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

Abstract

Background: Cognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Ab) 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 Ab drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tightjunction 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 Ab 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), Ab 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 Ab deposits and reverse cognitive decline in an animal model of AD. One month posttreatment 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 Ab 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.

Role of Glial Cell-Derived Oxidative Stress in Blood-Brain Barrier Damage after Acute Ischemic Stroke

“…BBB dysfunction begins in the hippocampus in early stage of AD detected with magnetic resonance imaging, and BBB damage may initiate a range of tissue damage, lead to synaptic and neuronal dysfunction and cognitive impairment, end with AD [43]. Notably, BBB breakdown and vascular dysfunction are hallmarks of AD, and targeting BBB has great translational potential in AD therapy [44].…”

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

“…They also target β -amyloid. The promising results of preclinical studies have triggered several clinical trials [ 2 , 3 ]. Moreover, Type 2 diabetes mellitus (T2D) has been identified as a high-risk factor for AD [ 4 ].…”

Associations of plasma angiostatin and amyloid-β and tau levels in Alzheimer’s disease

“…A previous study demonstrated that angiostatin can inhibit neuronal loss, reduce inflammation and stabilize vascular remodeling in an animal model of AD [ 14 ]. Furthermore, a recent study demonstrated that targeting the proangiogenic pathway using the anticancer drug axitinib, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT receptors, dramatically reduced cerebrovascular angiogenesis and promoted blood-brain barrier integrity, resulting in improved Aβ clearance and diminished brain Aβ burden in a mouse model of AD [ 13 ]. This evidence suggests that angiogenic inhibition may have therapeutic potential for AD and that angiostatin may also be useful in AD treatment.…”

“…Disruption of the BBB has been shown to coincide with the onset of cognitive impairment [ 11 , 12 ]. In addition, modulating cerebrovascular neoangiogenesis could reverse brain pathology in a preclinical model of AD, which strengthens the link between angiogenesis and AD [ 13 ].…”