Li Gan, United States of America
Weill Cornell Medicine Helen and Robert Appel Alzheimer’s Disease Research InstituteAuthor Of 1 Presentation
KIBRA RESTORES TAU-MEDIATED SYNAPSE DYSFUNCTION AND MEMORY LOSS
Abstract
Aims
Aggregation of pathological tau in the brain coincides with synapse loss and cognitive decline in Alzheimer’s disease. Studies on tauopathy mouse models have shown that pathogenic tau triggers synaptic dysfunction underlying memory deficits, yet it is unclear how the mechanisms that regulate synaptic strength are affected by tau. We previously showed that acetylated tau in Alzheimer’s disease drives the loss of KIBRA, a memory-related protein, from postsynaptic sites which causes impaired long-term potentiation (LTP). Our objectives are to establish whether and how enhancing KIBRA levels can rescue Alzheimer’s disease-related cognitive deficits and pathophysiology in mice with pathogenic tau.
Methods
We generated truncated KIBRA constructs to investigate which KIBRA functional domain is critical for restoring LTP in neurons with pathogenic tau. We next made lentivirus to express the KIBRA C-terminal domain in the hippocampus of transgenic mice with pathogenic human tau to examine its effect on tauopathy-related synaptic plasticity and behavioral impairments.
Results
We found that the C-terminal domain of KIBRA was sufficient to restore LTP and hippocampal-dependent memory in mice with pathogenic tau. The KIBRA C-terminal domain interacts with protein kinase Mζ (PKMζ), a postsynaptic protein that regulates AMPA-type glutamate receptors during synaptic plasticity. PKMζ is required for the KIBRA C-terminal domain rescue of LTP in neurons with pathogenic tau.
Conclusions
Our findings suggest that enhancing levels of KIBRA at synapses can restore synaptic plasticity and memory impairments associated with tauopathy. The mechanism for this effect involves the interaction between KIBRA and PKMζ which modulates the activity-dependent trafficking of AMPA-type glutamate receptors.