title: Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform.
abstract: Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similarto FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (MTs), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).
authors.affiliation: The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Hong
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: V M
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002493:Central Nervous System Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005911:Gliosis / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018908:Muscle Weakness / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017433:Protein Structure, Secondary; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins