Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation

Ana Claudia Amaral; Beatriz G Perez-Nievas; Michael Siao Tick Chong; Alicia Gonzalez-Martinez; Herminia Argente-Escrig; Sara Rubio-Guerra; Caitlin Commins; Serra Muftu; Bahareh Eftekharzadeh; Eloise Hudry; Zhanyun Fan; Prianca Ramanan; Shuko Takeda; Matthew P Frosch; Susanne Wegmann; Teresa Gomez-Isla

doi:10.1016/j.isci.2021.102058

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation

iScience. 2021 Jan 13;24(2):102058. doi: 10.1016/j.isci.2021.102058. eCollection 2021 Feb 19.

Authors

Ana Claudia Amaral^{1

2}, Beatriz G Perez-Nievas^{1

2}, Michael Siao Tick Chong^{1

2}, Alicia Gonzalez-Martinez^{1

2}, Herminia Argente-Escrig^{1

2}, Sara Rubio-Guerra^{1

2}, Caitlin Commins^{1

2}, Serra Muftu^{1

2}, Bahareh Eftekharzadeh^{1

2}, Eloise Hudry^{1

2}, Zhanyun Fan^{1

2}, Prianca Ramanan^{1

2}, Shuko Takeda^{1

2}, Matthew P Frosch^{2

3}, Susanne Wegmann^{1

2}, Teresa Gomez-Isla^{1

2}

Affiliations

¹ Neurology Department, Massachusetts General Hospital, Boston, MA, USA.
² Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA.
³ C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.

Abstract

It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

Keywords: Biological Sciences; Cellular Neuroscience; Neuroscience.