Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy.
Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenic tau gene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds. RW but not hWT tau Tg mice developed an age-dependent accumulation of insoluble filamentous tau aggregates in neuronal perikarya of the cerebral cortex, hippocampus, cerebellum, and spinal cord. Significantly, CNS axons in RW mice contained reduced levels of tau when compared with hWT mice, and this was linked to retarded axonal transport and increased accumulation of an insoluble pool of RW but not hWT tau. Furthermore, RW but not hWT mice demonstrated neurodegeneration and a reduced lifespan. These data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport. This altered tau function caused by the RW mutation leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.
Zhang
Bin
B
The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA.
Higuchi
Makoto
M
Yoshiyama
Yasumasa
Y
Ishihara
Takeshi
T
Forman
Mark S
MS
Martinez
Dan
D
Joyce
Sonali
S
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000375:Aging / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008026:Ligation; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D011843:Radiculopathy / Q000503:physiopathology; D012995:Solubility; D015996:Survival Rate; D024801:Tauopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
C054369:MAPT protein, human; D008869:Microtubule-Associated Proteins; D016875:tau Proteins