Role of KDM6B in Alzheimer’s disease related dementia

Project summary Alzheimer's disease (AD) is a leading cause of dementia characterized by memory and cognitive loss interfering with daily life. Clinical studies showed that the aberrant neuronal activity switch from hyperexcitability at the early stage of disease to hypo-excitability at the late stage is a key feature shared in AD patients. In line with this, levels of the principal excitatory neurotransmitter glutamate and vesicular glutamate transporters (vGluT1/2), the primary mediators of glutamate uptake into synaptic vesicles, were decreased at the late stage of AD patients, which contributed to AD dementia. However, the underlying pathology that leads to glutamate misregulation, aberrant neuronal activity and synaptic dysfunction in AD dementia remains largely unknown. Our recent work identified histone H3K27 demethylase KDM6B as a specific epigenetic regulator of synaptic plasticity and cognitive functions. Conditional knockout of KDM6B in the excitatory neurons reduced presynaptic vesicle numbers, spine density and glutamate release/synaptic activity in mice. Moreover, KDM6B KO mice showed behavioral learning and memory deficits. Importantly, KDM6B expression was reduced in aged brain, while trimethyl lysine 27 on histone H3 (H3K27me3) was increased in brain from late-onset AD patients, which were highly correlated with their cognitive deficits. Tau was required for KDM6B recruitment and regulation in synaptic plasticity and cognitive functions. Tau knockdown interfered with synaptic gene expression. As we know, pathological Tau often occurred in AD and perturbed its physiological functions. These findings led us to hypothesize that epigenetic alteration caused by KDM6B-Tau dysregulation contributes to aberrant neuronal activity switch, cognitive impairment and AD pathogenesis. The goals of this R01 project are to 1) decipher the role of pathological Tau in KDM6B-regulated synaptic activity and 2) determine effects of KDM6B dysregulation on AD pathogenesis in AD mouse models. To ensure the success of the proposed project, we have assembled a strong research team with expertise in AD-related neurodegeneration, epigenetic regulation, and synaptic activity. If successful, this project will reveal the importance of Tau-KDM6B-dependent epigenetic priming in AD pathogenesis and define a new epigenetic mechanism underlying synaptic hyper- and hypo-excitability switch and cognitive impairment in AD, which may provide an innovative therapeutic target and a knowledge foundation on development of a rational strategy to improve cognitive functions in AD patients.