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Title | High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Wheeler JM, McMillan PJ, Hawk M, Iba M, Robinson L, Xu GJ, Dombroski BA, Jeong D, Dichter MA, Juul H, Loomis E, Raskind M, Leverenz JB, Trojanowski JQ, M Y Lee V, Schellenberg GD, Kraemer BC |
Journal | Acta Neuropathol Commun |
Volume | 3 |
Pagination | 33 |
Date Published | 2015 Jun 04 |
ISSN | 2051-5960 |
Keywords | Age Factors, Analysis of Variance, Animals, Brain, Cognition Disorders, Disease Progression, DNA Copy Number Variations, Electroencephalography, Exploratory Behavior, Humans, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Muscle Strength, Neurofibrillary Tangles, tau Proteins, Tauopathies |
Abstract | INTRODUCTION: Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. RESULTS: We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence. CONCLUSIONS: Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes. |
DOI | 10.1186/s40478-015-0210-6 |
Alternate Journal | Acta Neuropathol Commun |
PubMed ID | 26041339 |
PubMed Central ID | PMC4453289 |
Grant List | I01 BX002619 / BX / BLRD VA / United States P01 AG017586 / AG / NIA NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States AG017586 / AG / NIA NIH HHS / United States |