Cellular and circuit mechanisms of Alzheimer's disease

点击翻译按钮获取中文摘要

Alzheimer's disease (AD) is a ticking time bomb for our society and health care system with populations aging and predictions of over 1 million people affected in the UK by 2025. The overarching aim of this proposal is to understand why neurons and brain circuits become dysfunctional in AD, resulting in devastating impairments of memory and other cognitive abilities. Genetic studies clearly implicate amyloid-beta (Abeta) as a driving force of the disease. However, in sharp contrast to mice that are a model of AD because they overexpress a causative gene (e.g., mutant amyloid precursor protein), blocking or removing Abeta failed in dozens of large-scale clinical trials, involving in total tens of thousands of patients. Perhaps the most obvious difference between the mouse models and Alzheimer patients is the presence of tau-containing neurofibrillary tangles in Alzheimer brains. Importantly, every Alzheimer patient has tau and Abeta. However, the impact of tau on neural circuit function, and the complex interactions among tau and Abeta, are largely unknown. Here I propose to perform cutting-edge cell-type, -layer and brain region-specific in vivo deep two-photon calcium imaging of large neuronal populations to test the hypothesis that tau - but not necessarily neurofibrillary tangles - impairs neuronal activities in neocortex and hippocampus, and that there is synergy between tau and Abeta, accelerating and worsening the impairments. I will 1) determine the specific type of tau causing impaired neuronal function, and identify the underlying mechanisms, 2) determine the mechanisms of the synergistic effects among tau and Abeta in the context of an intact nervous system, and 3) determine the consequences of the cell-specific impairments for long-range brain circuit activities including sleep-related slow-wave oscillations. If, as I propose, neural system impairments in Alzheimer patients start out dependent on Abeta, but become increasingly less so as tau accumulates in the brain, it follows that anti-Abeta treatments would be effective only during the initial Abeta-dependent phase, and help explain the multiple failures of clinical trials of anti-Abeta agents given later in the disease. Mapping the timing and mechanisms of these phases would have crucial importance in informing the next generation of clinical trials; furthermore the highly mechanistic experiments proposed here might reveal novel cellular and synaptic targets for effective therapeutic interventions even beyond Abeta and tau, which is a critical unmet clinical need.