Research Projects

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with many pathogenic elements. One contributing factor is vascular dysfunction, that can be both a result of the primary AD pathogenesis and a cause of neuronal loss and subsequent cognitive impairment. The molecular mechanisms by which AD and the vascular system intersect and influence each other are still unclear. To give molecular definition to this interaction, we have shown that crosstalk between pathogenic AD associated amyloid-beta (Aβ) peptide and blood clotting proteins contributes to BBB damage, abnormal thrombosis and impaired fibrinolysis in AD. However, more mechanistic studies are needed to understand the complexity of vascular dysfunction and AD progression. The Aβ peptides (40- and 42-residue long) are most studied canonical Aβ generated in the brain. Recent evidence suggests that the non-canonical longer Aβ peptides (for example, Aβ43, Aβ45, Aβ46, Aβ48, Aβ49) are the key players in inducing the neurodegeneration and dementia in AD. However, their pathogenic mechanism is not well defined. The hypothesis of this proposal is that the longer non-canonical Aβ peptides exacerbate vascular dysfunction and neuroinflammation by interacting with fibrinogen and other blood clotting proteins (Factor XII, High molecular weight kininogen), promoting BBB impairment, abnormal thrombosis, vessel occlusion, neurodegeneration and dementia. Additionally, this proposal hypothesizes that shorter Aβ peptides (e.g., Aβ38), when in excess, may also exacerbate vascular dysfunction, synaptic toxicity, BBB damage, and provoke inflammation. If validated, this hypothesis could provide a likely explanation for why some gamma-secretase modulators (GSMs), designed to increase Aβ38 over Aβ42 by altering APP processing, have shown marginal benefits in clinical trials. We will use biophysical, biochemical, neuronal cell culture, and electron microscopy techniques. The effect of different Aβ variants on vascular abnormalities (such as proinflammatory bradykinin generation, thrombosis, clot structure, and clot lysis) will be examined using commercially available synthetic Aβ variants, purified clotting proteins (in vitro) as well as commercially available pooled normal human plasma (ex-vivo). AD is a complex disease, and it is unlikely that one central mechanism can be targeted for treatment in all patients. However, defining pathogenic pathways for AD would be invaluable so patients could be stratified and better diagnoses and treatments developed. Therefore, it is important to pursue the novel concepts described in this application. Any new information on the vascular mechanisms of action of these Aβ variants would have immediate human clinical relevance in AD. This understanding could drive the development of more effective therapies that target both amyloid and vascular pathways and improve treatment outcomes in AD.