title: Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam.
abstract: Intracytoplasmic filamentous tau inclusions are neuropathological hallmarks of amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of Guam and the defining lesions of other neurodegenerative disorders known as tauopathies. Here we review current insights into the cell and molecular neuropathology of ALS/PDC, a common tauopathy in the Chamorro population on Guam. We also summarize recent advances in understanding this disorder through studies of transgenic (Tg) mouse models of this tauopathy. Briefly, overexpression of human tau isoforms in the central nervous system of Tg mice resulted in a neurodegenerative tauopathy with a phenotype similar to ALS/PDC. Specifically, argyrophilic, congophilic, and tau immunoreactive inclusions accumulated with age in cortical and brainstem neurons of these mice, but they were most abundant in spinal cord neurons, and the inclusions contained 10- to 20-nm tau-positive straight filaments. There also was extensive gliosis in spinal cord associated with axonal degeneration in the ventral roots, while remaining axons in spinal nerves showed a loss of microtubules and reduced fast axonal transport. With advancing age, these Tg mice showed increasing motor weakness, and this was accompanied by a progressive increase in the phosphorylation and insolubility of brain and spinal cord tau proteins. Thus, tau Tg mice recapitulate key phenotypic features of ALS/PDC neuropathology in an ethnic minority on Guam, and these animal models provide new opportunities to discover novel therapies for this and related tauopathies.
authors.affiliation: The Center for Neurodegenerative Disease Research, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishihara
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Yoshiyama
authors.forename: Ming
authors.initials: M
authors.lastname: Hong
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Forman
authors.forename: Victoria
authors.initials: V
authors.lastname: Zhukareva
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D000818:Animals; D015897:Comorbidity; D003704:Dementia / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006141:Guam / Q000453:epidemiology / Q000208:ethnology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020734:Parkinsonian Disorders / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D024801:Tauopathies / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*