Lung-derived proteinopathy: A new framework for peripheral contributions to neurodegeneration

ABSTRACT: Neurodegenerative diseases are characterized by the abnormal aggregation of amyloid-β, tau, and α-synuclein and have traditionally been viewed as disorders driven primarily by cell-autonomous processes within the central nervous system. Emerging evidence from in vitro, animal, and epidemiological studies suggests that neurodegeneration occurs within a systemic context in which peripheral organs, particularly the lung, serve as sources and modulators of central proteinopathy. The lung continuously encounters airborne pollutants, infectious agents, and inflammatory stimuli that perturb pulmonary proteostasis, trigger amyloid-like conformations of endogenous proteins, including surfactant protein C, and release cytotoxic, prion-like tau and amyloid-β from the pulmonary endothelium. This narrative review synthesizes evidence on pulmonary sources of misfolded proteins (bacterial and viral infections, fine particulate matter, ozone, diesel exhaust, surfactant protein mutations, and oxidative stress), molecular mechanisms driving misfolding and proteostatic collapse, candidate routes by which lung-derived aggregates reach the central nervous system (hematogenous transport with blood-brain barrier disruption, extracellular vesicle trafficking, vagal transmission, and peripheral immune cell trafficking), and proposed neurodegenerative consequences including tauopathy, amyloid-β deposition, microglial priming, synaptic loss, and cognitive decline. Emerging therapeutic strategies include immunomodulation, extracellular vesicle-targeted interventions, blood-brain barrier stabilization, and aggregation inhibitors. Current evidence distinguishes causal mechanistic data from epidemiological associations and hypothesis-generating observations. To date, no direct causal evidence in humans has demonstrated that lung-derived aggregates seed brain pathology; this framework is hypothesis-generating and intended to guide targeted experimental testing.