Tauopathy after long‐term cervical lymphadenectomy

Abstract INTRODUCTION This study examined the effects of long‐term cervical lymphadenectomy (cLE) on cognitive and Alzheimer's disease (AD)–like tauopathy changes. METHODS Male C57BL/6 mice were used to assess cLE impacts on sleep, brain pathways, and pathologies. RNA sequencing and proteomics analyzed gene/protein changes, with results verified by western blotting and immunofluorescence. RESULTS CLE led to sleep and psychiatric disorders, linked to mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK) pathway activation. Activation of ERK may interfere with autophagy and is associated with phosphorylated tau accumulation. Peripheral blood analysis shows decreased brain waste in the peripheral blood post‐cLE, implicating impaired lymphatic drainage and brain waste build‐up. DISCUSSION These findings suggest a potential connection between cLE and AD‐like tauopathy, potentially influencing surgical decisions. Highlights Cervical lymphadenectomy (cLE) is the cornerstone of head and neck cancers, affecting millions of people each year. We provide the first evidence of mildly impaired cognitive functioning with significant anxiety–depressive disorders in mice after long‐term cLE. Long‐term cLE not only directly impairs brain wastes (amyloid beta, phosphorylated tau [p‐tau]) drainage, but also activates the Erk1/2 signaling pathway leading to attenuation of autophagy. We found for the first time that long‐term cLE accelerated the deposition of p‐tau in young mice. Patients after clinical cervical lymph node dissection showed reduced brain waste in peripheral blood consistent with mouse models. This study suggests the need for further evaluation of the neurologic effects of cervical lymph node dissection, a procedure that affects millions of people each year.