Data from: 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 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.