| First Author | Xiong M | Year | 2023 |
| Journal | Mol Neurodegener | Volume | 18 |
| Issue | 1 | Pages | 17 |
| PubMed ID | 36922879 | Mgi Jnum | J:339797 |
| Mgi Id | MGI:7445861 | Doi | 10.1186/s13024-023-00610-x |
| Citation | Xiong M, et al. (2023) Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy. Mol Neurodegener 18(1):17 |
| abstractText | BACKGROUND: Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-beta (Abeta) accumulation in the brain, although Abeta deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the epsilon4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage. METHODS: We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Abeta plaque and CAA pathology, gliosis, and vascular integrity. RESULTS: Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Abeta from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Abeta-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. CONCLUSION: In a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Abeta deposition in the vasculature, is sufficient to reduce Abeta-mediated gliosis and cerebrovascular dysfunction. |
