 to 40.9 years old or from 0.5 to 20.8 years, respectively. Cases 3 and 4 had been treated with antiviral therapies. All evaluated cases showed marked brain atrophy with cerebral ventricle dilatation; additionally, marked demyelination with fibrillary gliosis were observed in the cerebral white matter. The brainstem, cerebellum, and spinal cord were relatively preserved. Immunoreactivity (IR) against measles virus was seen in the brainstem tegmentum, neocortex, and/or limbic cortex of the untreated cases but was rarely seen in the two treated cases. Activated microglia were broadly observed from the cerebrum to the spinal cord and had no meaningful difference among cases. Neurofibrillary tangles characterized by a combination of 3‐ and 4‐repeat tau were observed mainly in the oculomotor nuclei, locus coeruleus, and limbic cortex. IR against phosphorylated tau was seen mainly in the cingulate gyrus, oculomotor nuclei, and pontine tegmentum, and tended to be observed frequently in cases with long disease durations but also tended to decrease along with neuronal loss, as in Case 5, which had the longest disease duration. Since the distribution of phosphorylated tau was independent from that of measles virus, the tauopathy following SSPE was inferred to be the result of diffuse brain inflammation triggered by measles rather than a direct result of measles virus. Moreover, antiviral therapies seemed to suppress measles virus but not the progression of tauopathy. [ABSTRACT FROM AUTHOR]

Pallido‐nigro‐luysian atrophy (PNLA) is a variant of progressive supranuclear palsy (PSP). Patients with PSP sometimes show psychiatric signs, but there are few reports about such signs being associated with PSP‐PNLA. Here, we report a case of PSP‐PNLA with argyrophilic grains (AGs) in a patient clinically diagnosed as having PSP‐frontotemporal dementia (PSP‐F). A 74‐year‐old man described as "kind" presented with impaired memory, irritability, and apathy. He showed levodopa‐resistant parkinsonism and postural instability. Brain magnetic resonance imaging revealed mild atrophy of the midbrain and right‐side‐dominant atrophy of the hippocampus and temporal lobe. The patient was diagnosed as having PSP with frontal lobe cognitive or behavioral presentations (PSP‐F). He died of aspiration pneumonia at age 81. At autopsy, macroscopic examination revealed depigmentation of the substantia nigra and grayish discoloration of the dentate nucleus, globus pallidus, and subthalamic nucleus. Severe gliosis was observed in the same regions. There were many phosphorylated tau‐immunoreactive equivocal tufted astrocytes in the globus pallidus. Many neurofibrillary tangles and neuropil threads were observed in the substantia nigra and subthalamic nucleus, and few tau aggregates were observed in the frontal cortex. In contrast, AGs were abundant in the amygdala, entorhinal cortex, and anterior cingulate gyrus, with an asymmetric distribution. The pathological observations led us to change the diagnosis to PSP‐PNLA with AGs. Although most cases of PSP‐F derive from tau pathology in the frontal cortex, this patient did not have phosphorylated tau‐immunoreactive aggregates in that location. Our observations suggest that the psychiatric signs of PSP‐F should be considered as being due to the presence of limbic AGs, not frontal tau pathology. [ABSTRACT FROM AUTHOR]

The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents. [ABSTRACT FROM AUTHOR]

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease, three-repeat tau in Pick's disease (PiD) and four-repeat tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryogenic electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and Alzheimer's disease (AD)-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrate. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity. [ABSTRACT FROM AUTHOR]

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease. [ABSTRACT FROM AUTHOR]

Prion‐like propagation has been proposed to underlie the pathogenesis and progression of many progressive neurodegenerative diseases, and considerable experimental evidence has been accumulated to support this idea. However, only limited evidence is available from the brains of patients, and it is not clear how well various experimental models reflect the clinical situation. In this review, I discuss experimental models of prion‐like propagation, focusing on three major disease‐associated intracellular proteins, α‐synuclein, tau and transactivation response DNA‐binding protein 43 kDa, which provide a molecular basis for evaluating the spread of pathologies in diseased brains, known as Braak staging. Although some issues remain, and further biochemical and structural analyses are needed, it seems clear that the concept of prion‐like propagation is the key to understanding disease progression, as well as for the development of disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

Granular/fuzzy astrocytes (GFAs), a subtype of "aging‐related tau astrogliopathy," are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer's disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies. [ABSTRACT FROM AUTHOR]

Keywords: tau; propagation; prion; aggregation; secretion EN tau propagation prion aggregation secretion 1 3 3 05/21/20 20200519 NES 200519 Tau is a major component of neurofibrillary tangles, one of the cardinal pathological features of Alzheimer's disease (AD) and tauopathies. Pernègre et al. provide a comprehensive review of current knowledge of tau secretion pathways in relation to CSF-tau and suggest muscarinic receptors as a possible physiological target of extracellular secreted tau. [Extracted from the article]

Intracellular inclusions composed of abnormal protein aggregates are one of the neuropathological features of neurodegenerative diseases, and the formation of intracellular aggregates is believed to be associated with neurodegeneration leading to the onset of these diseases. In typical or pure cases, characteristic pathologies with one particular protein, such as tau, alpha‐synuclein or trans‐activation response DNA protein 43 (TDP‐43), can be observed in brains of patients. On the other hand, multiple protein pathologies co‐exist in many cases, raising the possibility that they may influence each other reciprocally in the pathogenesis and progression of the diseases. However, the molecular mechanisms through which these proteins interact with each other and through which they are co‐deposited in brains of patients remain poorly understood. In this review, we focus on the mechanisms of deposition of multiple pathological proteins, such as tau, alpha‐synuclein and/or TDP‐43, and on co‐deposition models of these proteins in vitro and in vivo intended to recapitulate the multiple pathologies found in diseased brains. [ABSTRACT FROM AUTHOR]

The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not Aβ, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea. [ABSTRACT FROM AUTHOR]

Prion-like propagation of abnormal intracytoplasmic proteins, which are the defining features of major neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), has been proposed. A growing body of evidence strongly suggests that abnormal tau, α-synuclein and TDP-43 have prion-like properties, convert the corresponding normal proteins into abnormal forms, and are transmitted from cell to cell, spreading throughout the brain. This idea is extremely important not only for understanding the pathogenesis and progression of these diseases, but also for the development of molecular therapies. Since the distributions and spreading of the abnormal proteins are closely associated with disease symptoms and progression, gain-of-toxic-function of these proteins may affect the neurons and glial cells either directly or indirectly, or both. It is essential to regulate the aggregation of abnormal intracellular proteins and their cell-to-cell transmission in order to stop, or at least slow, the progression of these diseases. [ABSTRACT FROM AUTHOR]

Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage-matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas-positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP. [ABSTRACT FROM AUTHOR]

No clear clinical syndrome for argyrophilic grain disease (AGD) has yet been identified. Previous studies have documented its clinical features, namely, personality changes characterized by emotional disorder involving aggression or ill temper and relatively well-preserved cognitive function, but the clinical manifestations of delusions and hallucinations as they appear in AGD have not been thoroughly described. Here, we report on a 72-year-old Japanese AGD patient who showed psychiatric symptoms, memory impairment and emotional change. He perceived and described a person who was not present and tried to grasp things on the floor though nothing was there. He also insisted that somebody was watching him and consequently always kept his curtains closed. These psychiatric symptoms were observed at an early stage in the patient's disease course. Serial neuroradiological examination showed progressive atrophy of the bilateral temporal lobes. The patient died at 79 years-of-age. Microscopic neuropathological examination showed transactivation responsive region (TAR)-DNA-binding protein of 43 kDa (TDP-43) positive structures in addition to widespread argyrophilic grains and coiled bodies. According to recent recommendations for pathological diagnosis, this case corresponds to AGD with limbic TDP-43 pathology. This case shows that patients with AGD that is eventually confirmed through autopsy can present with delusions and hallucinations early in the course of their disease. The clinical significance of TDP-43 pathology in the brains of patients with AGD remains uncertain. [ABSTRACT FROM AUTHOR]

Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are major neurodegenerative diseases with TDP-43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer’s disease (AD), on the formation of TDP-43 aggregates in SH-SY5Y cells. Following treatment with 0.05μMMB or 5μM dimebon, the number of TDP-43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD-U and other TDP-43 proteinopathies. [Copyright &y& Elsevier]

Abstract: The conversion of soluble peptides and proteins into amyloid fibrils and/or intermediate oligomers is believed to be the central event in the pathogenesis of most human neurodegenerative diseases. Existing treatments are at best symptomatic. Accordingly, small molecule inhibitors of amyloid fibril formation and their mechanisms are of great interest. Here we report that the conformational changes undergone by α -synuclein as it assembles into amyloid fibrils can be detected by epitope-specific antibodies. We show that the conformations of polyphenol-bound α-synuclein monomers and dimers differ from those of unbound monomers and resemble amyloid fibrils. This strongly suggests that small molecule inhibitors bind and stabilize intermediates of amyloid fibril formation, consistent with the view that inhibitor-bound molecular species are on-pathway intermediates. [Copyright &y& Elsevier]

Abstract: A monoclonal antibody specific for phosphoserines 409 and 410 of TDP-43 (mAb pS409/410) has been produced. It strongly stained TDP-43-positive inclusions in brain of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis, but did not stain nuclei, in which normal TDP-43 is localized. It did not recognize TDP-43 rapidly extracted from brains of rats at various developmental stages, strongly suggesting that phosphorylation of Ser409/410 is an abnormal event. Analysis of postmortem changes of TDP-43 revealed that the amounts of Sarkosyl-insoluble, urea-soluble full-length TDP-43 and a 35kDa N-terminal fragment increased time-dependently. [Copyright &y& Elsevier]

Filamentous tau deposits in neurons or glial cells are the hallmark lesions of neurodegenerative tauopathies, such as Alzheimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Biochemical analyses of Sarkosyl-insoluble tau from brains with tauopathies have revealed that tau deposits in different diseases consisted of different tau isoforms (i.e., all six tau isoforms occur in Alzheimer's disease, four repeat tau isoforms occur in corticobasal degeneration or progressive supranuclear palsy, and three repeat tau isoforms occur in Pick's disease). The discovery of mutations in the tau gene in FTDP-17 has established that abnormalities in tau function or expression are sufficient to cause filamentous aggregation of hyperphosphorylated tau and neurodegeneration similar to that seen in sporadic tauopathies. Because the number of tau inclusions and their regional distribution correlate with clinical symptoms, inhibition of tau aggregation or filament formation in neurons or glial cells may prevent neurodegeneration. We have investigated the effects of 42 compounds belonging to nine different chemical classes on tau filament formation, and found that several phenothiazine and polyphenol compounds, and one porphyrin compound inhibit tau filament formation. [ABSTRACT FROM AUTHOR]

Neuronal and glial cytoplasmic inclusions (NCIs and GCIs), which contain α-synuclein as a major component, are characteristic cytopathological features of multiple system atrophy (MSA). We report MSA of 19 years' duration in a 73-year-old woman. Her initial symptom was parkinsonism, with dementia appearing about 8 years later. Postmortem examination showed marked atrophy of the frontal and temporal white matter and limbic system, in addition to the pathology typical of MSA. In the limbic system, severe neuronal loss and astrocytosis were observed, and the remaining neurons often had lightly eosinophilic, spherical cytoplasmic inclusions. Interestingly, a double-labeling immunofluorescence study revealed that the NCIs in the dentate gyrus and amygdaloid nucleus, and the GCIs in the frontal and temporal white matter often expressed both α-synuclein NACP-5 and phosphorylated tau AT8 epitopes. Double-immunolabeling electron microscopy of the NCIs in the dentate gyrus and the GCIs in the temporal white matter clearly revealed labeling of their constituent granule-associated filaments with NACP-5, and some of them were also labeled with AT8. These findings strongly suggested that some α-synuclein filaments were decorated with phosphorylated tau without formation of fibrils such as paired helical filaments. Immunoblotting of sarkosyl-insoluble tau indicated that the accumulated tau consisted mainly of four-repeat tau isoforms of 383 amino acids and 412 amino acids. We consider that the limbic system can be a major site of neurodegeneration in MSA of long duration. The mechanisms of such abnormal tau accumulation in the NCIs and GCIs are unknown. [ABSTRACT FROM AUTHOR]

• Tauopathies are neurodegenerative diseases specified by pathological tau deposits. • Phosphorylation of tau in tauopathy is analyzed by Phos-tag phosphoaffinity SDS-PAGE. • Tauopathies show disease-specific phosphorylation profiles of tau. • Site-specific phosphorylation is different among tauopathies. • Neurotoxic cis conformation of tau at pT231 is increased in AD and AGD patients. Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies. [ABSTRACT FROM AUTHOR]

We examined the immunoreactivity of p62 in five cases of frontotemporal dementia (FTD) with ubiquitin-positive, tau-negative inclusions. Only one case had clinical features suggestive of motor neuron disease (MND). In all cases, ubiquitin-positive neuronal inclusions and neurites in the hippocampal region and cerebral neocortex were immunohistochemically positive for p62. Moreover, in the temporal region of a case of FTD with MND, many oligodendrocytes and some astrocytes were positive for p62. These results suggest that the degenerative process involves p62 in FTD and that the process takes place not only in neurons but also in glial cells. [Copyright &y& Elsevier]

Abstract: Presence of cytoplasmic tau aggregates is a hallmark of brains in patients with tauopathies such as Alzheimer''s disease. However, the mechanism underlying formation of these insoluble tau aggregates remains elusive. In this study, we investigated the impact of prolonged nitric oxide (NO) exposure on neuronal SH-SY5Y cells overexpressing human tau. Treatment with the NO donor DETA NONOate for up to 48h resulted in an increase in S-nitrosation of cellular proteins, inactivation of proteasome, and impairment of respiration. Western blot analysis of Triton X-soluble fractions of NO-treated cells revealed that persistent NO treatment increased heterogeneity in tau molecule size, as a result of dephosphorylation, and induced the formation of sodium dodecyl sulfate (SDS)-stable oligomeric tau aggregates, stabilized by disulfide bonds. Moreover, further NO treatment induced the formation of SDS-stable insoluble tau mega-aggregates that were composed of dephosphorylated full-length tau molecules and other proteins, and were stabilized through disulfide bonds. Evaluation of the role of these tau aggregates as potential seeds for tau fibrillization and elucidation of their formation mechanism in our model, could lead to better understanding of the pathogenesis of tauopathies. [Copyright &y& Elsevier]

Abstract: TAR DNA-binding protein of 43kDa (TDP-43) is the major component of the intracellular inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we show that both monoclonal (60019-2-Ig) and polyclonal (10782-2-AP) anti-TDP-43 antibodies recognize amino acids 203–209 of human TDP-43. The monoclonal antibody labeled human TDP-43 by recognizing Glu204, Asp205 and Arg208, but failed to react with mouse TDP-43. The antibodies stained the abnormally phosphorylated C-terminal fragments of 24–26kDa in addition to normal TDP-43 in ALS and FTLD brains. Immunoblot analysis after protease treatment demonstrated that the epitope of the antibodies (residues 203–209) constitutes part of the protease-resistant domain of TDP-43 aggregates which determine a common characteristic of the pathological TDP-43 in both ALS and FTLD-TDP. The antibodies and methods used in this study will be useful for the characterization of abnormal TDP-43 in human materials, as well as in vitro and animal models for TDP-43 proteinopathies. [Copyright &y& Elsevier]

Abnormalities in tau mRNA splicing cause frontotemporal dementia and parkinsonism linked to chromosome 17, and similar alterations are suggested in sporadic tauopathies such as progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). We have analyzed the expression of three-repeat (3R) and four-repeat (4R) tau isoforms in brains with familial and sporadic tauopathies. By RT-PCR analysis, decreased levels of 3R tau mRNA were detected not only in severely affected cases with progressive supranuclear palsy or corticobasal degeneration but also in cases with Alzheimer''s disease or Pick''s disease. Levels of 3R tau transcripts were closely correlated with levels of neurofilament transcripts. By contrast, expressions of glial fibrillary acidic protein and myelin basic protein were similar in all brains. These results suggest that decrease of 3R tau mRNA associated with loss of neuronal element may largely contribute to the increased ratio of 4R/3R tau mRNA in sporadic tauopathies. [Copyright &y& Elsevier]

We report a sporadic case of tauopathy with unusual clinical and neuropathological features. The patient presented with progressive symmetric rigid-akinetic parkinsonism and dementia of the subcortical type. Magnetic resonance imaging of the brain revealed atrophy resembling multiple system atrophy. The level of cerebrospinal fluid tau protein phosphorylated at serine 199 was markedly elevated. The autopsy revealed more glial than neuronal tauopathy, with much heavier involvement of subcortical white matter and the brainstem than of the cerebral cortex. Analysis of dephosphorylated tau revealed that hyperphosphorylated four-repeat tau isoforms were deposited in the brain of the patient. Despite morphological and biochemical resemblance to a certain form of familial fronto-temporal dementia, no mutation of the tau gene including exon 10 could be found. Our findings, taken together with those in previous similar case reports, indicate that the case represents an atypical form of corticobasal degeneration or a new variant of sporadic tauopathy. [Copyright &y& Elsevier]

The neuropathological features of chronic traumatic encephalopathy (CTE), caused by repeated traumatic brain injury (TBI), include abnormal accumulations of hyper-phosphorylated tau (p-tau) protein in neurons, neurites and astrocytes, considered to progress via neuronal circuits in brains. Some previous reports suggest that a single severe TBI (sTBI) can also induce CTE and p-tau accumulation, but it is not clear whether the pathology is the same as that of repetitive TBI (rTBI). Since prefrontal leucotomy could be regarded as a model of sTBI, in this study we evaluated two autopsied schizophrenia with this procedure. Histopathologically, gliosis and neuronal loss were found not only in the primary ablated prefrontal region, but also in secondary affected areas, i.e., cingulate gyrus, medial nucleus of the thalamus, and nucleus accumbens, which are connected to prefrontal areas. Accumulation of p-tau was mostly seen in neurons, neurites and glias around small blood vessels in the leucotomized prefrontal region. In addition, secondary regions showed some p-tau-positive neurons/glias, as well as many axonal spheroids. Regions of neuronal/glial p-tau pathology showed immunoreactivity to both 3R/4R tau antibodies. Immunoblot analyses of sarkosyl-insoluble tau from frozen brains showed an AD-type tau banding pattern with strong immunoreactivities. sTBI patients showed limited comorbidities, such as TDP-43, alpha-synuclein or AD pathology, whereas rTBI patients have high frequencies of them. The findings suggest that p-tau in the primary affected lesion might progress to connected regions via neuronal circuits over time, and a single severe axonal injury might lead to CTE pathology different from that caused by rTBI. • We examined the neuropathology of schizophrenia with prefrontal leucotomy as a single severe traumatic brain injury (sTBI). • Neuronal loss/gliosis with tau pathology were found not only in the ablated region, but also in secondary areas connected to the primary lesions. • Abnormal tau might progress to connected regions via neuronal circuits over time. • The mechanism of progression in sTBI might be different from that in the diagnostic criteria for CTE. [ABSTRACT FROM AUTHOR]