Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

Abstract

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Peripheral Pathways to Neurovascular Unit Dysfunction, Cognitive Impairment, and Alzheimer’s Disease

“…For example, RNAseq studies from the Betsholtz lab in mice 2 ( He et al, 2018 ; Vanlandewijck et al, 2018 ) and from the Human Protein Atlas in humans show that MAPT gene is expressed in lung endothelial cells. We recently confirmed that tau is indeed expressed in lung capillary endothelial cells, is released in response to P. aeruginosa infection, and is able to seed neuronal tau ( Choi et al, 2021 ).…”

“…Strikingly, several studies have shown that toxic tau is transmissible ( Clavaguera et al, 2009 , 2013 ; Nonaka et al, 2010 ), leading to the idea that progression of the diverse but characteristic tau pathologies occurs through prion-like seed-dependent aggregation ( Hasegawa, 2016 ; Goedert and Spillantini, 2017 ). Importantly, transmissible tau can be generated not only in the brain but also by peripheral organs in response to an infection, including lung endothelial cells ( Balczon et al, 2013 , 2017 , 2019 ; Choi et al, 2021 ), and has been shown to reduce dendritic spine density ( Scott et al, 2020 ), impair learning and memory ( Balczon et al, 2019 ), and cause neuronal tauopathy ( Choi et al, 2021 ). The role of peripheral infections or inflammation leading to brain tau tangles is an understudied and vital area of research.…”

“…Are peripheral amyloids generated in response to an infection or organ dysfunction involved in the seeding of brain amyloid or are they the same amyloids accumulating in the brain? Is the tau generated by lung endothelial cells in response to P. aeruginosa that seeded neuronal tau ( Choi et al, 2021 ) a possible contributor to sporadic AD?…”

Neurovascular Dysfunction in Diverse Communities With Health Disparities—Contributions to Dementia and Alzheimer’s Disease

“…However, when exposed to virulent clinical bacterial strains, including bacteria such as Pseudomonas aeruginosa , Klebsiella pneumoniae , and Staphylococcus aureus , the amyloids produced by lung endothelium become cytotoxic. In addition to Aβ, lung endothelium also produces several tau isoforms that are also released upon bacterial infection ( Balczon et al, 2017 ; Choi et al, 2021 ).…”

“…Intriguingly, virulent bacteria-elicited lung endothelial Aβ and tau gain tropism toward the brain (i.e., neurotropic), are neurotoxic to brain cells, and may cause Aβ and tau aggregation ( Choi et al, 2021 ). Thus, a bacterial lung infection that elicits the release of endothelial Aβ and tau may induce incident dementia indirectly by triggering the senile plaques and/or NFT pathways ( Lin et al, 2018 ; Balczon et al, 2019 , 2021 ; Scott et al, 2020 ).…”