Communicating Lung Dysfunction to the Brain in Alzheimer's Disease

总结

Summary An estimated 5 million individuals have Alzheimer’s disease (AD) in the US, which is expected to grow to 16 million by 2050. Identifying and mitigating relevant environmental risk factors is a current strategy to slow or prevent AD progression. The growing appreciation of peripheral to brain immune cell communication during disease progression suggests that chronic peripheral inflammatory disease may influence brain changes during AD. Based upon the fact that asthma prevalence increases in the elderly, we will test the idea that a lung-brain communication axis can potentiate AD by focusing mainly on asthma pathophysiology. Our preliminary data using a mixed allergen-induced mouse model of asthma demonstrated a significant increase in brain cytokines in female mice, validating possible crosstalk of inflammation between the lung and brain. Moreover, examining a transgenic AppNL-G-F mouse model of AD, we observed basal lung dysfunction and increased APP expression in the lung epithelium due to AD. More importantly, asthma induction in these mice increased brain Aβ levels, supporting the notion that there is not only altered lung inflammation because of AD, but additional lung inflammatory stress potentiates AD pathology in the brain. We will fully characterize the temporal changes in AD-related lung dysfunction in Aim one and determine whether lung epithelial APP or Aβ is responsible for the unique AD-associated lung dysfunction. In Aim two, we will use a genetic approach to assess whether attenuating APP expression or Aβ production specifically in the lung is sufficient to attenuate an asthma phenotype but also the ability of asthma to potentiate brain changes in AD mice. Finally, in Aim three, we will determine whether pharmacologic inhibition of Aβ production in AD mice is sufficient to ameliorate an asthma phenotype and exacerbation of AD. This study will define a novel aspect of AD that involves lung dysfunction and a largely uncharacterized ability of asthma to communicate changes to the brain to exacerbate AD. We will also illustrate a bi-directional lung-brain axis in asthma and AD in which either condition can increase the risk or severity of the other. The outcomes of our work will provide a new understanding of disease comorbidities that may be relevant to needs beyond AD. Finally, we will define a novel approach to attenuate AD by targeting changes outside the brain.