Alzheimer’s disease (AD) is characterized by two pathological hallmarks, extracellular aggregation of Aβ as well as intracellular deposition of tau protein.
Glymphatic system has been shown to play a significant role in Aβ clearance, whose impairment has been implicated in AD development. Contrary to Aβ that is normally released from neurons, it has been long assumed that tau has no immediate interaction with extracellular clearance pathway due to its primarily cytoplasmic localization. However, recently we have discovered that tau released from neurons is also cleared from brain parenchyma to cerebrospinal fluid (CSF) by glymphatic systems and subsequently transported to deep cervical lymph nodes. Strikingly, deletion of aquaporin-4, a critical component of glymphatic system, not only elevated tau in CSF but also markedly exacerbated intracellular phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau (Ishida, Yamada et al., J Exp Med 2022). This finding highlights the previously underappreciated, unique interplay between extracellular tau clearance and tau pathophysiology and motivates future therapies targeting modulation of extracellular tau. Along with our discoveries, this presentation will provide current knowledges on glymphatic/lymphatic systems as well as its roles on AD pathogenesis and discuss the possible future prospective.