Cellular and molecular mechanisms of neurotoxicity and cognitive deficits due to hyperphosphorylated tau

PROJECT SUMMARY/ABSTRACT Hyperphosphorylation of tau, a microtubule associated protein, is a hallmark of neurofibrillary tangles (NFT) that correlate with cognitive impairment in Alzheimer's disease (AD) patients. While tau is natively unfolded, it has 80+ phosphorylation sites, and the alteration from tau to phosphorylated tau (ptau) to hyperphosphorylated tau (hyper-ptau) changes its biophysical properties and transforms from soluble oligomers to sarkosyl (detergent)-insoluble NFTs. Growing evidence suggests that hyper-ptau oligomers are already neurotoxic, but there have been few experimental systems to directly test this idea and develop therapeutic strategies. In preliminary work, the Kuan lab has generated recombinant hyper-ptau oligomers using the Protein Interaction Module-Assisted Function X (PIMAX) system and tested their effects in vitro and in vivo using the mouse model system. The lab has found that intrahippocampal injection of hyper-ptau induces neuroinflammation, neuronal cell death, and cognitive deficits similar to AD patients. These findings establish that hyper-ptau oligomers directly promote neurotoxicity and cognitive dysfunction. The objective of my proposal is to further investigate the molecular and physiological effects of hyper-ptau oligomers on brain function using a combination of hypothesis-free transcriptomic profiling and neurophysiology approaches. I hypothesize that hyper-ptau oligomers induce neuroinflammation and alters synaptic plasticity of hippocampal neurons, leading to neurodegeneration and altered cognition. Aim 1 will characterize the cellular and molecular effects of hyper p-tau oligomers in vivo using unbiased single-cell transcriptomic profiling. Aim 2 will investigate the impact of hyper p-tau oligomers on hippocampal function by measurement of long-term potentiation in brain slices. Completion of these aims will help to elucidate the mechanisms underlying the neurotoxicity and cognitive effects of hyperphosphorylated tau, informing future treatment strategies of AD and tauopathies. In addition, it will provide me with valuable mentored-training in areas I lack expertise to continue my development as a physician-scientist and better prepare me to become an independent investigator.