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      Pathological conformations involving the amino terminus of tau occur early in Alzheimer’s disease and are differentially detected by monoclonal antibodies

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          Abstract

          Conformational changes involving the amino terminus of the tau protein are among the earliest alterations associated with tau pathology in Alzheimer’s disease and other tauopathies. This region of tau contains a phosphatase-activating domain (PAD) that is aberrantly exposed in pathological forms of the protein, an event that is associated with disruptions in anterograde fast axonal transport. We utilized four antibodies that recognize the amino terminus of tau, TNT1, TNT2 (a novel antibody), Tau12, and Tau13, to further study this important region. Using scanning alanine mutations in recombinant tau proteins, we refined the epitopes of each antibody. We examined the antibodies’ relative abilities to specifically label pathological tau in non-denaturing and denaturing assays to gain insight into some of the mechanistic details of PAD exposure. We then determined the pattern of tau pathology labeled by each antibody in human hippocampal sections at various disease stages in order to characterize PAD exposure in the context of disease progression. The characteristics of reactivity for the antibodies fell into two groups. TNT1 and TNT2 recognized epitopes within amino acids 7–12 and specifically identified recombinant tau aggregates and pathological tau from Alzheimer’s disease brains in a conformation-dependent manner. These antibodies labeled early pre-tangle pathology from neurons in early Braak stages and colocalized with thiazine red, a marker of fibrillar pathology, in classic neurofibrillary tangles. However, late tangles were negative for TNT1 and TNT2 indicating a loss of the epitope in later stages of tangle evolution. In contrast, Tau12 and Tau13 both identified discontinuous epitopes in the amino terminus and were unable to differentiate between normal and pathological tau in biochemical and tissue immunohistological assays. Despite the close proximity of these epitopes, the antibodies demonstrated remarkably different abilities to identify pathological changes in tau indicating that detection of conformational alterations involving PAD exposure is not achieved by all N-terminal tau antibodies and that a relatively discrete region of the N-terminus (i.e., amino acids 7–12, the TNT1 and TNT2 epitope) is central to the differences between normal and pathological tau. The appearance of PAD in early tau pathology and its disappearance in late-stage tangles suggest that toxic forms of tau are associated with the earliest forms of tau deposits. Collectively, these findings demonstrate that the TNT antibodies are useful markers for early conformational display of PAD and provide information regarding conformational changes that have potential implications in the toxic mechanisms of tau pathology.

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          Most cited references40

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          Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease.

          To assess the relationship between dementia, neuronal loss, and neuropathological findings in Alzheimer's disease (AD), we counted the number of neurons, senile plaques, and neurofibrillary tangles in a high-order association cortex. We studied the superior temporal sulcus of 34 individuals with AD and 17 nondemented control subjects, using statistically unbiased, stereological counting techniques. The number of superior temporal sulcus neurons in nondemented control subjects was stable across the sixth to ninth decades. In AD, more than 50% of the neurons were lost. Both neuronal loss and neurofibrillary tangles increased in parallel with the duration and severity of illness, but the amount of neuronal loss exceeded by manyfold the amount of neurofibrillary tangles accumulated. In contrast to the correlation between neurofibrillary tangles and neuronal loss, the number of senile plaques and the percentage of the superior temporal sulcus that was covered by Abeta (amyloid burden) were not related to neuronal loss, number of neurofibrillary tangles, or duration of disease. Neither the amount nor the rate of neuronal loss in the superior temporal sulcus in AD correlated with apolipoprotein E genotype. These data suggest that neuronal loss in association areas such as the superior temporal sulcus contributes directly to cognitive impairment in AD.
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            Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles.

            The microtubule-binding protein tau has been implicated in the pathogenesis of Alzheimer's disease and related disorders. However, the mechanisms underlying tau-mediated neurotoxicity remain unclear. We created a genetic model of tau-related neurodegenerative disease by expressing wild-type and mutant forms of human tau in the fruit fly Drosophila melanogaster. Transgenic flies showed key features of the human disorders: adult onset, progressive neurodegeneration, early death, enhanced toxicity of mutant tau, accumulation of abnormal tau, and relative anatomic selectivity. However, neurodegeneration occurred without the neurofibrillary tangle formation that is seen in human disease and some rodent tauopathy models. This fly model may allow a genetic analysis of the cellular mechanisms underlying tau neurotoxicity.
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              Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain

              The neuronal microtubule-associated protein tau is required for the development of cell polarity in cultured neurons. Using PC12 cells that stably express tau and tau amino-terminal fragments, we report that tau interacts with the neural plasma membrane through its amino-terminal projection domain. In differentiated PC12 transfectants, tau is found in growth cone-like structures in a nonmicrotubule-dependent manner. In hippocampal neurons, tau is differentially extracted by detergent and enriched in the growth cone and the distal axon when membrane is left intact. In PC12 transfectants, overexpression of tau's amino-terminal fragment, but not of full-length tau, suppresses NGF-induced process formation. Our data suggest that tau's amino-terminal projection domain has an important role in neuritic development and establishes tau as a mediator of microtubule-plasma membrane interactions.
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                Author and article information

                Contributors
                Journal
                9500169
                20475
                Neurobiol Dis
                Neurobiol. Dis.
                Neurobiology of disease
                0969-9961
                1095-953X
                22 June 2016
                31 May 2016
                October 2016
                01 October 2017
                : 94
                : 18-31
                Affiliations
                [a ]Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
                [b ]Neuroscience Program, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
                [c ]Hauenstein Neuroscience Center, Mercy Health Saint Mary’s, 220 Cherry St SE, Grand Rapids, MI 49503, USA
                Author notes
                [* ]Corresponding author at: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, 333 Bostwick Ave NE, Grand Rapids, MI 49503, USA
                Article
                NIHMS795386
                10.1016/j.nbd.2016.05.016
                4983528
                27260838
                578bd8f6-b23c-4ff4-9a19-b7e0bf1e0166

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Neurosciences
                tau,alzheimer’s disease,tauopathies,neurodegeneration,protein misfolding,protein aggregation,conformation,antibodies

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