ApoE4 and TRPM2 in Border-Associated Macrophages as Key Drivers of Cerebral Amyloid Angiopathy

Amyloid-related imaging abnormalities (ARIA) remain the most discussed side effect of the approved anti-amyloid immunotherapies. ARIA, which manifests either as brain swelling or microhemorrhages, is tied directly to the vascular system of the brain. There are several factors that can increase one’s risk of developing ARIA, but one of the most important is the presence of a type of amyloid pathology called cerebral amyloid angiopathy (CAA). CAA consists of aggregated amyloid beta, similar to the typical plaques associated with Alzheimer’s disease (AD). However, CAA accumulates along the blood vessels of the brain, unlike plaques, which aggregate in the rest of the brain tissue (the parenchyma). As a result, CAA can interfere with blood vessel function, leading to complications and other adverse effects. CAA is incredibly common in AD cases, with 80-90% of patients diagnosed with AD having some level of CAA. Given its prevalence and role as a risk factor for ARIA, a CAA-targeting therapy is a critical need in the field.

ApoE4, the largest genetic risk factor for late-onset, sporadic Alzheimer’s disease, is also a risk factor independently for CAA, ARIA, and other neurovascular pathologies. However, the mechanism by which ApoE4 contributes to these pathologies remains unclear. Drs. Iadecola and Faraco have been investigating the contributions and interactions between vascular pathologies and AD for years and believe they are homing in on the mechanism linking ApoE4 and CAA. Their hypothesis centers on an immune cell type in the brain, called border-associated macrophages (BAMs), found around blood vessels. BAMs produce high levels of ApoE4, which can negatively influence nearby blood vessels and other BAMs, causing them to begin expressing a different set of genes and change their activity, leading to neurovascular dysfunction. Their overarching hypothesis is that this dysfunction impairs the rate at which amyloid beta can be cleared from the brain via the blood vessels, leading to a buildup of amyloid along the vessels and causing CAA. Here, they aim to test this hypothesis and determine if they can prevent the process by preventing early signaling between the BAMs.

The project consists of three aims. The first will focus on confirming that the rate of amyloid clearance from the brain is reduced by the presence of ApoE4. They will utilize mouse models that carry humanized ApoE4 and measure clearance rates through several key routes, as well as the ability of BAMs to engulf and degrade amyloid pathology. The second aim will then begin testing the effective point for therapeutic intervention in the proposed mechanisms by knocking down ApoE4 or its receptor, LRP1, in the BAMs. They will assess changes in the neurovascular function and BAM activity to see if limiting this signaling prevents the cascade leading to vascular dysfunction and CAA. The final aim takes a further step by testing whether interfering with a key channel on the cell surface, TRPM2, can also prevent the cascade of events. TRPM2 is opened in response to ApoE4 binding LRP1, causing calcium to enter the BAMs, which then acts as a potent signal for the multitude of detrimental changes observed in BAMs with ApoE4. By targeting this channel, Drs. Iadecola and Faraco can test the therapeutic potential of targeting another integral part of their hypothesized mechanism, thereby providing more avenues for future studies and enabling them to assess which approach is more effective and safer with respect to potential side effects.

Overall, this project aims to define the mechanisms connecting ApoE4 and CAA, while also setting the groundwork for future projects to develop and test a therapeutic approach to prevent CAA. This work is critical to improving the field’s available options for treating AD and could enable more patients to safely take advantage of existing therapies.