Reversing pathology in a preclinical model of Alzheimer's disease by hacking cerebrovascular neoangiogenesis with advanced cancer therapeutics
| Autor: | Lonna Munro, Chaahat S.B. Singh, Wilfred A. Jefferies, Cheryl G. Pfeifer, Hong Yue Wang, Kyung Bok Choi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Vascular Endothelial Growth Factor A
Pathology Medicine (General) Amyloid-beta (Aβ) Axitinib Fluorescent Antibody Technique Pathogenesis Mice chemistry.chemical_compound 0302 clinical medicine Tissue Distribution Senile plaques Cognitive decline 0303 health sciences Behavior Animal Neovascularization Pathologic biology Brain General Medicine Immunohistochemistry 3. Good health Vascular endothelial growth factor Treatment Outcome Blood-Brain Barrier Cognitive restoration Alzheimer's disease (AD) Medicine Disease Susceptibility Drug Monitoring medicine.drug medicine.medical_specialty Tau protein Antineoplastic Agents General Biochemistry Genetics and Molecular Biology Tight Junctions 03 medical and health sciences R5-920 Alzheimer Disease medicine Animals Humans Dementia Protein Kinase Inhibitors 030304 developmental biology business.industry Hypervascularity medicine.disease Blood-brain barrier (BBB) Disease Models Animal chemistry biology.protein Angiogenesis business Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | EBioMedicine, Vol 71, Iss, Pp 103503-(2021) |
| ISSN: | 2352-3964 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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