Deficient KIBRA Signaling at Synapses in Alzheimer's Disease
Alzheimer’s disease (AD) afflicts many elderly people in our society; however, there are few treatment options available and no known cure for this devastating disease. The structures by which neurons communicate with each other in the brain, called synapses, are especially vulnerable to toxicity in AD. My research will advance our understanding of how the loss of a kidney and brain-expressed (KIBRA) protein at synapses contributes to cognitive decline in AD.
Impaired synaptic function in the brain in Alzheimer’s disease (AD) underlies memory loss; however the factors involved in synapse deterioration are not well understood. Tau accumulates in the brain in AD, and growing evidence suggests that it plays a key role in disrupting synaptic signaling. We found that acetylation of tau is linked to dementia in AD and to the loss of KIBRA, a memory-associated protein, at synapses. The goal of my research is to delineate how insufficient KIBRA signaling promotes synaptic dysfunction and cognitive decline in AD. My first aim is to determine the KIBRA-dependent signaling pathway at synapses that is blocked by tau. To address this, the functional domain of the KIBRA protein that is sufficient to restore tau-mediated synaptic deficits will be identified. The effect of tau on synaptic components downstream of KIBRA will also be investigated. My second aim is to establish whether increasing KIBRA signaling can reverse synaptic dysfunction and memory loss in transgenic mice that express pathogenic tau.
This study is based on a novel hypothesis that acetylated tau triggers cognitive decline in AD by disrupting postsynaptic KIBRA signaling. Enhancing KIBRA signaling at synapses is an innovative approach to restore synaptic and memory deficits caused by tau, and this work could lead to the development of new strategies for treating AD patients. Our findings will also advance progress in AD research by highlighting the loss of KIBRA signaling as a critical factor underlying cognitive decline.
About the Researcher
I received my bachelor’s degree in biology and neuroscience at Wesleyan University. In 2004, I began my graduate training in the Helen Wills Neuroscience Institute at the University of California, Berkeley. Under the mentorship of Lu Chen, PhD, I studied the role of AMPA-type glutamate receptors in synapse development. For my postdoctoral work, I wanted to apply my knowledge of synapse biology to research on neurodegenerative disease. In 2011, I joined the laboratory of Li Gan, PhD, at the Gladstone Institute of Neurological Disease, for my postdoctoral training. We found that an increase in the acetylation of two lysine residues on tau, K274 and K281, is associated with severe dementia in AD. Using transgenic mice expressing tau mutated to mimic K274 and K281 acetylation, we showed that acetylated tau inhibits hippocampal synaptic plasticity and causes AD-related memory impairments. At synapses, acetylated tau blocks the actin cytoskeleton remodeling and glutamate receptor recruitment required for long-term synaptic strengthening. We found that this plasticity deficit involves a reduction in KIBRA levels at synapses, and we are continuing to investigate how the loss of KIBRA contributes to memory loss in AD.
There are millions of people in our country currently suffering from the debilitating memory loss caused by Alzheimer’s disease (AD). The number of people diagnosed with AD is steadily rising and now, more than ever, AD represents an urgent public health concern. Research to identify the mechanisms that cause memory loss in AD is crucial if we are to find new molecular targets for drug intervention. With our research, we hope to provide a foundation from which to develop novel therapeutic strategies for AD. I offer my sincere thanks and gratitude to those who have donated to BrightFocus Foundation and made this research possible.
First published on: August 1, 2016
Last modified on: April 1, 2018