[Alzheimer ́s disease: pathophysiology and hypotheses]
sou shrnuty biologické hypotézy Alzheimerovy nemoci (AD) založené na poznatcích o patofyziologii AD, které slouží jako východiska pro farmakoterapeutické strategie. Pokroky v poznání úlohy rizikových faktorů a biomarkerů AD v neurodegenerativních procesech umožňují jednak upřesnění stávajících hypotéz nebo tvorbu nových, jednak zlepšení diagnostiky onemocnění, sledování progrese onemocnění a nalezení molekulárních cílů nových léčiv. Kromě amyloidové a tau hypotézy, resp. patologie amyloidu beta a tau proteinu, se při vývoji nových léčiv a studiu mechanismů jejich účinků vychází především z hypotézy mitochondriální, metabolické, neurozánětlivé, oxidačního stresu, synaptoplastické a neurotransmiterové. Významné pro pochopení patofyziologie AD se jeví poznatky o vzájemném propojení, interakcích a synergiích buněčných patologických procesů považovaných za klíčové v hypotézách AD.
Biological hypotheses of Alzheimer ́s disease (AD) based on knowledge about the pathophysiology of AD are summarized, which serve as starting points for pharmacotherapeutic strategies. Advances in the knowledge of the role of risk factors and biomarkers of AD in neurodegenerative processes allow the refinement of existing hypotheses or the generation of new ones, as well as the improvement of disease diagnostics, the monitoring of disease progression, and the discovery of molecular targets for new drugs. In addition to the amyloid and tau hypothesis, respectively the pathology of amyloid beta and tau protein, the mitochondrial, metabolic, neuroinflammatory, oxidative stress, synaptoplastic, and neurotransmitter hypotheses are being used to develop new drugs and to study the mechanisms of their action. Important for the understanding of the pathophysiology of AD is the knowledge about the interrelationships, interactions, and synergies of the cellular pathological processes that are considered to be key in the various AD hypotheses.
- MeSH
- Alzheimerova nemoc * diagnóza etiologie patofyziologie MeSH
- amyloidní beta-protein metabolismus toxicita MeSH
- biologické markery analýza MeSH
- lidé MeSH
- mitochondrie metabolismus patologie MeSH
- nervový přenos fyziologie MeSH
- neuroplasticita fyziologie MeSH
- proteiny tau metabolismus toxicita MeSH
- rizikové faktory MeSH
- signální transdukce fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.
- MeSH
- Alzheimerova nemoc * patologie MeSH
- krysa rodu rattus MeSH
- metabolismus lipidů MeSH
- modely nemocí na zvířatech MeSH
- mozek metabolismus MeSH
- myši transgenní MeSH
- myši MeSH
- neurofibrilární klubka metabolismus MeSH
- potkani transgenní MeSH
- proteiny tau genetika metabolismus MeSH
- tauopatie * patologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive deterioration of upper and lower motor neurons. A definitive diagnostic test or biomarker for ALS is currently unavailable, leading to a diagnostic delay following the onset of initial symptoms. Our study focused on cerebrospinal fluid (CSF) concentrations of clusterin, tau protein, phosphorylated tau protein, and beta-amyloid1-42 in ALS patients and a control group. METHODS: Our study involved 54 ALS patients and 58 control subjects. Among the ALS patients, 14 presented with bulbar-onset ALS, and 40 with limb-onset ALS. We quantified biomarker levels using enzyme-linked immunosorbent assay (ELISA) and compared the results using the Mann-Whitney U-test. RESULTS: Significant elevations in neurodegenerative markers, including tau protein (p < 0.0001), phosphorylated tau protein (p < 0.0001), and clusterin (p = 0.038), were observed in ALS patients compared to controls. Elevated levels of tau protein and phosphorylated tau protein were also noted in both bulbar and limb-onset ALS patients. However, no significant difference was observed for beta-amyloid1-42. ROC analysis identified tau protein (AUC = 0.767) and p-tau protein (AUC = 0.719) as statistically significant predictors for ALS. CONCLUSION: Our study demonstrates that neurodegenerative marker levels indicate an ongoing neurodegenerative process in ALS. Nonetheless, the progression of ALS cannot be predicted solely based on these markers. The discovery of a specific biomarker could potentially complement existing diagnostic criteria for ALS.
- MeSH
- amyotrofická laterální skleróza * diagnóza MeSH
- biologické markery MeSH
- klusterin MeSH
- lidé MeSH
- opožděná diagnóza MeSH
- proteiny tau MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC50 = 1.53 μM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay.
- MeSH
- antitumorózní látky * chemie farmakologie MeSH
- apoptóza MeSH
- ethinylestradiol * chemie farmakologie MeSH
- kontrolní body fáze G2 buněčného cyklu účinky léků MeSH
- mikrotubuly MeSH
- modulátory tubulinu * chemie farmakologie MeSH
- nádorové buněčné linie MeSH
- triazoly * chemie farmakologie MeSH
- tubulin * metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bardet-Biedl syndrome (BBS) is an archetypal ciliopathy caused by dysfunction of primary cilia. BBS affects multiple tissues, including the kidney, eye and hypothalamic satiety response. Understanding pan-tissue mechanisms of pathogenesis versus those which are tissue-specific, as well as gauging their associated inter-individual variation owing to genetic background and stochastic processes, is of paramount importance in syndromology. The BBSome is a membrane-trafficking and intraflagellar transport (IFT) adaptor protein complex formed by eight BBS proteins, including BBS1, which is the most commonly mutated gene in BBS. To investigate disease pathogenesis, we generated a series of clonal renal collecting duct IMCD3 cell lines carrying defined biallelic nonsense or frameshift mutations in Bbs1, as well as a panel of matching wild-type CRISPR control clones. Using a phenotypic screen and an unbiased multi-omics approach, we note significant clonal variability for all assays, emphasising the importance of analysing panels of genetically defined clones. Our results suggest that BBS1 is required for the suppression of mesenchymal cell identities as the IMCD3 cell passage number increases. This was associated with a failure to express epithelial cell markers and tight junction formation, which was variable amongst clones. Transcriptomic analysis of hypothalamic preparations from BBS mutant mice, as well as BBS patient fibroblasts, suggested that dysregulation of epithelial-to-mesenchymal transition (EMT) genes is a general predisposing feature of BBS across tissues. Collectively, this work suggests that the dynamic stability of the BBSome is essential for the suppression of mesenchymal cell identities as epithelial cells differentiate.
- MeSH
- Bardetův-Biedlův syndrom * genetika metabolismus patologie MeSH
- cilie metabolismus MeSH
- lidé MeSH
- myši knockoutované MeSH
- myši MeSH
- proteiny asociované s mikrotubuly metabolismus MeSH
- proteiny metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
An increase in phosphorylation of the Tau protein is associated with Alzheimer's disease (AD) progression through unclear molecular mechanisms. In general, phosphorylation modifies the interaction of intrinsically disordered proteins, such as Tau, with other proteins; however, elucidating the structural basis of this regulation mechanism remains challenging. The bridging integrator-1 gene is an AD genetic determinant whose gene product, BIN1, directly interacts with Tau. The proline-rich motif recognized within a Tau(210-240) peptide by the SH3 domain of BIN1 (BIN1 SH3) is defined as 216PTPP219, and this interaction is modulated by phosphorylation. Phosphorylation of T217 within the Tau(210-240) peptide led to a 6-fold reduction in the affinity, while single phosphorylation at either T212, T231, or S235 had no effect on the interaction. Nonetheless, combined phosphorylation of T231 and S235 led to a 3-fold reduction in the affinity, although these phosphorylations are not within the BIN1 SH3-bound region of the Tau peptide. Using nuclear magnetic resonance (NMR) spectroscopy, these phosphorylations were shown to affect the local secondary structure and dynamics of the Tau(210-240) peptide. Models of the (un)phosphorylated peptides were obtained from molecular dynamics (MD) simulation validated by experimental data and showed compaction of the phosphorylated peptide due to increased salt bridge formation. This dynamic folding might indirectly impact the BIN1 SH3 binding by a decreased accessibility of the binding site. Regulation of the binding might thus not only be due to local electrostatic or steric effects from phosphorylation but also to the modification of the conformational properties of Tau.
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- Alzheimerova nemoc * metabolismus MeSH
- fosforylace MeSH
- jaderné proteiny metabolismus MeSH
- lidé MeSH
- nádorové supresorové proteiny chemie MeSH
- peptidy chemie MeSH
- prolin metabolismus MeSH
- proteiny tau * metabolismus MeSH
- src homologní domény MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tardigrades are microscopic ecdysozoans that can withstand extreme environmental conditions. Several tardigrade species undergo reversible morphological transformations and enter into cryptobiosis, which helps them to survive periods of unfavorable environmental conditions. However, the underlying molecular mechanisms of cryptobiosis are mostly unknown. Tubulins are evolutionarily conserved components of the microtubule cytoskeleton that are crucial in many cellular processes. We hypothesize that microtubules are necessary for the morphological changes associated with successful cryptobiosis. The molecular composition of the microtubule cytoskeleton in tardigrades is unknown. Therefore, we analyzed and characterized tardigrade tubulins and identified 79 tardigrade tubulin sequences in eight taxa. We found three α-, seven β-, one γ-, and one ε-tubulin isoform. To verify in silico identified tardigrade tubulins, we also isolated and sequenced nine out of ten predicted Hypsibius exemplaris tubulins. All tardigrade tubulins were localized as expected when overexpressed in mammalian cultured cells: to the microtubules or to the centrosomes. The presence of a functional ε-tubulin, clearly localized to centrioles, is attractive from a phylogenetic point of view. Although the phylogenetically close Nematoda lost their δ- and ε-tubulins, some groups of Arthropoda still possess them. Thus, our data support the current placement of tardigrades into the Panarthropoda clade.
- MeSH
- fylogeneze * MeSH
- Tardigrada * klasifikace MeSH
- tubulin genetika MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In neurodegenerative diseases, changes in neuronal proteins in the cerebrospinal fluid and blood are viewed as potential biomarkers of the primary pathology in the central nervous system (CNS). Recent reports suggest, however, that level of neuronal proteins in fluids also alters in several types of epilepsy in various age groups, including children. With increasing evidence supporting clinical and sub-clinical seizures in Alzheimer's disease, Lewy body dementia, Parkinson's disease, and in other less common neurodegenerative conditions, these findings call into question the specificity of neuronal protein response to neurodegenerative process and urge analysis of the effects of concomitant epilepsy and other comorbidities. In this article, we revisit the evidence for alterations in neuronal proteins in the blood and cerebrospinal fluid associated with epilepsy with and without neurodegenerative diseases. We discuss shared and distinctive characteristics of changes in neuronal markers, review their neurobiological mechanisms, and consider the emerging opportunities and challenges for their future research and diagnostic use.
- MeSH
- Alzheimerova nemoc * patologie MeSH
- amyloidní beta-protein MeSH
- biologické markery MeSH
- dítě MeSH
- epilepsie * MeSH
- lidé MeSH
- neurodegenerativní nemoci * komplikace diagnóza MeSH
- proteiny tau MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Spinal muscular atrophy (SMA) is a degenerative disease of the motoneurons of the anterior horns of the spinal cord, which in approximately 95% of cases is caused by a mutation in the SMN1 gene on chromosome 5q13. Progress in genetic testing, particularly next-generation sequencing, has led to the discovery of additional causative genes underlying non-5q forms of SMA. These are very rare and genetically and phenotypically very heterogeneous. One of these subtypes is caused by a mutation in the cytoplasmic heavy chain gene dynein, gene DYNH1C1. It is a form of SMA with dominant involvement of the lower autosomal dominantly inherited and thus described in the literature under the acronym SMALED. Although it is SMA, this phenotype of the disease is only very slowly progressive and does not significantly impair quality of life.
Spinální muskulární atrofie (SMA) je degenerativní onemocnění motoneuronů předních rohů míšních, které je přibližně v 95 % případů způsobené mutací v SMN1 genu na chromozomu 5q13. Pokroky v genetickém testování, především sekvenování nové generace, vede k objevům dalších kauzálních genů podmiňujících vznik non-5q forem SMA. Ty jsou velmi vzácné a geneticky i fenotypově velmi heterogenní. Jeden z těchto subtypů je podmíněn mutací genu pro těžký řetězec cytoplazmatického dyneinu, genu DYNH1C1. Jedná se o formu SMA s dominantním postižením dolních končetin, autosomálně dominantně dědičnou, v literatuře tedy popisovanou pod zkratkou SMALED. Ačkoli se jedná o SMA, tento fenotyp choroby je jen velmi pomalu progredující a významně nenarušuje kvalitu života.
- MeSH
- anamnéza MeSH
- cytoplazmatické dyneiny genetika MeSH
- dolní končetina diagnostické zobrazování patologie MeSH
- lidé MeSH
- mutace genetika MeSH
- neurologické poruchy chůze etiologie MeSH
- neuromuskulární nemoci genetika MeSH
- předškolní dítě MeSH
- spinální svalová atrofie * diagnóza genetika patologie MeSH
- svalová slabost MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Tauopathies are a group of neurodegenerative diseases categorised into three types, 3R, 4R, or 3R+4R (mixed) tauopathies, based on the tau isoforms that make up the aberrant filaments. It is supposed that all six tau isoforms share functional characteristics. However, differences in the neuropathological features associated with different tauopathies offer the possibility that disease progression and tau accumulation may vary depending on the isoform composition. The presence or absence of repeat 2 (R2) in the microtubule-binding domain defines the type of isoform, which might influence tau pathology associated with a particular tau isoform. Therefore, our study aimed to identify the differences in the seeding propensities of R2 and repeat 3 (R3) aggregates using HEK293T biosensor cells. We show that the seeding induced by R2 was generally higher than by R3 aggregates, and lower concentrations of R2 aggregates are sufficient to induce seeding. Next, we found that both R2 and R3 aggregates dose-dependently increased triton-insoluble Ser262 phosphorylation of native tau, which is only visible in cells seeded with higher concentrations (12.5 nM or 100 nM) of R2 and R3 aggregates, despite the seeding by the lower concentrations of R2 aggregates after 72 h. However, the accumulation of triton-insoluble pSer262 tau was visible earlier in cells induced with R2 than in R3 aggregates. Our findings suggest that the R2 region may contribute to the early and enhanced induction of tau aggregation and define the difference in disease progression and neuropathology of 4R tauopathies.
