Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington’s Disease Prefrontal Cortex

Article type: Research Article

Authors: Petrozziello, Tiziana^a | Huntress, Sommer S.^a | Castillo-Torres, Ayleen L.^a | Quinn, James P.^b | Connors, Theresa R.^b | Auger, Corinne A.^b | Mills, Alexandra N.^a | Kim, Spencer E.^a | Liu, Sophia^b | Mahmood, Farah^b | Boudi, Adel^b | Wu, Muzhou^c | Sapp, Ellen^b | Kivisäkk, Pia^b | Sunderesh, Shekar R.^b | Pouladi, Mahmoud A.^d | Arnold, Steven E.^b | Hyman, Bradley T.^b | Rosas, H. Diana^b | DiFiglia, Marian^b | Mouro Pinto, Ricardo^{b; c; e} | Kegel-Gleason, Kimberly^b | Sadri-Vakili, Ghazaleh^{a; *}

Affiliations: [a] Sean M. Healey & AMG Center for ALS at Mass General, MassGeneral Brigham, Boston, MA, USA | [b] Department of Neurology, MassGeneral Brigham, Boston, MA, USA | [c] Center for Genomic Medicine, MassGeneral Brigham, Boston, MA, USA | [d] Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, Canada | [e] Department of Neurology, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Ghazaleh Sadri-Vakili, Ph.D., MassGeneral Institute for Neurodegenerative Disease, MassGeneral Brigham, Bldg 114 16th Street, R2200, Charlestown, MA 02129, USA. Tel.: +1 617 724 1487; Fax: +1 617 724 1480; E-mail: [email protected].

Abstract: Background:To date, it is still controversial whether tau phosphorylation plays a role in Huntington’s disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models. Objective:The goal of this study was to determine whether total tau and pTau levels are altered in HD. Methods:Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay. Results:Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls. Conclusions:Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.

Keywords: Huntington’s disease, total tau, phosphorylated tau, fractionations, postmortem brain, ESC-derived neurons, neuronal stem cells, mouse models, plasma

DOI: 10.3233/JHD-230588

Journal: Journal of Huntington's Disease, vol. 12, no. 3, pp. 267-281, 2023