Cerebral amyloid angiopathy: Role of ApoE, innate immunity, and meningeal lymphatics

Abstract: Project 2 will investigate the interplay of APOE genotype, innate immunity, and meningeal lymphatics on cerebral amyloid angiopathy (CAA) and the translational implications of modifying lymphatic function on passive immunotherapy of CAA. CAA occurs in ~90% of individuals who develop Alzheimer’s disease (AD) and can occur independently of AD. The pathological hallmarks of CAA are deposition of amyloid composed in the majority of cases of amyloid-β (Aβ) along small arteriole vessel walls of the cerebral vasculature and leptomeninges. CAA leads to loss of vascular smooth muscle cells, impaired vasoreactivity, hemorrhages, and ischemia resulting in cognitive impairment and transient ischemic episodes. CAA is also linked with edema and microhemorrhages that are common side effects observed with several anti-Aβ antibodies known as amyloid-related imaging abnormalities (ARIA). The mechanisms underlying the development of CAA are not well understood, but prior studies indicate that APOE genotype, perivascular fluid flux, and innate immune cells can all influence CAA pathology. Like AD, APOE4 increases the risk of developing CAA. Recently, we demonstrated that anti-apoE antibodies that target a form of apoE that co- deposits with vascular amyloid reduced CAA and improved vascular function. In the brain parenchyma, apoE is predominantly expressed by astrocytes and reactive microglia. Vascular-associated cells, such as perivascular macrophages (PVMs), pericytes, and the recently described fibroblast-like vascular leptomeningeal cells (VLMCs) are also reported to express apoE. ApoE produced by different cell types differ in their lipidation state and post-translational modifications which could suggest a cell-specific role for apoE in CAA or subsequent vascular dysfunction and inflammation. Recent studies by the Kipnis lab have shown important contributions of the meningeal lymphatic system to Aβ deposition in parenchymal and leptomeningeal plaques. Impaired clearance of Aβ from perivascular spaces may also contribute to the formation of CAA, although the role of the meningeal immune system and the meningeal lymphatics in CAA formation and pathogenesis is unexplored. We hypothesize that 1) apoE plays a multifaceted role in CAA formation by influencing perivascular Aβ seeding and clearance in part via the meningeal lymphatic system and perivascular immune cells, 2) the meningeal lymphatic system plays a key role in CAA formation; and 3) augmenting the meningeal lymphatic system will increase the efficacy of anti-apoE immunotherapy reduction of CAA. We propose these Aims: Aim 1: To determine effect of cell-type specific apoE expression on CAA and meningeal lymphatic function. Aim 2: To determine the role of meningeal lymphatics on CAA pathology and associated inflammation and vascular dysfunction. Aim 3: To determine the effect of lymphatic function on the efficacy of anti-apoE antibody treatment on CAA and vascular dysfunction. Project 2 will collaborate extensively with all Projects and Cores in this grant to accomplish these goals.