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While these cells perform diverse roles, their functional specialization across distinct subgroups remains poorly characterized. Lipoprotein receptor\u2010related 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\u2010negative and form specialized interactions with blood vessels (BVs), including direct soma\u2010artery contacts, suggesting they represent a distinct astrocyte subtype. Depletion of Lrp4+ astrocytes led to reduced levels of laminin\u2010\u03b15, 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\u2010\u03b2 (A\u03b2) plaques, unlike GFAP+ astrocytes. Strikingly, their depletion exacerbated both vascular and A\u03b2 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 A\u03b2 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 A\u03b2 pathology, highlighting their potential importance in AD development.<\/jats:p>","DOI":"10.1002\/glia.70114","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T11:28:41Z","timestamp":1765884521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>LRP4+<\/scp>\n                    Astrocytes: A Unique Subpopulation Crucial for Blood Vessel Maintenance and Function in the Somatosensory Cortex of Normal and\n                    <scp>5xFAD<\/scp>\n                    Mice"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8466-6672","authenticated-orcid":false,"given":"Emily","family":"Arzola","sequence":"first","affiliation":[{"name":"Department of Neurosciences, School of Medicine Case Western Reserve University  Cleveland Ohio USA"},{"name":"Louis Stokes Cleveland Veterans Affairs Medical Center  Cleveland 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