Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy.

Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (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 ε4 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. 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 Aβ plaque and CAA pathology, gliosis, and vascular integrity. Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA. In a mouse model of CAA, the reduction of  APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

Xiong M ，Wang C ，Gratuze M ，Saadi F ，Bao X ，Bosch ME ，Lee C ，Jiang H ，Serrano JR ，Gonzales ER ，Kipnis M ，Holtzman DM ... -  《Molecular Neurodegeneration》

Murine versus human apolipoprotein E4: differential facilitation of and co-localization in cerebral amyloid angiopathy and amyloid plaques in APP transgenic mouse models.

Liao F ，Zhang TJ ，Jiang H ，Lefton KB ，Robinson GO ，Vassar R ，Sullivan PM ，Holtzman DM ... -  《Acta Neuropathologica Communications》

Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model.

Fryer JD ，Simmons K ，Parsadanian M ，Bales KR ，Paul SM ，Sullivan PM ，Holtzman DM ... -  《-》

Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice.

Xu F ，Vitek MP ，Colton CA ，Previti ML ，Gharkholonarehe N ，Davis J ，Van Nostrand WE ... -  《-》

Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis.

One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.

Mahan TE ，Wang C ，Bao X ，Choudhury A ，Ulrich JD ，Holtzman DM ... -  《Molecular Neurodegeneration》