DOI: 10.1002/alz.080582 ISSN: 1552-5260

Alzheimer’s disease induces pathological changes in the lungs of humans and the AppNL‐G‐F mouse model

Bijayani Sahu, Suba Nookala, Angela M Floden, Nilesh Ambhore, Sathish Venkatachalem, Colin K Combs
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Alzheimer’s disease (AD) is an age‐related neurodegenerative disorder characterized by brain accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, neuron death, robust gliosis, and neuroinflammation, affecting around 35 million individuals worldwide. It is well known that brain immune changes are a component of the disease, but immune dysfunction in secondary organs has also been reported. To assess peripheral immune changes in AD, we asked whether lung dysfunction and inflammatory change are present during the disease.


Male and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were sacrificed, and broncho‐alveolar lavage fluid (BALF) and lungs were collected. BALF was used to quantify immune cell phenotype by flow cytometry, and the BALF supernatant was used to determine Aβ and cytokine concentrations and total protein content. Lungs were sectioned and stained with hematoxylin and eosin, Alcian blue and Masson’s trichrome. In addition, lung sections from wild‐type and AppNL‐G‐F mice and human AD patient and healthy controls were immunostained for APP, Aβ and claudin 4.


AD mice showed significantly increased pulmonary airway thickening and mucus and collagen production as indicated by hematoxylin and eosin, Alcian blue and Masson’s trichrome staining, respectively, compared to the wild‐type controls. Female but not male AppNL‐G‐F mice also demonstrated reduced B cell and neutrophil numbers and elevated IL‐1β in their BALF compared to controls. Although there were no differences in BALF supernatant total protein content between wild‐type and AppNL‐G‐F mice, lungs from both sexes of AppNL‐G‐F mice had decreased claudin‐4 immunoreactivity suggesting altered epithelial permeability. BALF supernatant from male and female AppNL‐G‐F mice also contained soluble Aβ1‐40 and Aβ1‐42 correlating with lung APP immunoreactivity. Human AD male and female lungs had reduced claudin‐4 immunoreactivity and increased APP and Aβ staining compared to controls verifying lung changes are also present in human disease.


These data demonstrate disease‐associated changes in the lungs of both human AD patients and the AppNL‐G‐F mouse model. Further characterization of lung dysfunction and its contribution to brain changes may define a novel lung‐to‐brain contribution to disease.

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