title: Assembly of filamentous tau aggregates in human neuronal cells.
abstract: Intraneuronal deposition of microtubule-associated protein tau in filamentous aggregates constitutes a pathological hallmark of neurofibrillary degeneration that is characteristic of Alzheimer's disease (AD) and related disorders known collectively as tauopathies. Formation of such fibril inclusions, consisting of hyperphosphorylated tau in multiple isoforms, correlates with the severity of cognitive decline in AD. How neurofibrillary pathology evolves in tauopathy remains unclear at present, but availability of a cellular model with robust tau aggregation will permit experimental scrutiny of the mechanistic process leading to such neurodegeneration. Through the use of a serial transfection strategy in conjunction with a tau minigene construct, we succeeded in generating conditional transfectants of human neuronal lineage that overproduce wild-type human brain tau in isoforms 4R0N, 3R1N and 4R1N via TetOff and ecdysone inducible expression mechanisms. Such transgenic overexpression of tau in multiple isoforms facilitated the assembly of filamentous tau aggregates that exhibit immunoreactivities, physicochemical properties, and ultrastructural attributes reminiscent of those found in human tauopathies. The conditional tau transfectants thus provide us with a useful tool to elucidate the molecular and cellular events leading to neurofibrillary degeneration and a convenient means to test hypothetical mechanisms implicated in the etiopathogenesis of AD and related tauopathies.
authors.affiliation: Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ko.li-wen@mayo.edu
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Ko
authors.forename: Toni
authors.initials: T
authors.lastname: Rush
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.forename: Jay S
authors.initials: JS
authors.lastname: Kersh
authors.forename: Colin
authors.initials: C
authors.lastname: Easson
authors.forename: Michael
authors.initials: M
authors.lastname: Deture
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Yamicia D
authors.initials: YD
authors.lastname: Connor
authors.forename: Shu-Hui C
authors.initials: SH
authors.lastname: Yen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002449:Cell Aggregation / Q000235:genetics; D002999:Clone Cells; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D017931:DNA Primers; D007074:Immunoglobulin G; D008869:Microtubule-Associated Proteins; D016875:tau Proteins