| First Author | Zhang H | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 28 | Pages | 5347-5361 |
| PubMed ID | 32457076 | Mgi Jnum | J:291055 |
| Mgi Id | MGI:6444567 | Doi | 10.1523/JNEUROSCI.0250-20.2020 |
| Citation | Zhang H, et al. (2020) A Role of Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4) in Astrocytic Abeta Clearance. J Neurosci 40(28):5347-5361 |
| abstractText | Amyloid-beta (Abeta) deposition occurs years before cognitive symptoms appear and is considered a cause of Alzheimer's disease (AD). The imbalance of Abeta production and clearance leads to Abeta accumulation and Abeta deposition. Increasing evidence indicates an important role of astrocytes, the most abundant cell type among glial cells in the brain, in Abeta clearance. We explored the role of low-density lipoprotein receptor-related protein 4 (LRP4), a member of the LDLR family, in AD pathology. We show that Lrp4 is specifically expressed in astrocytes and its levels in astrocytes were higher than those of Ldlr and Lrp1, both of which have been implicated in Abeta uptake. LRP4 was reduced in postmortem brain tissues of AD patients. Genetic deletion of the Lrp4 gene augmented Abeta plaques in 5xFAD male mice, an AD mouse model, and exacerbated the deficits in neurotransmission, synchrony between the hippocampus and PFC, and cognition. Mechanistically, LRP4 promotes Abeta uptake by astrocytes likely by interacting with ApoE. Together, our study demonstrates that astrocytic LRP4 plays an important role in Abeta pathology and cognitive function.SIGNIFICANCE STATEMENT This study investigates how astrocytes, a type of non-nerve cells in the brain, may contribute to Alzheimer's disease (AD) development. We demonstrate that the low-density lipoprotein receptor-related protein 4 (LRP4) is reduced in the brain of AD patients. Mimicking the reduced levels in an AD mouse model exacerbates cognitive impairment and increases amyloid aggregates that are known to damage the brain. We show that LRP4 could promote the clearance of amyloid protein by astrocytes. Our results reveal a previously unappreciated role of LRP4 in AD development. |
