The most common neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, are characterized by the misfolding of a small number of proteins that assemble into ordered ...aggregates in affected brain cells. For many years, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. Recent research has now shown that cell non-autonomous mechanisms are also important for the pathogenesis of neurodegenerative diseases with intracellular filamentous inclusions. The intercellular transfer of inclusions made of tau, α-synuclein, huntingtin and superoxide dismutase 1 has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system.
Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease, tangle-only dementia, Pick disease, argyrophilic ...grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
Filaments made of hyperphosphorylated tau protein are encountered in a number of neurodegenerative diseases referred to as ‘tauopathies’. In the most prevalent tauopathy, Alzheimer's disease, tau ...pathology progresses in a stereotypical manner with the first lesions appearing in the locus coeruleus and the entorhinal cortex from where they appear to spread to the hippocampus and neocortex. Propagation of tau pathology is also characteristic of argyrophilic grain disease, where the tau lesions appear to spread throughout distinct regions of the limbic system. These findings strongly implicate neurone‐to‐neurone propagation of tau aggregates. Isoform composition and morphology of tau filaments can differ between tauopathies suggesting the existence of conformationally diverse tau strains. Altogether, this points to prion‐like mechanisms in the pathogenesis of tauopathies.
This study, taking the example of Alzheimer's and Parkinson's diseases, presents the experimental and human data that support the hypothesis that Aβ, tau, and α-synuclein may seed and propagate the ...pathology and consider the potential clinical consequences.
Aβ aggregates transmit Aβ pathology to experimental animals. Interhuman transmission of Aβ pathology has also been observed in iatrogenic Creutzfeldt-Jakob disease, or after dural graft. Tau aggregates also transmit the pathology to mice when injected in the brain and propagates along neuronal pathways. Evidence of interhuman transmission is weak. Finally α-synuclein aggregates, when injected in specific areas of the brain may recapitulate Lewy pathology of Parkinson's disease but there is currently no hint of human to human transmission.
Since the first evidence that at least Aβ pathology of Alzheimer's disease could be transmitted to the animal, data have accumulated indicating that misfolded proteins characteristic of neurodegenerative diseases may seed and propagate pathology in a prion-like manner. The term propagon has been proposed to describe those proteins that act as prions at different levels. Taking the example of Alzheimer's and Parkinson's diseases, the experimental and human data supporting the hypothesis that Aβ, tau, and α-synuclein are indeed propagons are presented with their clinical consequences.
Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein ...being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. It is now believed that protein aggregates form in a small number of brain cells, from which they propagate intercellularly through templated recruitment, reminiscent of the mechanisms by which prions spread through the nervous system.
Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease. In the disease process, neuronal tau inclusions first ...appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The soluble microtubule‐associated protein tau forms hyperphosphorylated, insoluble and filamentous inclusions in a number of neurodegenerative diseases referred to as “tauopathies.” In Alzheimer's ...disease, tau pathology develops in a stereotypical manner, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of tau pathology is also a characteristic of argyrophilic grain disease, where the tau lesions spread throughout the limbic system. Significantly, isoform composition and morphology of tau filaments can differ between tauopathies, suggesting the existence of distinct tau strains. Extensive experimental findings indicate that prion‐like mechanisms underly the pathogenesis of tauopathies.
Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces ...tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tauopathies constitute neurodegenerative diseases that are characterized by the intracellular deposition of filaments made of hyperphosphorylated tau protein. The pattern of tau deposition in ...Alzheimer's disease follows a stereotypical progression, with the first lesions appearing in the locus coeruleus and entorhinal cortex, from where they appear to spread to the hippocampus and neocortex. Propagation of pathological tau is also characteristic of argyrophilic grain disease, where the lesions seem to spread through distinct regions of the limbic system. In chronic traumatic encephalopathy, tauopathy appears to spread from the neocortex to the brainstem. These findings implicate neuron-to-neuron propagation of tau aggregates. Isoform compositions and morphologies of tau filaments can differ between tauopathies, which is consistent with the existence of distinct tau strains. Here, we review recent findings that support prion-like mechanisms in the pathogenesis of tauopathies through the experimental use of transgenic mice.
PDF
