Neurodegenerative diseases and tau protein: new data
A new model of Alzheimer's disease progression is proposed
LifeSciencesToday based on materials from the University of Pennsylvania:
Transmission of Tangles in Alzheimer's Mice Provides More Authentic Model of Tau Pathology, Penn Study ShowsA characteristic feature of brain diseases associated with improperly folded tau protein, including Alzheimer's disease and frontotemporal lobar degeneration with tau pathologies, is the presence in neurons of neurofibrillary tangles (neurofibrillary tangles, NFTS) consisting of pathological tau filaments.
Tau tangles are also observed in progressive supranuclear paralysis, cortical-basal degeneration and other close taupathies, including chronic traumatic encephalopathy, which is a consequence of multiple traumatic brain injuries.
On an animal model of tau pathology, using synthetic fibers of pure recombinant protein, scientists at the University of Pennsylvania obtained the first direct and convincing evidence that tau fibrils alone are quite sufficient for the transformation of soluble intracellular tau protein into pathological tangles, followed by the transition of tau pathology to other interconnected areas of the brain.
The laboratory of Professor of Pathology and Laboratory Medicine of the Perelman School of Medicine at the University of Pennsylvania Virginia M.-Y. Lee, PhD, MBA, Director of the Center for the Study of Neurodegenerative Diseases (Center for Neurodegenerative Disease Research), published the results of her research in The Journal of Neuroscience (Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy).
"Our new model of the spread of tau pathology explains the stereotypical progression of Alzheimer's disease and other taupathies by involving the transmission of pathological tau protein from cell to cell in this process," Professor Lee comments on the results of the study.
Young mice overexpressing mutant human tau protein were injected with synthetic tau fibrils. These fibrils were a recombinant tau protein having a full length, or a shortened tau containing four microtubule-binding repeats. Synthetic tau fibers caused rapid formation of NFT-like inclusions in the brains of mice that spread from the injection site to the associated brain regions.
Tangle-filled (indicated by arrows) neurons in the medial region of the hippocampus
a month after the introduction of synthetic tau protein fibers into the hippocampus.
Scale = 50 microns. (Photo: Michiyo Iba, Perelman School of Medicine)
Interestingly, injections of synthetic tau fibers either into the hippocampus or into the striatum and cortex led to completely different patterns of its distribution, which reflects their functional connectivity. The simplest explanation for this phenomenon is that the introduced pathological tau protein is involved in the processes occurring in healthy neurons, where it then damages the normal protein. Intercellular transfer of the damaged tau protein is carried out due to the processes of its release and further capture by other neurons. This cycle repeats over and over again, thus leading to the progression of the disease.
Moreover, unlike tau pathology, which spontaneously develops in old mice with an Alzheimer's disease model, the physical structure and biochemical composition of inclusions induced by injections of synthetic tau to young mice corresponded more to the structure and composition of neurofibrillary tangles characteristic of this disease.
The study shows that the introduction of synthetic tau fibrils is sufficient to form authentic NFT-like tau tangles and initiate the spread of tau pathology in a mouse model of Alzheimer's disease.
Now scientists are searching for monoclonal antibodies for passive immunotherapy of diseases associated with tau pathologies.
"In addition, we are studying the mechanisms of the spread of tau protein tangles and their relationship with senile plaques," says Professor Li. "We believe that the transmission model just described most likely reproduces the pathogenesis of Alzheimer's disease in humans more accurately than traditional transgenic mouse models with overexpression of mutant genes and the formation of aggregates. Therefore, another of our priorities is to study whether this injection-transmissive model is more appropriate for the progression of Alzheimer's disease, as well as Parkinson's disease."
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