Tau Is Truncated in Five Regions of the Normal Adult Human Brain.
Ontology highlight
ABSTRACT:
SUBMITTER: Friedrich MG
PROVIDER: S-EPMC8036332 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Tau is a predominantly neuronal, soluble and natively unfolded protein that can bind and stabilize microtubules in the central nervous system. Tau has been extensively studied over several decades, especially in the context of neurodegenerative diseases where it can aberrantly aggregate to form a spectrum of pathological inclusions. The presence of tau inclusions in the form of neurofibrillary tangles, neuropil threads and dystrophic neurites within senile plaques are essential and defining features of Alzheimer's disease. The current dogma favors the notion that tau is predominantly an axonal protein, and that in Alzheimer's disease there is a redistribution of tau towards the neuronal soma that is associated with the formation of pathological inclusions such as neurofibrillary tangles and neuropil threads. Using novel as well as previously established highly specific tau antibodies, we demonstrate that contrary to this overwhelmingly accepted fact, as asserted in numerous articles and reviews, in adult human brain, tau is more abundant in cortical gray matter that is enriched in neuronal soma and dendrites compared to white matter that is predominantly rich in neuronal axons. Additionally, in Alzheimer's disease tau pathology is significantly more abundant in the brain cortical gray matter of affected brain regions compared to the adjacent white matter regions. These findings have important implications for the biological function of tau as well as the mechanisms involved in the progressive spread of tau associated with the insidious nature of Alzheimer's disease.
| S-EPMC9237980 | biostudies-literature
Project description:The activity of six hydrolytic enzymes-carboxyl esterase, acid phosphatase, alkaline phosphatase, ?-galactosidase, ?-glucosidase and ?-hexosaminidase, were studied in different regions of the normal human brain tissue obtained at autopsy. Protein estimation and activities of the hydrolytic enzymes with respective substrates were assayed by spectrophotometric and spectroflourometric methods. Amongst the eight regions of the brain-frontal, parietal, occipital, temporal, thalamus, cerebellum and hippocampus, the pineal gland showed highest activity for all hydrolytic enzymes studied except for carboxyl esterase. Among six hydrolases studied, hexosaminidase exhibited highest activity in all regions of the human brain while alkaline phosphatase activity was the least amongst all regions studied. A majority of the enzymes studied showed higher activity in gray matter as compared to the white matter except acid phosphatase and ?-glucosidase which exhibited higher activity in the white matter. The most significant finding in the present study was the high activity of all hydrolytic enzymes noted in the pineal gland as compared to all other regions of the human brain. Such a finding has not been hitherto reported earlier in human brain tissue samples. If the specific activities of these enzymes are to be considered as any functional index, then pineal gland may be more metabolically active tissue with respect to the hydrolytic function as compared to the other regions of the brain.
| S-EPMC3689325 | biostudies-literature
Project description:Tau is a microtubule-associated protein that ensures neuronal shape and function. Besides, Tau is a central player in Alzheimer’s disease (AD) and related Tauopathies where it is found aggregated in degenerating neurons. Mechanisms leading to Tau pathology and its progression are far from being elucidated. Among Tau species found in AD brains, several yet unidentified truncated Tau fragments are showed. A major step forward in the understanding of the role of Tau truncation would be to identify the precise cleavage sites of Tau species. This key step is mandatory to generate appropriate experimental tools in order to investigate the impact of each identified truncated-species on Tau function/dysfunction. Here, we achieved an optimized proteomics approach and succeed in identifying a number of new N-terminally truncated-Tau species from human brain. As N-terminal residues of these fragments are located broadly across Tau sequence, one could expect to have different effects on Tau. We initiated cell-based functional studies by analyzing biochemical characteristics of two N-terminally truncated Tau species starting at residues Met11 and Gln124 (accordingly to the longest Tau isoform) regarding Tau microtubule function. Our results surprisingly showed that the ability of Tau to bind and stabilize microtubules was greater when the first 123 residues are truncated, suggesting that Tau N-terminus would have a role in regulation of microtubule stabilization. Overall, future studies based on our new N-terminally truncated-Tau species will provide new knowledge on the role of truncation in Tau biology as well as in AD pathological process.
2017-04-27 | MSV000081020 | MassIVE
Project description:(1) Background: Epigenome-wide association studies (EWAS) in peripheral blood have repeatedly found associations between tobacco smoking and aberrant DNA methylation (DNAm), but little is known about DNAm signatures of smoking in the human brain, which may contribute to the pathophysiology of addictive behavior observed in chronic smokers. (2) Methods: We investigated the similarity of DNAm signatures in matched blood and postmortem brain samples (n = 10). In addition, we performed EWASs in five brain regions belonging to the neurocircuitry of addiction: anterior cingulate cortex (ACC), Brodmann Area 9, caudate nucleus, putamen, and ventral striatum (n = 38-72). (3) Results: cg15925993 within the LOC339975 gene was epigenome-wide significant in the ACC. Of 16 identified differentially methylated regions, two (PRSS50 and LINC00612/A2M-AS1) overlapped between multiple brain regions. Functional enrichment was detected for biological processes related to neuronal development, inflammatory signaling and immune cell migration. Additionally, our results indicate the association of the well-known AHRR CpG site cg05575921 with smoking in the brain. (4) Conclusion: The present study provides further evidence of the strong relationship between aberrant DNAm and smoking.
| S-EPMC9029407 | biostudies-literature
Project description:Neurofibrillary tangles are a pathological hallmark of Alzheimer's disease, and their levels correlate with the severity of cognitive dysfunction in humans. However, experimental evidence suggests that soluble tau species cause cognitive deficits and memory impairment. Our recent study suggests that caspase-2 (Casp2)-catalyzed tau cleavage at aspartate 314 mediates synaptic dysfunction and memory impairment in mouse and cellular models of neurodegenerative disorders. ?tau314, the C-terminally-truncated cleavage products, are soluble and present in human brain. In addition, levels of ?tau314 proteins are elevated in the brain of the cognitively impaired individuals compared to the cognitively normal individuals, indicating a possible role for ?tau314 proteins in cognitive deterioration. Here we show that (1) ?tau314 proteins are present in the inferior temporal gyrus of human brains; (2) ?tau314 proteins are generated from all six tau splicing isoforms, (3) levels of both Casp2 and ?tau314 proteins are elevated in cognitively impaired individuals compared to cognitively normal individuals, and (4) levels of ?tau314 proteins show a modest predictive value for dementia. These findings advance our understanding of the characteristics of ?tau314 proteins and their relevance to cognitive dysfunction and shed light on the contribution of Casp2-mediated ?tau314 production to cognitive deterioration.
| S-EPMC7052165 | biostudies-literature
Project description:Tau is a microtubule-associated protein (MAP) that is localized to the axon. In Alzheimer's disease (AD), the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. While the abnormal aggregated tau has been extensively studied in human patient tissues and animal models of AD, how normal tau localizes to the axon, which would be the foundation to understand how the mis-localization occurs, has not been well studied due to the poor detectability of normal unaggregated tau in vivo. Therefore, we developed immunohistochemical techniques that can detect normal mouse and human tau in brain tissues with high sensitivity. Using these techniques, we demonstrate the global distribution of tau in the mouse brain and confirmed that normal tau is exclusively localized to the axonal compartment in vivo. Interestingly, tau antibodies strongly labeled nonmyelinated axons such as hippocampal mossy fibers, while white matters generally exhibited low levels of immunoreactivity. Furthermore, mouse tau is highly expressed not only in neurons but also in oligodendrocytes. With super resolution imaging using the stimulated-depletion microscopy, axonal tau appeared punctate rather than fibrous, indicating that tau decorates microtubules sparsely. Co-labeling with presynaptic and postsynaptic markers revealed that normal tau is not localized to synapses but sparsely distributes in the axon. Taken together, this study reports novel antibodies to investigate the localization and mis-localization of tau in vivo and novel findings of normal tau localization in the mouse brain.
| S-EPMC6587864 | biostudies-literature
Project description:Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis-effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cis-regulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated.
| S-EPMC3298852 | biostudies-literature
Project description:Tau is a neuronal protein involved in microtubule stabilization and intracellular vesicle transport in axons. In neurodegenerative disorders termed "tauopathies," like Alzheimer's and Parkinson's disease, tau becomes hyperphosphorylated and forms intracellular inclusions. Rhesus macaques are widely used for studying ageing processes and modeling neurodegenerative disorders, yet little is known about endogenous tau expression in their brains. In this study, immunohistochemical methods were used to map and characterize total tau, 3R- and 4R-tau isoforms, and phosphorylated tau (pThr231-tau and pSer202/Thr205-tau/AT8) expression bilaterally in 16 brain regions of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian adult rhesus macaques. Tau-immunoreactivity (-ir), including both 3R and 4R isoforms, was observed throughout the brain, with varying regional intensities. The anterior cingulate cortex, entorhinal cortex, and hippocampus displayed the most robust tau-ir, while the subthalamic nucleus and white matter regions had minimal expression. Tau was present in neurons of gray matter regions; it was preferentially observed in fibers of the globus pallidus and substantia nigra and in cell bodies of the thalamus and subthalamic nucleus. In white matter regions, tau was abundantly present in oligodendrocytes. Additionally, neuronal pThr231-tau-ir was abundant in all brain regions, but not AT8-ir. Differences in regional and intracellular protein expression were not detected between control subjects and both brain hemispheres of MPTP-treated animals. Specifically, tau-ir in the substantia nigra of all subjects colocalized with GABAergic neurons. Overall, this report provides an in-depth characterization of tau expression in the rhesus macaque brain to facilitate future investigations for understanding and modeling tau pathology in this species.
| S-EPMC10247506 | biostudies-literature
Project description:In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.
| S-EPMC2259385 | biostudies-literature
Project description:Microtubule-associated TAU protein is a pathological hallmark in Alzheimer's disease (AD), where hyperphosphorylation of TAU generates neurofibrillary tangles. To investigate the effects of TAU in a regenerative adult vertebrate brain system, we generated a cre/lox-based transgenic model of zebrafish that chronically expresses human TAUP301L, which is a variant of human TAU protein that forms neurofibrillary tangles in mouse models and humans. Interestingly, we found that although chronic and abundant expression of TAUP301L starting from early embryonic development led to hyperphosphorylation, TAUP301L did not form oligomers and neurofibrillary tangles, and did not cause elevated apoptosis and microglial activation, which are classical symptoms of tauopathies in mammals. Additionally, TAUP301L neither increased neural stem cell proliferation nor activated the expression of regenerative factor Interleukin-4, indicating that TAUP301L toxicity is prevented in the adult zebrafish brain. By combining TAUP301L expression with our established A?42 toxicity model, we found that A?42 ceases to initiate neurofibrillary tangle formation by TAUP301L, and TAUP301L does not exacerbate the toxicity of A?42. Therefore, our results propose a cellular mechanism that protects the adult zebrafish brain against tauopathies, and our model can be used to understand how TAU toxicity can be prevented in humans.
| S-EPMC5636889 | biostudies-other