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Basic Science and Pathogenesis
Jonathan Nyandu Kanyinda1, Olivia J Marola1, Gareth R Howell1,2,3
1The Jackson Laboratory, Bar Harbor, ME, USA.
Insights
Genetic background influences cerebral amyloid angiopathy (CAA) development. BXW mice show increased CAA, while WSB mice have fewer plaques, suggesting differential roles for microglia and astrocytes in amyloid beta deposition.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Cerebral amyloid angiopathy (CAA) involves amyloid beta (Aβ) accumulation in cerebral vasculature, disrupting the blood-brain barrier and potentially causing cognitive decline.
- The roles of microglia and astrocytes in CAA pathogenesis, particularly in Aβ clearance via the glymphatic system, are not fully understood.
- Previous studies suggest microglia may play a protective role against CAA, as their depletion worsened CAA in Alzheimer's disease models.
Purpose of the Study:
- To investigate the genetic drivers of cerebral amyloid angiopathy (CAA) development.
- To understand the differential roles of microglia and astrocytes in modulating CAA susceptibility across various genetic backgrounds.
Main Methods:
- Utilized APP/PS1 transgenic mice on diverse genetic backgrounds (B6, WSB, BXW) to study CAA development.
- Assessed CAA, parenchymal plaques, and glial cell (microglia and astrocytes) responses using immunohistochemistry and quantitative image analysis at 8 months of age.
- Analyzed differences in CAA area, plaque characteristics, and glial area (IBA1+ for microglia, GFAP+ for astrocytes) between genetic strains.
Main Results:
- BXW mice exhibited robust CAA, while B6 and WSB mice were less susceptible.
- WSB brains showed fewer but larger plaques compared to B6 and BXW.
- WSB mice had less astrocyte (GFAP+) area per plaque, whereas BXW mice had more microglial (IBA1+) area per plaque than B6 and WSB mice.
Conclusions:
- Differential susceptibility to CAA across B6, WSB, and BXW genetic backgrounds suggests a significant role for the host's genetic makeup.
- The distinct cellular responses of microglia and astrocytes in these strains likely influence amyloid deposition in cerebral vasculature, thereby modulating CAA.
- Targeting microglial activity and proliferation may be a promising therapeutic strategy for CAA, given the observed inverse relationship between microglial presence and CAA severity across strains.
Background:
Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid beta (Aβ) in the walls of the cerebral vasculature. CAA can cause damage to the vasculature and disrupt proper functioning of the blood brain barrier (BBB). CAA has also been associated with cerebral microbleeds, cognitive decline, and dementia. The roles of the brain's resident immune cells (microglia and astrocytes) in preventing or driving CAA are not fully understood. Microglia and astrocytes are important in the clearance of Aβ through the glymphatic system. Additionally, depletion of microglia has been shown to lessen parenchymal plaque deposition but increase CAA in models of AD, suggesting a potentially protective role for microglia against CAA development.
Methods:
Mice with diverse genetic backgrounds (B6, WSB, and BXW) expressing APP/PS1 were utilized to understand genetic drivers of CAA development. Brains were evaluated at 8M. CAA was assessed using immunohistochemistry (X34+ plaques) within arteries (αSMA + vessels). CAA area, plaque area, IBA1+ area, and GFAP+ area of 8M brains (n = 3) were quantified using custom FIJI scripts that employed standardized thresholding settings. A quantitative analysis was performed using GraphPad Prism to assess the differences between the different genetic backgrounds. Brains at 12M are currently undergoing analysis.
Results:
We have shown that B6 and WSB genetic backgrounds are less susceptible to CAA compared to BXW, which develops robust CAA. Preliminary analysis indicates WSB brains have fewer but larger plaques than B6 and BXW. WSB mice also had less GFAP+ area per plaque compared to B6 and BXW mice. In contrast, BXW mice had more IBA+ area per plaque compared to B6 and WSB mice.
Conclusions:
Given the differential susceptibility of B6, WSB, and BXW genetic backgrounds to CAA development and the potential role of microglia and astrocytes in modulating susceptibility to CAA. It is possible that B6, WSB and BXW.APP/PS1's unique cell response influences amyloid deposition in the vasculature, leading to CAA. Understanding the role of microglia and astrocytes in AD-relevant pathologies will help further the field in the target microglial activity and proliferation as it shows an inverse relationship with CAA expression across strains.
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