Acetylation changes tau interactome to degrade tau in Alzheimer's disease animal and organoid models.
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ABSTRACT:
SUBMITTER: Choi H
PROVIDER: S-EPMC6974726 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In Alzheimer's disease, soluble tau accumulates and deposits as neurofibrillary tangles (NFTs). However, a precise toxic mechanism of tau is not well understood. We hypothesized that overexpression of wild-type tau downregulates brain-derived neurotrophic factor (BDNF), a neurotrophic peptide essential for learning and memory. Two transgenic mouse models of human tau expression and human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells were used to examine the effect of excess or pathologically modified wild-type human tau on BDNF expression. Both transgenic mouse models, with or without NFTs, as well as hTau40-SH-SY5Y cells significantly downregulated BDNF messenger RNA compared with controls. Similarly, transgenic mice overexpressing amyloid-β (Aβ) significantly downregulated BDNF expression. However, when crossed with tau knockout mice, the resulting animals exhibited BDNF levels that were not statistically different from wild-type mice. These results demonstrate that excess or pathologically modified wild-type human tau downregulates BDNF and that neither a mutation in tau nor the presence of NFTs is required for toxicity. Moreover, our findings suggest that tau at least partially mediates Aβ-induced BDNF downregulation. Therefore, Alzheimer's disease treatments targeting Aβ alone may not be effective without considering the impact of tau pathology on neurotrophic pathways.
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Project description:Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.
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Project description:Both aging and Alzheimer's disease (AD) are associated with widespread epigenetic changes, with most evidence suggesting global hypomethylation in AD. It is, however, unclear how these age-related epigenetic changes are linked to molecular aberrations as expressed in animal models of AD. Here, we investigated age-related changes of epigenetic markers of DNA methylation and hydroxymethylation in a range of animal models of AD, and their correlations with amyloid plaque load. Three transgenic mouse models, including the J20, APP/PS1dE9 and 3xTg-AD models, as well as Caribbean vervets (a non-transgenic non-human primate model of AD) were investigated. In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus (DG) and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the DG and cornu ammonis (CA) 3. In the 3xTg-AD mice, an age-related increase in DNA methylation was found in the DG and CA1-2. No significant age-related alterations were found in the APP/PS1dE9 mice and non-human primate model. In the J20 model, hippocampal plaque load showed a significant negative correlation with DNA methylation in the DG, and with the ratio a negative correlation in the DG and CA3. For the APP/PS1dE9 model a negative correlation between the ratio and plaque load was observed in the CA3, as well as a negative correlation between DNA methyltransferase 3A (DNMT3A) levels and plaque load in the DG and CA3. Thus, only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-AD model. Given these differences between animal models, future studies are needed to further elucidate the contribution of different AD-related genetic variation to age-related epigenetic changes.
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Project description:Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.
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Project description:The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Abeta precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Abeta) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Abeta cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Abeta-targeted drugs or new therapeutic strategies against this devastating disease.
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Project description:In Alzheimer's disease (AD), vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ) deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature.
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Project description:Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but promotes amyloid formation of three-repeat tau. We further identify acetylation of lysine 298 as a hot spot for isoform-specific tau aggregation. Solid-state NMR spectroscopy demonstrates that amyloid fibrils formed by unmodified and acetylated three-repeat tau differ in structure indicating that site-specific acetylation modulates tau structure. The results implicate acetylation as a critical regulator that guides the selective aggregation of three-repeat tau and the development of tau isoform-specific neurodegenerative diseases.
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Project description:Despite extensive studies regarding tau phosphorylation progression in both human Alzheimer's disease cases and animal models, the molecular and structural changes responsible for neurofibrillary tangle development are still not well understood. Here, by using the antibodies AT100 (recognizes tau protein phosphorylated at Thr212 and Ser214 in the proline-rich region) and pS396 (recognizes tau protein phosphorylated at serine residue 396 in the C-terminal region), we examined phospho-tau immunostaining in neurons from the hippocampal CA1 region of 21 human cases with tau pathology ranging from Braak stage I to VI. Our results indicate that the AT100/pS396 ratio decreases in CA1 in accordance with the severity of the disease, along with its colocalization. We therefore propose the AT100/pS396 ratio as a new tool to analyze the tau pathology progression. Our findings also suggest a conformational modification in tau protein that may cause the disappearance of the AT100 epitope in the late stages of tau pathology, which may play a role in the toxic tangle aggregation. Thus, this study provides new insights underlying the stages for the formation of neurofibrillary tangles in Alzheimer's disease.
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Project description:The most common age-related neurodegenerative disease is Alzheimer's disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.
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Project description:Alzheimer's disease (AD) brains are characterized by amyloid-beta-containing plaques and hyperphosphorylated tau-containing neurofibrillary tangles (NFTs); however, in frontotemporal dementia, the tau pathology manifests in the absence of overt amyloid-beta plaques. Therapeutic strategies so far have primarily been targeting amyloid-beta, although those targeting tau are only slowly beginning to emerge. Here, we identify sodium selenate as a compound that reduces tau phosphorylation both in vitro and in vivo. Importantly, chronic oral treatment of two independent tau transgenic mouse strains with NFT pathology, P301L mutant pR5 and K369I mutant K3 mice, reduces tau hyperphosphorylation and completely abrogates NFT formation. Furthermore, treatment improves contextual memory and motor performance, and prevents neurodegeneration. As hyperphosphorylation of tau precedes NFT formation, the effect of selenate on tau phosphorylation was assessed in more detail, a process regulated by both kinases and phosphatases. A major phosphatase implicated in tau dephosphorylation is the serine/threonine-specific protein phosphatase 2A (PP2A) that is reduced in both levels and activity in the AD brain. We found that selenate stabilizes PP2A-tau complexes. Moreover, there was an absence of therapeutic effects in sodium selenate-treated tau transgenic mice that coexpress a dominant-negative mutant form of PP2A, suggesting a mediating role for PP2A. Taken together, sodium selenate mitigates tau pathology in several AD models, making it a promising lead compound for tau-targeted treatments of AD and related dementias.
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