Researchers from the Gladstone Institutes have revealed how the protein tau disrupts brain cells’ ability to strengthen connections with other brain cells in dementia, preventing the formation of new memories. The findings are published in Neuron.
While scientists have long known that tau affects cognitive function in dementia, the way in which it hinders cognitive function has remained uncertain.
“Understanding why and how tau is toxic to neurons is the first step in repairing or preventing the damage it causes in Alzheimer’s disease,” senior author Li Gan, PhD, a senior investigator at Gladstone, said in a statement. “We learned that tau disrupts memory in models of Alzheimer’s disease by depleting another protein, KIBRA, which is critical for memory formation. With this knowledge, we can explore ways to increase KIBRA with drugs that block the harmful effects of tau.”
Using a mouse model of Alzheimer’s disease, the researchers discovered that the acetylation of tau, which is exacerbated in Alzheimer’s disease, resulted in the tau moving from its normal location in neurons to the synapse. From this location at the synapse, the tau depleted the protein KIBRA (KIdney/BRAin protein), preventing the neurons from adapting and strengthening their connections and therefore inhibiting their ability to form memories. They found that increasing KIBRA levels reversed the acetylated tau’s harmful effects and restored the cells’ ability to form memories.
As further clinical evidence of these findings, the researchers also discovered that KIBRA is decreased in the brains of patients with Alzheimer’s disease, correlating with an increase in acetylated tau.
“Our findings suggest that KIBRA may be the missing link between tau and memory loss in Alzheimer’s disease,” Tara Tracy, PhD, a postdoctoral scholar at Gladstone, said in a statement. “The next step is to determine precisely how acetylated tau causes KIBRA levels to drop, and to explore whether our findings may help develop better treatments for Alzheimer’s disease.”
Tracy TE, Sohn PD, Minami SS, et al. Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron. 2016; Mar 31. In press. doi:10.1016/j.neuron.2016.03.005.