Age-dependent Induction of Congophilic Neurofibrillary Tau Inclusions in Tau Transgenic Mice

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2001 Feb 13

PMID 11159192

Citations 53

Authors

T Ishihara

B Zhang

M Higuchi

Y Yoshiyama

J Q Trojanowski

V M Lee

Affiliations

Soon will be listed here.

Abstract

Intraneuronal filamentous tau inclusions such as neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer's disease (AD) and related sporadic and familial tauopathies. NFTs identical to those found in AD brains have also been detected in the hippocampus and entorhinal cortex of cognitively normal individuals as they age. To recapitulate age-induced NFT formation in a mouse model, we examined 12- to 24-month-old transgenic (Tg) mice overexpressing the smallest human brain tau isoform. These Tg mice develop congophilic tau inclusions in several brain regions including the hippocampus, amygdala, and entorhinal cortex. NFT-like inclusions were first detected in Tg mice at 18 to 20 months of age and they were detected by histochemical dyes that bind specifically to crossed beta-pleated sheet structures (eg, Congo red, Thioflavin S). Moreover, ultrastructurally these lesions contained straight tau filaments comprised of both mouse and human tau proteins but not other cytoskeletal proteins (eg, neurofilaments, microtubules). Isolated tau filaments were also recovered from detergent-insoluble tau fractions and insoluble tau proteins accumulated in brain in an age-dependent manner. Thus, overexpression of the smallest human brain tau isoform resulted in late onset and age-dependent formation of congophilic tau inclusions with properties similar to those in the tangles of human tauopathies, thereby implicating aging in the pathogenesis of fibrous tau inclusions.

Citing Articles

Three-repeat and four-repeat tau isoforms form different oligomers.

Shahpasand-Kroner H, Portillo J, Lantz C, Seidler P, Sarafian N, Loo J Protein Sci. 2021; 31(3):613-627.

PMID: 34902187 PMC: 8862439. DOI: 10.1002/pro.4257.

A novel orally active HDAC6 inhibitor T-518 shows a therapeutic potential for Alzheimer's disease and tauopathy in mice.

Onishi T, Maeda R, Terada M, Sato S, Fujii T, Ito M Sci Rep. 2021; 11(1):15423.

PMID: 34326423 PMC: 8322070. DOI: 10.1038/s41598-021-94923-w.

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.

Wheeler J, McMillan P, Strovas T, Liachko N, Amlie-Wolf A, Kow R Sci Transl Med. 2019; 11(523).

PMID: 31852801 PMC: 7311111. DOI: 10.1126/scitranslmed.aao6545.

Developmental Pathogenicity of 4-Repeat Human Tau Is Lost with the P301L Mutation in Genetically Matched Tau-Transgenic Mice.

Gamache J, Kemper L, Steuer E, Leinonen-Wright K, Choquette J, Hlynialuk C J Neurosci. 2019; 40(1):220-236.

PMID: 31685653 PMC: 6939485. DOI: 10.1523/JNEUROSCI.1256-19.2019.

The Role of Protein Misfolding and Tau Oligomers (TauOs) in Alzheimer's Disease (AD).

Mroczko B, Groblewska M, Litman-Zawadzka A Int J Mol Sci. 2019; 20(19).

PMID: 31547024 PMC: 6802364. DOI: 10.3390/ijms20194661.

References

Galvin J, Uryu K, Lee V, Trojanowski J . Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc Natl Acad Sci U S A. 1999; 96(23):13450-5. PMC: 23968. DOI: 10.1073/pnas.96.23.13450. View

Lee V, Wang J, Trojanowski J . Purification of paired helical filament tau and normal tau from human brain tissue. Methods Enzymol. 1999; 309:81-9. DOI: 10.1016/s0076-6879(99)09008-4. View

Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee M, Trojanowski J . Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron. 1999; 24(3):751-62. DOI: 10.1016/s0896-6273(00)81127-7. View

Ginsberg S, Hemby S, Lee V, Eberwine J, Trojanowski J . Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons. Ann Neurol. 2000; 48(1):77-87. View

Gallyas F . Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung. 1971; 19(1):1-8. View

Weingarten M, Lockwood A, Hwo S, Kirschner M . A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975; 72(5):1858-62. PMC: 432646. DOI: 10.1073/pnas.72.5.1858. View

Binder L, Frankfurter A, REBHUN L . The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985; 101(4):1371-8. PMC: 2113928. DOI: 10.1083/jcb.101.4.1371. View

Goedert M, Spillantini M, Jakes R, Rutherford D, Crowther R . Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989; 3(4):519-26. DOI: 10.1016/0896-6273(89)90210-9. View

Lee V, Balin B, Otvos Jr L, Trojanowski J . A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991; 251(4994):675-8. DOI: 10.1126/science.1899488. View

10.

Andreadis A, Brown W, Kosik K . Structure and novel exons of the human tau gene. Biochemistry. 1992; 31(43):10626-33. DOI: 10.1021/bi00158a027. View

11.

Drechsel D, Hyman A, Cobb M, Kirschner M . Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell. 1992; 3(10):1141-54. PMC: 275678. DOI: 10.1091/mbc.3.10.1141. View

12.

Xu Z, Cork L, Griffin J, Cleveland D . Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell. 1993; 73(1):23-33. DOI: 10.1016/0092-8674(93)90157-l. View

13.

Cote F, Collard J, Julien J . Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell. 1993; 73(1):35-46. DOI: 10.1016/0092-8674(93)90158-m. View

14.

Bramblett G, Goedert M, Jakes R, Merrick S, Trojanowski J, Lee V . Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993; 10(6):1089-99. DOI: 10.1016/0896-6273(93)90057-x. View

15.

Lee M, Marszalek J, Cleveland D . A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron. 1994; 13(4):975-88. DOI: 10.1016/0896-6273(94)90263-1. View

16.

Tu P, Raju P, Robinson K, Gurney M, Trojanowski J, Lee V . Transgenic mice carrying a human mutant superoxide dismutase transgene develop neuronal cytoskeletal pathology resembling human amyotrophic lateral sclerosis lesions. Proc Natl Acad Sci U S A. 1996; 93(7):3155-60. PMC: 39778. DOI: 10.1073/pnas.93.7.3155. View

17.

Zhang B, Tu P, Abtahian F, Trojanowski J, Lee V . Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol. 1998; 139(5):1307-15. PMC: 2140205. DOI: 10.1083/jcb.139.5.1307. View

18.

Hong M, Zhukareva V, Wszolek Z, Reed L, Miller B, Geschwind D . Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998; 282(5395):1914-7. DOI: 10.1126/science.282.5395.1914. View

19.

DSouza I, Poorkaj P, Hong M, Nochlin D, Lee V, Bird T . Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A. 1999; 96(10):5598-603. PMC: 21906. DOI: 10.1073/pnas.96.10.5598. View

20.

Lee V, Trojanowski J . Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron. 1999; 24(3):507-10. DOI: 10.1016/s0896-6273(00)81106-x. View