Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

Background Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-beta (A beta) accumulation in the brain, although A beta deposits mostly in the brain parenchyma in AD and in the cerebrovas-culature 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 epsilon 4 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 A beta plaque and CAA pathology, gliosis, and vascular integrity.Results Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar A beta from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall A beta-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 A beta deposition in the vasculature, is sufficient to reduce A beta-mediated gliosis and cerebrovascular dysfunction.

Automated summary

Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-beta (Aβ) accumulation in the brain, although Aβ 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 epsilon 4 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.