BACKGROUND AND PURPOSE: Globular glial tauopathies (GGTs) have heterogeneous presentations; little evidence regarding typical clinical and magnetic resonance imaging (MRI) presentations are available. METHODS: We retrospectively assessed MRIs from three postmortem-confirmed GGT cases, in two patients with atypical progressive aphasia and one with corticobasal syndrome. RESULTS: We suggest that four principal concomitant MRI findings characterize GGT type I: a sagittal callosal hyperintense band, marked focal callosal atrophy suggesting white matter degeneration originating in cortical areas responsible for symptoms (anterior atrophy in predominantly language manifestations and posterior atrophy in predominantly apraxia), periventricular white matter lesions, and mild-to-moderate brain stem atrophy. CONCLUSIONS: We observed four concomitant MRI abnormalities in patients with atypical dementia, parkinsonism, and late incomplete supranuclear gaze palsy. Two patients had atypical progressive aphasia and one had corticobasal syndrome.

• Klíčová slova
• corpus callosum, dementia, globular glial tauopathy, magnetic resonance, tauopathy,
• MeSH
• atrofie patologie   MeSH
• corpus callosum * patologie   MeSH
• lidé MeSH
• neurozobrazování MeSH
• retrospektivní studie MeSH
• tauopatie * komplikace   diagnostické zobrazování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alzheimer's disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151-391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography - matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.

• Klíčová slova
• Cerebrospinal fluid, LC-MALDI MS, peptidomics, rat model, tauopathy,
• MeSH
• chromatografie kapalinová MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• peptidy mozkomíšní mok   MeSH
• potkani transgenní MeSH
• proteiny tau genetika   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• tauopatie mozkomíšní mok   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• peptidy MeSH
• proteiny tau MeSH

BACKGROUND: Tauopathies represent heterogeneous groups of neurodegenerative diseases that are characterised by abnormal deposition of the microtubule-associated protein tau. Alzheimer's disease is the most prevalent tauopathy, affecting more than 35 million people worldwide. In this study we investigated changes in metabolic pathways associated with tau-induced neurodegeneration. METHODS: Cerebrospinal fluid (CSF), plasma and brain tissue were collected from a transgenic rat model for tauopathies and from age-matched control animals. The samples were analysed by targeted and untargeted metabolomic methods using high-performance liquid chromatography coupled to mass spectrometry. Unsupervised and supervised statistical analysis revealed biochemical changes associated with the tauopathy process. RESULTS: Energy deprivation and potentially neural apoptosis were reflected in increased purine nucleotide catabolism and decreased levels of citric acid cycle intermediates and glucose. However, in CSF, increased levels of citrate and aconitate that can be attributed to glial activation were observed. Other significant changes were found in arginine and phosphatidylcholine metabolism. CONCLUSIONS: Despite an enormous effort invested in development of biomarkers for tauopathies during the last 20 years, there is no clinically used biomarker or assay on the market. One of the most promising strategies is to create a panel of markers (e.g., small molecules, proteins) that will be continuously monitored and correlated with patients' clinical outcome. In this study, we identified several metabolic changes that are affected during the tauopathy process and may be considered as potential markers of tauopathies in humans.

• Klíčová slova
• Metabolomics, Tau protein, Tauopathy, Transgenic rat model,
• MeSH
• apoptóza genetika   MeSH
• biologické markery metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• metabolomika MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   patologie   MeSH
• mutace genetika   MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• proteiny tau genetika   metabolismus   MeSH
• tauopatie mozkomíšní mok   diagnóza   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• proteiny tau MeSH

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

• Klíčová slova
• Alzheimer’s disease, amyloid β, membrane dysfunction, tauopathy,
• MeSH
• Alzheimerova nemoc * metabolismus   patologie   etiologie   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• protein 1 související s LDL-receptory * metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• tauopatie * metabolismus   patologie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• LRP1 protein, human MeSH Prohlížeč
• peptidové fragmenty MeSH
• protein 1 související s LDL-receptory * MeSH
• proteiny tau * MeSH

Glycosphingolipids (GSLs) are amphipathic lipids composed of a sphingoid base and a fatty acyl attached to a saccharide moiety. GSLs play an important role in signal transduction, directing proteins within the membrane, cell recognition, and modulation of cell adhesion. Gangliosides and sulfatides belong to a group of acidic GSLs, and numerous studies report their involvement in neurodevelopment, aging, and neurodegeneration. In this study, we used an approach based on hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution tandem mass spectrometry (HRMS/MS) to characterize the glycosphingolipid profile in rat brain tissue. Then, we screened characterized lipids aiming to identify changes in glycosphingolipid profiles in the normal aging process and tau pathology. Thorough screening of acidic glycosphingolipids in rat brain tissue revealed 117 ganglioside and 36 sulfatide species. Moreover, we found two ganglioside subclasses that were not previously characterized-GT1b-Ac2 and GQ1b-Ac2. The semi-targeted screening revealed significant changes in the levels of sulfatides and GM1a gangliosides during the aging process. In the transgenic SHR24 rat model for tauopathies, we found elevated levels of GM3 gangliosides which may indicate a higher rate of apoptotic processes.

• Klíčová slova
• aging, gangliosides, glycosphingolipids, liquid chromatography, mass spectrometry, neurodegeneration, sulfatides, tauopathy,
• MeSH
• chromatografie kapalinová MeSH
• G(M3) gangliosid genetika   MeSH
• geneticky modifikovaná zvířata MeSH
• hydrofobní a hydrofilní interakce účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyselé glykosfingolipidy genetika   izolace a purifikace   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mozek metabolismus   patologie   MeSH
• neurofibrily genetika   patologie   MeSH
• proteiny tau genetika   MeSH
• stárnutí genetika   patologie   MeSH
• sulfoglykosfingolipidy izolace a purifikace   metabolismus   MeSH
• tauopatie genetika   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• G(M3) gangliosid MeSH
• kyselé glykosfingolipidy MeSH
• proteiny tau MeSH
• sulfoglykosfingolipidy MeSH

Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer's disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand-receptor and cytokine-cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4, and SNAP25, converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

• MeSH
• autistická porucha * MeSH
• biologické markery MeSH
• dítě MeSH
• DNA-helikasy MeSH
• homeodoménové proteiny metabolismus   MeSH
• jaderné proteiny MeSH
• lidé MeSH
• mozek diagnostické zobrazování   metabolismus   MeSH
• poruchy autistického spektra * genetika   MeSH
• proteiny nervové tkáně MeSH
• senioři MeSH
• tauopatie * genetika   MeSH
• transkripční faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ADNP protein, human MeSH Prohlížeč
• biologické markery MeSH
• DNA-helikasy MeSH
• homeodoménové proteiny MeSH
• jaderné proteiny MeSH
• proteiny nervové tkáně MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

Globular glial tauopathies (GGTs) have heterogeneous presentations with little available information regarding typical clinical manifestations. We report on a case of atypical primary progressive aphasia (PPA) due to comorbid GGT and limbic transactive response DNA binding protein of 43 kDa (TDP-43) proteinopathy. The initial clinical phenotype was compatible with the nonfluent-agrammatical variant of PPA and early hippocampal amnesia. Progressively, parkinsonism and supranuclear oculomotor impairment occurred, and finally, late mutism with frontal-type dementia, impaired comprehension, and behavioral manifestations developed. The neuropathology was characteristic of GGT type I with vascular changes and comorbid limbic-predominant age-related TDP-43 encephalopathy (LATE). Our findings expand the clinical spectrum of GGTs to include a complex progressive aphasia syndrome. The extraordinary feature, in this case, was the combination of two progressive aphasia subtypes, that is, the early nonfluent-agrammatical variant and the late semantic variant. Our findings also expand the spectrum of neuropathological comorbidities in GGT.

• Klíčová slova
• TDP-43 proteinopathy, dementia, globular glial inclusions, primary progressive aphasia, tauopathy,
• Publikační typ
• časopisecké články MeSH

Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.

• Klíčová slova
• Alzheimer’s disease, phosphorylation, synaptic damage, tau mislocalization, truncated tau,
• Publikační typ
• časopisecké články MeSH

Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25α (TPPP/p25α), α-synuclein (α-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10). Loss of nuclear TPPP/p25α immunoreactivity correlated significantly with the degree of microglial reaction and loss of myelin basic prtein density as a marker of tract degeneration. This was more prominent in MSA and GGT, which, together with enlarged cytoplasmic TPPP/p25α immunoreactivity and inclusion burden allowed these disorders to be grouped as predominant oligodendroglial proteinopathies. However, distinct features, ie more colocalization of α-syn than tau with TPPP/p25α, more obvious loss of oligodendrocyte density in MSA, but more prominent association of tau protein inclusions in GGT to loss of nuclear TPPP/p25α immunoreactivity, were also recognized. In addition, we observed previously underappreciated oligodendroglial α-synuclein pathology in the pallidothalamic tract in LBD. Our study demonstrates common and distinct aspects of oligodendroglial involvement in the pathogenesis of diverse NDDs.

• Klíčová slova
• Globular glial tauopathy, Lewy body disease, Multiple system atrophy, Oligodendroglia, Progressive supranuclear palsy, TPPP/p25α,
• MeSH
• alfa-synuklein metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek metabolismus   patologie   MeSH
• neurodegenerativní nemoci metabolismus   patologie   MeSH
• oligodendroglie metabolismus   patologie   MeSH
• proteiny nervové tkáně metabolismus   MeSH
• proteiny tau metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tauopatie metabolismus   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-synuklein MeSH
• proteiny nervové tkáně MeSH
• proteiny tau MeSH
• TPPP protein, human MeSH Prohlížeč

Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.

• Klíčová slova
• Alzheimer's disease, CSPGs, Object recognition memory, Perineuronal nets, Plasticity,
• MeSH
• Alzheimerova nemoc farmakoterapie   etiologie   patofyziologie   psychologie   MeSH
• antigeny imunologie   metabolismus   fyziologie   MeSH
• cílená molekulární terapie MeSH
• extracelulární matrix metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• neurodegenerativní nemoci farmakoterapie   etiologie   patofyziologie   psychologie   MeSH
• neuroplasticita MeSH
• neutralizující protilátky terapeutické užití   MeSH
• paměť fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• proteoglykany imunologie   metabolismus   fyziologie   MeSH
• protilátky aplikace a dávkování   MeSH
• reakční čas MeSH
• tauopatie komplikace   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny MeSH
• Cat316 antibody MeSH Prohlížeč
• chondroitin sulfate proteoglycan 4 MeSH Prohlížeč
• neutralizující protilátky MeSH
• proteoglykany MeSH
• protilátky MeSH