Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

Abstract

The imbalance between production and clearance of amyloid-beta (Aβ) is a key step in the onset and development of Alzheimer's disease (AD). Therefore, reducing Aβ accumulation in the brain is a promising therapeutic strategy for AD. The recently discovered glymphatic system and meningeal lymphatic vasculature have been shown to be critical for the elimination of interstitial waste products, especially Aβ, from the brain. In the present study, ligation of deep cervical lymph nodes was performed to block drainage of this system and explore the consequences on Aβ-related pathophysiology. Five-month-old APP/PS1 mice and their wild-type littermates received deep cervical lymphatic node ligation. One month later, behavioral testing and pathological analysis were conducted. Results demonstrated that ligation of dcLNs exacerbated AD-like phenotypes of APP/PS1 mice, showing more severe brain Aβ accumulation, neuroinflammation, synaptic protein loss, impaired polarization of aquaporin-4 and deficits in cognitive and exploratory behaviors. These results suggest that brain lymphatic clearance malfunction is one of the deteriorating factors in the progression of AD, and restoring its function is a potential therapeutic target against AD.

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

“…Recent studies have shown that brain interstitial fluid and macromolecules can be transported into the dcLNs through meningeal lymphatics [42][43][44]. Our previous studies have also suggested that the extracranial brain clearance pathway remains intact in 6-month-old APP/PS1 mice, but the deposition of Aβ plaques significantly increases after the mice received bilateral ligation of afferent vessels of the dcLNs [45]. More importantly, clearance of Aβ is improved by activation of microglia and astrocytes.…”

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

“…Recent studies have shown that brain interstitial uid and macromolecules can be transported into the dcLNs through meningeal lymphatics [44][45][46]. Our previous studies have also suggested that the extra cranial brain clearance pathway remains intact in 6-month-old APP/PS1 mice, but the deposition of Aβ plaques signi cantly increases after the mice received bilateral ligation of afferent vessels of the dcLNs [47]. More importantly, clearance of Aβ may be improved by activation of microglia [24,25].…”

Sleep Disturbance as Potential Risk and Progression Factor for Parkinson’s Disease

“…However, the existence of the olfactory/nasal lymphatic route where CSF passes through the cribriform plate along perineural spaces near the olfactory nerves to a lymphatic network at the nasal mucosa, and finally reaches to cervical lymph nodes [57,58] raises the possibility that changes in the integrity of nasal mucosal or cervical lymph nodes could be another source for abnormal proteinopathy. For example, a recent study showed that ligation of deep cervical lymph nodes exacerbated AD-like phenotypes of APP/PS1 mice, showing more severe brain A␤ accumulation, neuroinflammation, synaptic protein loss, impaired polarization of aquaporin-4 and deficits in cognitive and exploratory behaviors [59]. Further research into these speculative and hypothetical mechanisms is important as positive findings may provide novel clues for therapeutic interventions.…”