Publications

Many patients suffer from incident dementia after lung infections. Previous studies demonstrated that cytotoxic tau is released from the lungs in response to bacterial pneumonia, causing cognitive deficits and tau seeding. We aimed to determine the impact pneumonia has on blood-brain barrier (BBB) permeability, glial activation, and tau phosphorylation in the brain following infection and the involvement of tau. We found that lung infection with Pseudomonas aeruginosa (P. aeruginosa) increased BBB permeability, astrocyte activation, and phosphorylated tau (ptau) levels in the brain 24-hours (h) post-infection in C57BL/6J mice. Conversely, tau knockout (KO) mice had no BBB injury or glial activation 24 h after infection. Additionally, we found increased levels of several kinases and proinflammatory cytokines with infection in C57BL/6J and tau KO mice. Thus, tau is necessary for pneumonia-induced BBB dysfunction and astrocyte reactivity in the brain and may be an innate immune response link between infection and dementia.

Cytopathic tau variants are recovered from the lung, circulation, and brain following lower respiratory tract infection. Cytopathic tau injures the lung and brain, yet its cellular origin during infection is unknown. Here, we assessed whether lung capillary endothelium is a source of cytopathic tau that contributes to brain injury during infection. Alveolar-capillary permeability was higher in tau knockout than wild type mice following sublethal Pseudomonas aeruginosa infection, indicating endogenously expressed tau contributes to integrity of the lung’s gas exchange unit. Hippocampal long-term potentiation was inhibited following sublethal infection in wild type but not tau knockout mice, even though the blood-brain barrier was not overtly disrupted. Tau expression solely in lung capillaries of tau knockout mice was sufficient to restore alveolar-capillary barrier integrity and impair hippocampal long-term potentiation following sublethal infection. Thus, endogenous lung capillary endothelial tau preserves alveolar-capillary integrity, yet it is a source of cytopathic tau that injures the brain during pneumonia.

Critically ill patients rescued with extracorporeal membrane oxygenation (ECMO) are at risk for devastating complications, including stroke and intracerebral hemorrhage (ICH).¹ Despite an appreciation of some clinical risk factors, we cannot explain or predict neurologic complications, which occur in both venovenous (VV) and venoarterial (VA) ECMO, demonstrating a lack of mechanistic insight. The diagnosis of these complications in real time is challenging, potentially delaying timely intervention. We have previously shown that pneumonia elicits the pulmonary endothelium to produce cytotoxic variants of tau and amyloid-beta (Aβ) proteins that disseminate from the lungs and cause end-organ dysfunction, including the loss of long-term potentiation (persistent enhancement of synaptic transmission after hyperstimulation, necessary for learning and memory formation) in the hippocampus of mice.² In our pilot ECMO cohort, the presence of cytotoxic tau from oxygenator effluent correlated precisely with patients with pneumonia, was transmissible, and caused similar end-organ dysfunction; significantly higher tau levels were identified in oxygenators of patients who died, including 2 with ICH.³ In this follow-up study, we tested our hypothesis that higher circulating levels of Aβ and tau would be identified in adult ECMO patients with pneumonia and would be temporally associated with neurologic complications and death.

Lung endothelia in the arteries, capillaries, and veins are heterogeneous in structure and function. Lung capillaries in particular represent a unique vascular niche, with a thin yet highly restrictive alveolar-capillary barrier that optimizes gas exchange. Capillary endothelium surveys the blood while simultaneously interpreting cues initiated within the alveolus and communicated via immediately adjacent type I and type II epithelial cells, fibroblasts, and pericytes. This cell-cell communication is necessary to coordinate the immune response to lower respiratory tract infection. Recent discoveries identify an important role for the microtubule-associated protein tau that is expressed in lung capillary endothelia in the host-pathogen interaction. This endothelial tau stabilizes microtubules necessary for barrier integrity, yet infection drives production of cytotoxic tau variants that are released into the airways and circulation, where they contribute to end-organ dysfunction. Similarly, beta-amyloid is produced during infection. Beta-amyloid has antimicrobial activity, but during infection it can acquire cytotoxic activity that is deleterious to the host. The production and function of these cytotoxic tau and amyloid variants are the subject of this review. Lung-derived cytotoxic tau and amyloid variants are a recently discovered mechanism of end-organ dysfunction, including neurocognitive dysfunction, during and in the aftermath of infection.

Alzheimer’s disease (AD) is the most common form of dementia. It was first described more than a century ago, and scientists are acquiring new data and learning novel information about the disease every day. Although there are nuances and details continuously being unraveled, many key players were identified in the early 1900’s by Dr. Oskar Fischer and Dr. Alois Alzheimer, including amyloid-beta (Aβ), tau, vascular abnormalities, gliosis, and a possible role of infections. More recently, there has been growing interest in and appreciation for neurovascular unit dysfunction that occurs early in mild cognitive impairment (MCI) before and independent of Aβ and tau brain accumulation. In the last decade, evidence that Aβ and tau oligomers are antimicrobial peptides generated in response to infection has expanded our knowledge and challenged preconceived notions. The concept that pathogenic germs cause infections generating an innate immune response (e.g., Aβ and tau produced by peripheral organs) that is associated with incident dementia is worthwhile considering in the context of sporadic AD with an unknown root cause. Therefore, the peripheral amyloid hypothesis to cognitive impairment and AD is proposed and remains to be vetted by future research. Meanwhile, humans remain complex variable organisms with individual risk factors that define their immune status, neurovascular function, and neuronal plasticity. In this focused review, the idea that infections and organ dysfunction contribute to Alzheimer’s disease, through the generation of peripheral amyloids and/or neurovascular unit dysfunction will be explored and discussed. Ultimately, many questions remain to be answered and critical areas of future exploration are highlighted.