Longitudinal multiphoton imaging of cerebral amyloid angiopathy in response to anti-ApoE4 immunotherapy in mice.

Abstract

Background: There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time.

Methods: Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows.

Results: Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice.

Conclusions: Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.