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Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy
Monica Xiong1,2,3, Chao Wang4, Maud Gratuze1,5
1Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Insights
Reducing astrocytic apolipoprotein E4 (APOE4) in mice with Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) shifted amyloid-beta (Aβ) to blood vessels. This reduction improved cerebrovascular integrity despite increased CAA.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) involve amyloid-beta (Aβ) accumulation.
- Cerebral amyloid angiopathy (CAA) exacerbates AD outcomes, increasing hemorrhage and ischemia risks.
- The apolipoprotein E ε4 allele (APOE4) is a shared genetic risk factor, but its role in CAA pathogenesis is understudied.
Purpose of the Study:
- To investigate if suppressing astrocyte-derived APOE4 can ameliorate CAA and associated vascular damage.
- To understand the specific role of astrocytic APOE4 in the pathogenesis of CAA.
Main Methods:
- Generated transgenic mice modeling both AD and CAA with inducible suppression of astrocytic APOE4.
- Administered APOE4 suppression in astrocytes at 2 months, before pathology onset.
- Assessed Aβ plaque and CAA pathology, gliosis, and vascular integrity at 10 months.
Main Results:
- Reducing astrocytic APOE4 shifted fibrillar Aβ deposition from brain parenchyma to cerebrovasculature.
- Despite increased CAA, astrocytic APOE4 suppression reduced Aβ-mediated gliosis.
- Cerebrovascular integrity and function were improved in vessels with CAA.
Conclusions:
- In a mouse model, reducing astrocyte-derived APOE4 ameliorates Aβ-mediated gliosis and cerebrovascular dysfunction.
- This occurs despite an increase in fibrillar Aβ deposition within the vasculature.
- Targeting astrocytic APOE4 may offer a therapeutic strategy for CAA-related complications.
Background:
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.
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 Aβ plaque and CAA pathology, gliosis, and vascular integrity.
Results:
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.
Conclusion:
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.
