Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation

Aleksandra M. Wojtas; Yari Carlomagno; Jonathon P. Sens; Silvia S. Kang; Tanner D. Jensen; Aishe Kurti; Kelsey E. Baker; Taylor J. Berry; Virginia R. Phillips; Monica Casey Castanedes; Ayesha Awan; Michael DeTure; Cristhoper H.Fernandez De Castro; Ariston L. Librero; Mei Yue; Lillian Daughrity; Karen R. Jansen-West; Casey N. Cook; Dennis W. Dickson; Leonard Petrucelli; John D. Fryer

doi:10.1186/s40478-020-01079-1

Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation

Aleksandra M. Wojtas, Yari Carlomagno, Jonathon P. Sens, Silvia S. Kang, Tanner D. Jensen, Aishe Kurti, Kelsey E. Baker, Taylor J. Berry, Virginia R. Phillips, Monica Casey Castanedes, Ayesha Awan, Michael DeTure, Cristhoper H.Fernandez De Castro, Ariston L. Librero, Mei Yue, Lillian Daughrity, Karen R. Jansen-West, Casey N. Cook, Dennis W. Dickson, Leonard PetrucelliJohn D. Fryer

Neuroscience

Research output: Contribution to journal › Article › peer-review

Abstract

The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer’s disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.

Original language	English (US)
Article number	210
Journal	Acta Neuropathologica Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1186/s40478-020-01079-1
State	Published - Dec 2020

Keywords

Alzheimer’s disease
Clusterin
Tau
Tauopathy

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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Wojtas, A. M., Carlomagno, Y., Sens, J. P., Kang, S. S., Jensen, T. D., Kurti, A., Baker, K. E., Berry, T. J., Phillips, V. R., Castanedes, M. C., Awan, A., DeTure, M., De Castro, C. H. F., Librero, A. L., Yue, M., Daughrity, L., Jansen-West, K. R., Cook, C. N., Dickson, D. W., ... Fryer, J. D. (2020). Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. Acta Neuropathologica Communications, 8(1), [210]. https://doi.org/10.1186/s40478-020-01079-1

Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. / Wojtas, Aleksandra M.; Carlomagno, Yari; Sens, Jonathon P.; Kang, Silvia S.; Jensen, Tanner D.; Kurti, Aishe; Baker, Kelsey E.; Berry, Taylor J.; Phillips, Virginia R.; Castanedes, Monica Casey; Awan, Ayesha; DeTure, Michael; De Castro, Cristhoper H.Fernandez; Librero, Ariston L.; Yue, Mei; Daughrity, Lillian; Jansen-West, Karen R.; Cook, Casey N.; Dickson, Dennis W.; Petrucelli, Leonard; Fryer, John D.

In: Acta Neuropathologica Communications, Vol. 8, No. 1, 210, 12.2020.

Research output: Contribution to journal › Article › peer-review

Wojtas, AM, Carlomagno, Y, Sens, JP, Kang, SS, Jensen, TD, Kurti, A, Baker, KE, Berry, TJ, Phillips, VR, Castanedes, MC, Awan, A, DeTure, M, De Castro, CHF, Librero, AL, Yue, M, Daughrity, L, Jansen-West, KR, Cook, CN , Dickson, DW , Petrucelli, L & Fryer, JD 2020, 'Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation', Acta Neuropathologica Communications, vol. 8, no. 1, 210. https://doi.org/10.1186/s40478-020-01079-1

Wojtas, Aleksandra M. ; Carlomagno, Yari ; Sens, Jonathon P. ; Kang, Silvia S. ; Jensen, Tanner D. ; Kurti, Aishe ; Baker, Kelsey E. ; Berry, Taylor J. ; Phillips, Virginia R. ; Castanedes, Monica Casey ; Awan, Ayesha ; DeTure, Michael ; De Castro, Cristhoper H.Fernandez ; Librero, Ariston L. ; Yue, Mei ; Daughrity, Lillian ; Jansen-West, Karen R. ; Cook, Casey N. ; Dickson, Dennis W. ; Petrucelli, Leonard ; Fryer, John D. / Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. In: Acta Neuropathologica Communications. 2020 ; Vol. 8, No. 1.

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title = "Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation",

abstract = "The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer{\textquoteright}s disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.",

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note = "Funding Information: J.D.F. was supported by the Mayo Foundation, the Mayo Clinic Center for Individualized Medicine, a Mayo Clinic Gerstner Family Career Development Award, the Ed and Ethel Moore Alzheimer{\textquoteright}s Disease Research Program of Florida Department of Health (6AZ06), the Gilmer Family Foundation, Alzheimer{\textquoteright}s Association NIRP-12-25928, The Rotary Coins for Alzheimer{\textquoteright}s Research Trust Fund, CureAlz Foundation, Ben-Dov Family Foundation, and NIH Grants NS084974, AG062556, AG062110, NS094137, AG057997, AG062077, NS110435, AG047327, and AG049992. ",

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AU - Wojtas, Aleksandra M.

AU - Carlomagno, Yari

AU - Sens, Jonathon P.

AU - Kang, Silvia S.

AU - Jensen, Tanner D.

AU - Kurti, Aishe

AU - Baker, Kelsey E.

AU - Berry, Taylor J.

AU - Phillips, Virginia R.

AU - Castanedes, Monica Casey

AU - Awan, Ayesha

AU - DeTure, Michael

AU - De Castro, Cristhoper H.Fernandez

AU - Librero, Ariston L.

AU - Yue, Mei

AU - Daughrity, Lillian

AU - Jansen-West, Karen R.

AU - Cook, Casey N.

AU - Dickson, Dennis W.

AU - Petrucelli, Leonard

AU - Fryer, John D.

N1 - Funding Information: J.D.F. was supported by the Mayo Foundation, the Mayo Clinic Center for Individualized Medicine, a Mayo Clinic Gerstner Family Career Development Award, the Ed and Ethel Moore Alzheimer’s Disease Research Program of Florida Department of Health (6AZ06), the Gilmer Family Foundation, Alzheimer’s Association NIRP-12-25928, The Rotary Coins for Alzheimer’s Research Trust Fund, CureAlz Foundation, Ben-Dov Family Foundation, and NIH Grants NS084974, AG062556, AG062110, NS094137, AG057997, AG062077, NS110435, AG047327, and AG049992.

PY - 2020/12

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N2 - The molecular chaperone Clusterin (CLU) impacts the amyloid pathway in Alzheimer’s disease (AD) but its role in tau pathology is unknown. We observed CLU co-localization with tau aggregates in AD and primary tauopathies and CLU levels were upregulated in response to tau accumulation. To further elucidate the effect of CLU on tau pathology, we utilized a gene delivery approach in CLU knock-out (CLU KO) mice to drive expression of tau bearing the P301L mutation. We found that loss of CLU was associated with exacerbated tau pathology and anxiety-like behaviors in our mouse model of tauopathy. Additionally, we found that CLU dramatically inhibited tau fibrilization using an in vitro assay. Together, these results demonstrate that CLU plays a major role in both amyloid and tau pathologies in AD.

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