LRP4+ Astrocytes: A Unique Subpopulation Crucial for Blood Vessel Maintenance and Function in the Somatosensory Cortex of Normal and 5xFAD Mice.

Astrocytes exhibit significant heterogeneity in morphology, molecular profiles, and function. While these cells perform diverse roles, their functional specialization across distinct subgroups remains poorly characterized. Lipoprotein receptor-related protein 4 (LRP4), a transmembrane receptor critical for agrin signaling for neuromuscular junction (NMJ) formation and maintenance, is selectively expressed in a subset of cortical and hippocampal astrocytes. However, the properties and functions of Lrp4+ astrocytes in the brain remain largely unknown. In this study, we investigated the distribution, morphology, molecular features, and functions of Lrp4+ astrocytes in the cortex. We found that Lrp4+ astrocytes exhibit a unique spatial distribution, predominantly localizing along the pia. Unlike GFAP+ astrocytes, they are GFAP-negative and form specialized interactions with blood vessels (BVs), including direct soma-artery contacts, suggesting they represent a distinct astrocyte subtype. Depletion of Lrp4+ astrocytes led to reduced levels of laminin-α5, a key extracellular matrix (ECM) protein in the BV basement membrane, accompanied by decreased BV diameter, branching, and density, and impaired cerebral blood flow. Additionally, Lrp4+ astrocyte loss resulted in an increase in GFAP+ astrocytes and IBA1+ microglia. In the 5xFAD mouse model of Alzheimer's disease (AD), Lrp4+ astrocytes were diminished along the pia and did not associate with amyloid-β (Aβ) plaques, unlike GFAP+ astrocytes. Strikingly, their depletion exacerbated both vascular and Aβ pathology. Supporting these findings, human AD brain samples revealed an inverse correlation between astrocytic Lrp4 and GFAP expression, with no association between Lrp4+ astrocytes and Aβ plaques. Together, our results demonstrate that Lrp4+ astrocytes constitute a specialized subtype distinct from GFAP+ astrocytes, playing a crucial role in maintaining BV basement membrane integrity, vascular structure, and cerebral perfusion. Furthermore, they modulate Aβ pathology, highlighting their potential importance in AD development.