Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau

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 R-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 pathol..., , # Data from: Selective removal of astrocytic PERK protects against glymphatic impairment and decreases toxic aggregation of β-amyloid and tau

Dataset DOI: [10.5061/dryad.gb5mkkx43](https://doi.org/10.5061/dryad.gb5mkkx43)

## Description of the data and file structure

This dataset contains the individual source data supporting figures and analyses in the associated article (doi: 10.1016/j.neuron.2025.04.027).

### Files and variables

###### **File: SourceData_Fig_1.xlsx**

Description: Source data for Figure 1, panels C–F.

Sheet Fig. 1C: quantification of Eif2ak3 puncta number per S100β^+^ astrocyte in the cortex of 6-month-old WT and 5XFAD mice (n = 5 mice per group).

Sheet Fig. 1D: quantification of indicated proteins (fold change) in cortical astrocytes isolated from WT and 5XFAD mice (n = 5 mice per group).

Sheet Fig. 1E: quantification of p-PERK fluorescence intensity (fold change) in GFAP^+^ astrocytes from WT and 5XFAD mice (n = 5 mice per group).

Sheet Fig. 1F: quantifica...,