NeuronMay 22, 2025

Removing a specific protein in support cells may protect waste clearance and reduce harmful buildup of Alzheimer's proteins

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 5, 2026

Abstract

Chronic activation of the PERK pathway in astrocytes may disrupt glymphatic function and is associated with Alzheimer's disease pathology.

Dysfunction of the glymphatic system is linked to the buildup of β-amyloid and tau proteins in Alzheimer's disease.
Activation of the PERK-α subunit pathway in astrocytes was observed in human Alzheimer's brains and two mouse models.
Chronic PERK activation leads to decreased protein synthesis in astrocytes and mislocalization of aquaporin-4, impairing glymphatic flow.
Restoration of aquaporin-4 localization through astrocyte-specific PERK deletion or pharmacological inhibition enhances glymphatic clearance.
Targeting the astrocytic PERK-CK2-AQP4 pathway could provide a potential therapeutic approach for Alzheimer's disease.

Simplified

Dysfunction of the glymphatic system, a brain-wide waste clearance network, is strongly linked to Alzheimer's disease (AD) and the accumulation of β-amyloid (Aβ) and tau proteins. Here, we identify an astrocytic signaling pathway that can be targeted to preserve glymphatic function and mitigate neurotoxic protein buildup. Analysis of astrocytes from both human AD brains and two transgenic mouse models (5XFAD and PS19) reveals robust activation of the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-α subunit of eukaryotic initiation factor 2 (eIF2α) branch of the unfolded protein response. Chronic PERK activation suppresses astrocytic protein synthesis and, through casein kinase 2 (CK2)-dependent mechanisms, disrupts the perivascular localization of aquaporin-4 (AQP4), a water channel essential for glymphatic flow. Importantly, astrocyte-specific PERK deletion or pharmacological inhibition restores AQP4 localization, enhances glymphatic clearance, reduces Aβ and tau pathology, and improves cognitive performance in mice. These findings highlight the critical role of the astrocytic PERK-CK2-AQP4 axis in glymphatic dysfunction and AD pathogenesis, positioning this pathway as a promising therapeutic target.

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Competing interests

Declaration of interests Z.X. provided consulting services within the past 36 months to Baxter; NanoMosaic; Shanghai Fourth, Ninth, and Tenth Hospitals; the Shanghai Mental Health Center affiliated with Shanghai Jiao Tong University School of Medicine; and the journal Anesthesiology and Perioperative Science, but he is not currently engaged in any of these roles.

PubMed

Removing a specific protein in support cells may protect waste clearance and reduce harmful buildup of Alzheimer's proteins

Abstract

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Competing interests

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Abstract

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