Cellular and circuit mechanisms of Alzheimer's disease

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.

Impact through innovation/novelty:
There are many potential beneficiaries of this research program. The principal beneficiaries will be national and international academic and industry researchers working on the mechanisms, diagnosis and treatment of Alzheimer's disease. The overarching goal of the proposal is to address two major mysteries in Alzheimer's neurobiology: 1) What is the disease-specific neuronal damage? 2) What is the relationship of amyloid plaques and tau neurofibrillary tangles? We will provide new data related to these questions and this will enable researchers in the field to apply that knowledge, generate new hypothesis and help inform diagnostic and therapeutic approaches as well as clinical trials. This would also benefit many Alzheimer patients, their families, and the health service and the wider population upon which much of the economic burden falls.

Impact for UK Dementia Research Institute:
The expertise and knowledge acquired through the proposed research project will greatly benefit the UK Dementia Research Institute whose mission is to understand the biological mechanisms underpinning dementia. A large number of researchers from the institute may take advantage of the presence of a cutting-edge in vivo two-photon imaging platform developed during the Fellowship. Importantly, all methods will be made available to all researchers in the institute and will be open to collaborations.

Drug discovery companies
Industry benefits because the proposed experiments directly inform clinical trials and help 'failure analysis' of the numerous failed amyloid based trials. In addition, the research will advance our understanding of the basic processes underlying disease mechanisms and might uncover novel treatment targets beyond amyloid and tau, a critical unmet clinical need. Finally, the companies will in the long run benefit from the technology developed during the fellowship, as many problems of interest including the specific cell types involved in the disease can be readily studied using the proposed in vivo imaging platform.

Impact for Society:
Alzheimer's disease currently afflicts 850,000 people in the UK, costing the health care system billions. By understanding why neurons become dysfunctional in the disease, we will be able to inform clinical approaches, accelerating the development of successful treatments. The proposed research will also help to understand the recent failures of numerous amyloid based clinical trials which is of critical importance for public health, for therapeutic development, and for the many patients with Alzheimer's disease who continue to suffer without effective therapies. In case the proposed research leads to a novel treatment, the resulting reductions in morbidity and mortality (dementia is the leading cause of death in the UK) will benefit health and the economy.