An investigation of the bidirectional relationship between tau protein propagation and neural circuit activity in mouse models of Alzheimer's disease

点击翻译按钮获取中文摘要

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that is defined by the presenceof extracellular amyloid-beta plaques and intracellular tau-protein-containing neurofibrillary tangles inthe brain1. There are currently no effective treatments available and removing amyloid-beta has thus farbeen ineffective in clinical trials. As such, my project will focus on tau pathology and its mechanismsat the neural circuit level, with a view to elucidating the role of tau in pathoprogression of AD andinforming future circuit-level therapeutic approaches.Tau pathology in humans involves propagation of tau beginning in the entorhinal cortex, spreading tothe hippocampus, then the cerebral cortex2, and this propagation parallels the clinical stages of thedisease. However, the mechanism(s) linking protein accumulation and cognitive decline is unknown.Neuronal hyperexcitability precedes tau propagation and accumulation in disease models, and thereis evidence that neuronal activity enhances tau propagation and pathology in vivo3, although themechanism for this is not established. Furthermore, there is evidence for tau-dependent suppressionof activity and silencing of neurons4, with cell-type specific selective vulnerability5,6.The aim of this project will be to study neuronal dysfunction in the context of tau at the circuit level,employing complimentary large-scale electrophysiological (Neuropixels), two- and one-photoncalcium and voltage imaging, and behavioural studies to answer two key questions:How does activity in neural circuits affect tau propagation?How does tau propagation affect activity in neural circuits, and thereby cognition?In addressing these questions, I will investigate mechanisms for the interaction between tau andneural activity in multiple Alzheimer's disease mouse models, which will advance our understandingof the disease pathogenesis, and have relevance for therapeutic approaches based on modulatingexcitability, potentially in a cell-type specific manner.Bibliography:1. Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primer 7, 1-21 (2021).2. Busche, M. A. & Hyman, B. T. Synergy between amyloid-beta and tau in Alzheimer's disease. Nat.Neurosci. 23, 1183-1193 (2020).3. Wu, J. W. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat.Neurosci. 19, 1085-1092 (2016).4. Busche, M. A. et al. Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimermodels in vivo. Nat. Neurosci. 22, 57-64 (2019).5. Turkes, E. & Duff, K. E. Cell-type specific selective vulnerability to pathological tau in Alzheimer'sdisease. Alzheimers Dement. 16, e043149 (2020).6. Fu, H. et al. A tau homeostasis signature is linked with the cellular and regional vulnerability ofexcitatory neurons to tau pathology. Nat. Neurosci. 22, 47-56 (2019).