Chen K, Morizawa YM, Nuriel T, Al-Dalahmah O, Xie Z, Yang G. Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau. Neuron. 2025 Aug 6;113(15):2438-2454.e6. Epub 2025 May 21 PubMed.
Recommends
Please login to recommend the paper.
Comments
The University of Tokyo
In this study, the authors clearly demonstrate that the ER stress/UPR mediator PERK plays a critical role in the altered glymphatic function associated with changes in AQP4 localization in AD model mice. By crossing PERK fl/fl, Aldh1l1-CreERT2 mice with either 5xFAD or PS19 models, they show not only a reduction in amyloid and tau pathology but also a rescue of associated behavioral alterations, which I found particularly compelling.
The mechanistic basis by which PERK disrupts glymphatic clearance appears to be complex. As the authors note in the discussion, additional factors such as neuroinflammation and the interplay between dural lymphatic drainage and glymphatic flow may also be involved. These findings highlight the multifactorial nature of clearance deficits in neurodegeneration.
This study reinforces the increasingly appreciated view that astrocytes play active and dynamic roles in maintaining brain homeostasis. It contributes meaningfully to our evolving understanding of glial function in AD.
View all comments by Kaoru YamadaThe University of Texas Health Science Center at Houston
Columbia University
We were surprised to find that conditional knockout of PERK in astrocytes partially enhanced glymphatic function by restoring perivascular AQP4 localization. PERK activation is well-documented in Alzheimer’s disease, where it phosphorylates eIF2α and suppresses protein synthesis. While impaired protein synthesis in neurons and astrocytes has been reported in AD, the specific contribution of astrocytic protein synthesis to glymphatic function has been less explored. We were excited to find that PERK deletion in astrocytes improved glymphatic function in AD transgenic mice, suggesting that chronic activation of the PERK-eIF2α pathway may contribute to glymphatic failure in AD.
Our findings show that both genetic and pharmacological inhibition of PERK partially improved glymphatic function. This suggests that targeting the PERK signaling pathway could represent a novel therapeutic strategy to address glymphatic dysfunction, which is increasingly recognized in several neurodegenerative diseases, including AD, Parkinson’s disease, and amyotrophic lateral sclerosis.
Further investigation is planned. While we identified CK2 as a potential mediator between PERK and AQP4, the mechanisms remain unclear, particularly how CK2 regulates AQP4 trafficking to astrocyte perivascular endfeet in AD. Using a protein-protein interaction model, we have identified potential phosphorylation sites on AQP4 that CK2 may target. However, it remains to be determined which phosphorylation site is critical for AQP4 trafficking in the context of AD. In vitro cell culture systems may provide a more controlled environment to dissect the precise role of CK2 in modulating AQP4 dynamics.
View all comments by Guang YangMake a Comment
To make a comment you must login or register.