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
Affiliations
Ana Claudia Amaral
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Beatriz G. Perez-Nievas
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Michael Siao Tick Chong
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Alicia Gonzalez-Martinez
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Herminia Argente-Escrig
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Sara Rubio-Guerra
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Caitlin Commins
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Serra Muftu
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Bahareh Eftekharzadeh
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Eloise Hudry
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Zhanyun Fan
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Prianca Ramanan
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Shuko Takeda
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Matthew P. Frosch
Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA; C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA
Susanne Wegmann
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA
Teresa Gomez-Isla
Neurology Department, Massachusetts General Hospital, Boston, MA, USA; Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA; Corresponding author
Summary: 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.
