|
|
Role of tau phosphorylation in formation of tau envelopes
Karhanová, Adéla ; Lánský, Zdeněk (advisor) ; Štěpánek, Luděk (referee)
Tau is an intrinsically-disordered microtubule-associated protein important for axonal development and a critical regulator of microtubule functions in axons. Tau activity is controlled by phosphorylation and its deregulation resulting in tau hyperphosphorylation and aggregation has been linked to multiple neurodegenerative disorders, collectively termed tauopathies. On microtubules, tau molecules segregate into two kinetically distinct phases, consisting of either independently diffusing molecules or interacting molecules that form cohesive "envelopes" around microtubules. Tau envelopes regulate the action of other microtubule-associated proteins, such as the motility of molecular motors, and protect microtubules against degradation by microtubule-severing enzymes. How the formation, dynamics, and function of tau envelopes are regulated, however, is unknown. Here we show that tau phosphorylation impedes the formation and functioning of protective tau envelopes. Using a combination of reconstitution experiments and live cell imaging, we show that phosphorylated tau incorporates into tau envelopes and that it slows down the envelope growth. Importantly, we demonstrate that phosphorylated tau also destabilizes already existing envelopes leading to their disassembly. Together, our results demonstrate...
|
|
|
The effect of immunosupression on cell therapy in mouse model of Alzeimer's disease
Gajdoš, Roman ; Jendelová, Pavla (advisor) ; Chmelová, Martina (referee)
Alzheimer's disease is a chronic, progressive, neurodegenerative disease. It belongs to the most common type of dementia and worldwide it is statistically the fifth cause of mortality. The most common morphological markers are insoluble β amyloid plaques, hyperphosforylated tau proteins and formation of neurofibrilar tangles. Among the manifestations of the disease is amyloid angiopathy, synaptic transmission disorders and subsequent apoptosis, deterioration of cognitive functions and brain atrophy. Studies have shown that administration of mesenchymal stem cells (MSC) has an immunomodulatory effects and it can reduce the production and storage of β amyloid and thus improve cognitive functions. In preclinical studies, which are conducted in transgenic mice and often use xenografts, administration of immunosuppresion may lead to variety of positive or negative effects which can affect the results of the experiment. The subject of the master's thesis was to determine the effect of immunosuppression on experimental therapy with MSC in various time windows of AD progression (model 3xTg). At which scale and combination of immunosupression will influence the cell therapy's effects, the length of graft survival, mortality of experimental animals and changes at the cellular level. We have also assessed...
|
|
|
The effect of immunosupression on cell therapy in mouse model of Alzeimer's disease
Gajdoš, Roman ; Jendelová, Pavla (advisor) ; Chmelová, Martina (referee)
Alzheimer's disease is a chronic, progressive, neurodegenerative disease. It belongs to the most common type of dementia and worldwide it is statistically the fifth cause of mortality. The most common morphological markers are insoluble β amyloid plaques, hyperphosforylated tau proteins and formation of neurofibrilar tangles. Among the manifestations of the disease is amyloid angiopathy, synaptic transmission disorders and subsequent apoptosis, deterioration of cognitive functions and brain atrophy. Studies have shown that administration of mesenchymal stem cells (MSC) has an immunomodulatory effects and it can reduce the production and storage of β amyloid and thus improve cognitive functions. In preclinical studies, which are conducted in transgenic mice and often use xenografts, administration of immunosuppresion may lead to variety of positive or negative effects which can affect the results of the experiment. The subject of the master's thesis was to determine the effect of immunosuppression on experimental therapy with MSC in various time windows of AD progression (model 3xTg). At which scale and combination of immunosupression will influence the cell therapy's effects, the length of graft survival, mortality of experimental animals and changes at the cellular level. We have also assessed...
|
|
|
The role of m6A pathway in regulation of cognitive function in a rat model of Alzheimer's disease and caloric restriction
Pohanová, Petra ; Telenský, Petr (advisor) ; Stuchlík, Aleš (referee)
Reversible adenosine methylation (N6-methylation; m6A) at the RNA level was described in connection to the regulation of RNA fate. The N6-methyladenosine pathway is important for cognitive function and mechanisms related to memory, including the regulation of adult neurogenesis and synaptic plasticity. The objective of this study was to test the hypothesis that a decreased activity of the RNA-demethylase FTO is associated with improved cognitive function in rats. The RNA-demethylase FTO is a key regulator of the m6A pathway. In this study, we administered MO-I-500, a pharmacological inhibitor of FTO in TgF344-AD transgenic rats, which resulted in an improvement of spatial cognition. We further investigated the cognitive enhancement induced by a caloric restriction as a possible compensatory mechanism of cognitive disorders and its effect on the proteins regulating the N6-methyladenosine pathway. Long-term caloric restriction ameliorated cognitive functions and led to changes in the expression of the major proteins controlling the m6A pathway (FTO, METTL3) which are consistent with the aforementioned hypothesis. Although we do not know the exact mechanism of action, these findings support the hypothesis that m6A pathway regulators, such as the FTO demethylase, may be a promising molecular target for...
|
guest ::
