利用先进的癌症疗法在阿尔茨海默病的临床前模型中逆转病理学：通过攻击脑血管新血管生成。

Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics.

机构信息

Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6T 1Z4, Canada.

Department of Medical Genetics, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, BC V6T 1Z4, Canada; Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z4, Canada; Department of Zoology, University of British Columbia, 6270 University Blvd., Vancouver, BC V6T 1Z4, Canada; The Vancouver Prostate Centre, Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6T 1Z4, Canada.

出版信息

EBioMedicine. 2021 Sep;71:103503. doi: 10.1016/j.ebiom.2021.103503. Epub 2021 Sep 15.

DOI:10.1016/j.ebiom.2021.103503

PMID:34534764

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8449085/

Abstract

BACKGROUND

Cognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Aβ) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Aβ drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tight-junction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Aβ levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Aβ triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain.

METHODS

We explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Aβ deposits and reverse cognitive decline in an animal model of AD. One month post-treatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology.

FINDINGS

Targeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Aβ depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD.

INTERPRETATION

Modulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation.

FUNDING

None.

摘要

背景

认知能力下降导致痴呆，伴随着神经纤维缠结（NFT）中由过度磷酸化 tau 蛋白（tau）组成的淀粉样β（Aβ）的积累，这是阿尔茨海默病（AD）的先前公认的标志。我们之前发现 AD 患者的脑标本存在血管过度生成，并且与这一观察结果一致，我们证明 Aβ 的过度表达会导致脑血管新生，导致血管过度生成以及紧密连接破坏和血脑屏障（BBB）通透性增加 AD 动物模型中的通透性。随后，我们证明了当促血管生成 Aβ 水平降低时，淀粉样斑块负担和脑血管发病机制会消退。基于这些数据，我们提出了 AD 病因学的范例，即作为对脑血流（CBF）受损的代偿反应，Aβ 引发潜在的血管新生，这是 AD 的传统标志。因此，我们在此提供证据表明，重新利用抗癌药物来调节脑血管新生，而不是直接针对淀粉样蛋白级联反应，可能为 AD 和相关的脑血管疾病提供有效的治疗方法。