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.
The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of neuroinflammation (NI) of the central nervous system. A twelve-amino acid peptide that transcytoses the BBB, termed MTfp, was chemically conjugated to siRNA to create a novel peptide-oligonucleotide conjugate (POC), directed to downregulate NOX4, a gene thought responsible for oxidative stress in ischemic stroke. The MTfp-NOX4 POC has the ability to cross the intact BBB and knockdown NOX4 expression in the brain. Following induction of ischemic stroke, animals pretreated with the POC exhibited significantly smaller infarcts; accompanied by increased protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp can act as a nanomule to facilitate BBB transcytosis of siRNAs; where the NOX-4 specific siRNA moiety can elicit effective therapeutic knockdown of a gene responsible for oxidative stress in the central nervous system. This study is the first to conclusively demonstrate both siRNA-carrier delivery and therapeutic efficacy in any CNS disease model where the BBB remains intact and thus offers new avenues for potential treatments of oxidative stress underlying neuroinflammation in a variety of neuropathologies that are currently refractory to existing therapies.
Vascular dysfunction is a crucial pathological hallmark of Alzheimer's disease (AD). Studies have reported that beta amyloid (Aβ) causes increased blood vessel growth in the brains of AD mouse models, a phenomenon that is also seen in AD patients. This has given way to an alternative angiogenesis hypothesis according to which, increased leakiness in the blood vessels disrupts the blood-brain barrier (BBB) and allows unwanted blood products to enter the brain causing progression of disease pathology, promoting amyloid clumping and aggregation along with impaired cerebral blood flow. Furthermore, the expression of melanotransferrin in AD model and patients may contribute to angiogenesis. The objective of this chapter is to attempt to establish a link between the vascular damage and AD pathology. Curbing the vascular changes and resulting damage seen in the brains of AD model mice and improving their cognition by treating with FDA-approved anti-angiogenic drugs may expedite the translational potential of this research into clinical trials in human patients. This direction into targeting angiogenesis will facilitate new preventive and therapeutic interventions for AD and related vascular diseases.
The blood-brain barrier (BBB), hinders the distribution of therapeutics, intended for treatment of diseases of the brain. A twelve-amino acid peptide, termed MTfp, was derived from MTf, and retains the ability to cross the BBB intact and ferry cargo into intacellular organelles within neurons, glia and microglia in the brain. A novel MTfp-siRNA peptide-oligonucleotide conjugate (POC), directed against NOX4, a gene known to potentiate ischemic stroke, was chemically synthesized. The MTfp-NOX4 siRNA POC traversed the BBB, resulting in the knockdown of NOX4 expression in the brain. Following induction of ischemic stroke, animals treated with the POC exhibited significantly smaller infarcts; accompanied by significant protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp portion, of this novel POC, can facilitate BBB transcytosis; where the siRNA moiety can elicit effective therapeutic knockdown of a gene associated with a disease of the central nervous system (CNS). This is a general platform to transport therapeutics to the CNS and thereby, offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.
The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of diseases of the brain. Our previous studies demonstrated that that a soluble form of melanotransferrin (MTf; Uniprot P08582; also known as p97, MFI2, and CD228), a mammalian iron-transport protein, is an effective carrier for delivery of drug conjugates across the BBB into the brain and was the first BBB targeting delivery system to demonstrate therapeutic efficacy within the brain. Here, we performed a screen to identify peptides from MTf capable of traversing the BBB. We identified a highly conserved 12-amino acid peptide, termed MTfp, that retains the ability to cross the intact BBB intact, distributes throughout the parenchyma, and enter endosomes and lysosomes within neurons, astrocytes and microglia in the brain. This peptide may provide a platform for the transport of therapeutics to the CNS, and thereby offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.
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