Argyrophilic Grain Disease Is a Sporadic 4-Repeat Tauopathy

Togo, Takashi; Sahara, Naruhiko; Yen, Shu Hui; Cookson, Natalie; Ishizawa, Takashi; Hutton, Mike; Silva, Rohan de; Lees, Andrew J.; Dickson, Dennis W.

doi:10.1093/jnen/61.6.547

Cited by 238 publications

(187 citation statements)

References 47 publications

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“…The ALZ17 line expresses a single isoform of wild-type four-repeat human tau (19). With the exception of PiD, where the tau inclusions consist predominantly of three-repeat tau (7), the inclusions of the other tauopathies are made of four-repeat tau (AGD, PSP, and CBD) (8)(9)(10)(11) or of a mixture of three-repeat and four-repeat tau (AD and TD) (4,5). From the work on other neurodegenerative diseases, especially prionoses, it is known that the amount of misfolded protein formed is proportional to the sequence similarity between the seed and the soluble protein recruited by the seed (30).…”

Section: Discussionmentioning

confidence: 99%

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Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Clavaguera

Akatsu

Fraser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

657

675

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Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer's disease, tangle-only dementia, Pick disease, argyrophilic grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer's disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.

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Section: Discussionmentioning

confidence: 99%

“…Thus, in AD and TD, both three-and four-repeat tau make up the neurofibrillary lesions (4-6), whereas in PiD three-repeat tau predominates in the neuronal inclusions (7). The assembly of four-repeat tau into filaments is characteristic of PSP, CBD, and AGD (8)(9)(10)(11).…”

mentioning

confidence: 99%

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Clavaguera

Akatsu

Fraser

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

657

675

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“…Similar lesions, identified as either small neuropil threads or as argyrophilic grains, are encountered together in AD and in fronto-temporal dementia, whereas argyrophilic grain disease was recently classified as a sporadic tau-4R disease (43,44). The grains were mainly dendritic in tau-P301L mice but were also evident in ascending axons in the cerebellum, despite very low expression of the transgene in the cerebellum.…”

Section: Tauopathy and Conformational Epitopes Characterize Tau-p301lmentioning

confidence: 90%

Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice

Terwel

Lasrado

Snauwaert

et al. 2005

Journal of Biological Chemistry

235

366

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Protein tau-3R/4R isoform ratio and phosphorylation regulates binding to microtubules and, when disturbed by aging or mutations, results in diverse tauopathies and in neurodegeneration. The underlying mechanisms were studied here in three transgenic mouse strains with identical genetic background, all expressing the tau-4R/2N isoform driven specifically in neurons by the thy1 gene promoter. Two strains, expressing human tau-4R/2N or mutant tau-4R/2N-P301L at similar, moderate levels, developed very different phenotypes. Tau-4R/2N mice became motor-impaired already around age 6-8 weeks, accompanied by axonopathy (dilatations, spheroids), but no tau aggregates, and surviving normally. In contrast, tau-P301L mice developed neurofibrillary tangles from age 6 months, without axonal dilatations and, despite only minor motor problems, all succumbing before the age of 13 months. The third strain, obtained by tau knock-out/knock-in (tau-KOKI), expressed normal levels of wild-type human tau-4R/2N replacing all mouse tau isoforms. Tau-KOKI mice survived normally with minor motor problems late in life and without any obvious pathology. Biochemically, a fraction of neuronal tau in aging tau-P301L mice was hyperphosphorylated concomitant with conformational changes and aggregation, but overall, tau-4R/2N was actually more phosphorylated than tau-P301L. Significantly, tau with changed conformation and with hyperphosphorylation colocalized in the same neurons in aging tau-P301L mice. Taken together, we conclude that excessive binding of tau-4R/2N as opposed to reduced binding of tau-P301L to microtubules is responsible for the development of axonopathy and tauopathy, respectively, in tau-4R/2N and tau-P301L mice and that the conformational change of tau-P301L is a major determinant in triggering the tauopathy.

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“…63,64 Filamentous tau aggregates in PSP and CBD consist of four-repeat isoforms. 65 Why tau, a highly soluble protein, aggregates into PHFs is still a matter of debate. In AD brains, tau is redistributed from the axonal to the somatodendritic compartment and is hyperphosphorylated at 25 different sites at least, which are known to interfere with the affinity of tau-microtubule binding (FIG.…”

Section: Pathophysiologymentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Argyrophilic Grain Disease Is a Sporadic 4-Repeat Tauopathy

Cited by 238 publications

References 47 publications

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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