APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function.
Monica XiongHong JiangJavier Remolina SerranoErnesto R GonzalesChao WangMaud GratuzeRosa HoyleNga Bien-LyAdam P SilvermanPatrick M SullivanRyan J WattsJason D UlrichGregory J ZipfelDavid M HoltzmanPublished in: Science translational medicine (2021)
The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4 +/+ (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.
Keyphrases
- cognitive decline
- high fat diet
- endothelial cells
- late onset
- genome wide
- computed tomography
- subarachnoid hemorrhage
- mild cognitive impairment
- oxidative stress
- magnetic resonance
- magnetic resonance imaging
- high resolution
- type diabetes
- metabolic syndrome
- small cell lung cancer
- inflammatory response
- copy number
- emergency department
- gene expression
- multiple sclerosis
- pluripotent stem cells
- blood brain barrier
- resting state
- cerebral ischemia
- transcription factor
- high speed
- high fat diet induced
- single molecule
- replacement therapy
- smoking cessation