House dust mite‐induced asthma exacerbates Alzheimer's disease by increasing amyloid beta accumulation and neuroinflammation

Abstract

AbstractBackgroundAlzheimer's disease (AD) is an age‐related neurodegenerative disorder affecting around 35 million individuals worldwide. Besides aging, various comorbid factors increase the risk of AD, including air pollution and asthma. Epidemiological studies have reported a 2.17‐fold higher risk of dementia in asthmatic patients. However, the molecular mechanism(s) underlying this asthma‐associated AD exacerbation is unknown. This study was designed to explore house dust mite‐induced asthma effects on AD‐related brain changes using the App NL‐G‐F transgenic mouse model.MethodMale and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were exposed to either saline or house dust mite (dose: 833μg/kg in saline) every alternate day for 16 weeks. Mice were sacrificed at the end of the experiment, and broncho‐alveolar lavage fluid (BALF), blood, and brains were collected. BALF was analyzed for immune cell markers, inflammatory mediators and total protein content. Serum was analyzed for cytokine and soluble Aβ1‐40/42 levels. In addition, brain sections were immunostained for Aβ and GFAP. Finally, frozen hippocampi and cortices were used to perform Aβ ELISAs and cytokine arrays, respectively.ResultAs expected, dust mite exposure increased inflammatory cells, cytokine levels, and total protein content in the BALF from both sexes and genotypes, suggesting induction of a severe asthma‐like condition. This correlated with increased levels of serum cytokines in all dust‐mite exposed groups. Serum from the AppNL‐G‐F dust mite‐induced asthma group also had significantly increased soluble Aβ1‐42 levels in both sexes. In agreement with this peripheral change, hippocampi from asthma‐induced male and female AppNL‐G‐F mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1‐40/42 and insoluble Aβ 1‐40 levels. Dust mite exposure also increased astrogliosis in both sexes of AppNL‐G‐F mice, as indicated by GFAP immunoreactivity. Finally, dust mite exposure‐induced asthma elevated cortical levels of several cytokines in both sexes and genotypes.ConclusionDust mite exposure was responsible for a severe asthma‐like condition in the lungs that exacerbated Aβ pathology, astrogliosis, and cytokine changes in the brains of male and female App NL‐G‐F mice. Defining mechanisms of asthma effects on the brain may provide a novel therapeutic approach for both asthma and AD.