Past Projects
Alzheimer’s treatment may be more effective for people at highest risk
R01AG053990 Mechanisms of ApoE Isoform Conferred Susceptibility and Resistance to Alzheimer’s Disease
Though it is well known that APOE genotype substantially contributes to Alzheimer’s Disease risk with ApoE4 carriers having the greatest risk and ApoE2 carriers having the lowest risk, mechanisms behind this have not entirely been established. ApoE isoform impacts rate of Aβ clearance from extracellular space in the brain, microglia inflammatory response, and overall maintenance of neural network and synaptic plasticity functioning. This project is focused on exploring the specific mechanisms involved in ApoE engagement with Aβ that may hinder or enhance its clearance.
Alzheimer’s model mice expressing human ApoE alleles E2, E3, and E4, as well as mice with ApoE knockout will be treated with an antagonist that blocks the interaction between Aβ and ApoE to assess extracellular unbound Aβ. Additionally, primary microglia isolated from each genotype will be assessed with functional phagocytosis and transcriptomic analyses. Microglia may be impaired in both phagocytic ability and inflammatory profile in ApoE4 carriers.
R01AG031221 Targeting the apoE/Aβ Interaction as a Therapeutic Approach for AD
In mouse models of Alzheimer’s, treatment with Aβ12-28P reduces Aβ deposition and neuritic degeneration by binding apoE thereby preventing it from interacting with Aβ. However, developing this treatment for humans is precluded by the as yet uncharacterized Aβ binding domain on apoE and the structure of the sequence 12-28 in Aβ. Thus, this project aims to identify the Aβ binding domain in apoE, the variability in this domain across ApoE allele carriers, the epitope in Aβ which binds apoE, and to determine how apoE isotypes modify soluble Aβ metabolism in the extracellular space, and finally, to investigate a possible summative effect of combined Aβ12-28P with passive immunization against Aβ.
K02AG034176 Peptoid Antagonists of the ApoE/Aβ Interaction as a Novel Anti-Aβ Therapy
The interaction between beta-amyloid (Aβ) and apolipoprotein E (apoE) is an important part of the processes required for Aβ clearance from the brain, Aβ transport across the blood-brain-barrier, and Aβ fibrillization and deposition to form plaques. It is likely that APOE4 carriers have an increased risk for sporadic Alzheimer’s Disease in part because of isoform-specific apoE morphology that may hinder Aβ clearance and enhance its deposition. Thus, this project will test the effectiveness of a therapeutic agent that blocks the apoE/Aβ interaction by mimicking the apoE binding site on Aβ. This non-toxic peptoid compound will be based on the Aβ12-28 sequence with the ability to penetrate the blood-brain-barrier and with biostability. Preliminary data suggests such a peptoid may also disrupt β-sheet formation for an additive therapeutic effect against Aβ plaque formation.
R01AG029635 Therapeutic Monoclonal Antibodies for Human Prion Diseases
Prion disease is a transmissible and invariably fatal degenerative disease characterized by a conformational transformation of prion protein into a toxic and self-replicating prion protein conformer. This disease has no cure or treatment available and with rapid pathological progression, a therapeutic option is desperately needed. Prion infection typically occurs through ingestion of contaminated meat, or through accidental exposure through blood transfusion, organ transplant, or the use of prion-contaminated surgical instruments.
This project aims to test three distinct anti-prion monoclonal antibodies (mAbs) in a cell culture model of human prion infection. Based on whichever mAb appears most effective, in vivo testing in murine models of prion disease will determine whether peripheral treatment with an anti-prion mAb will prevent spread of the infection to the central nervous system. A final goal will be to establish at which point in prion conformational change the protein may be prevented from undergoing this change with mAb treatment.
K08AG024847 Alzheimer’s therapy: Blocking ApoE/Aβ binding
A synthetic peptide, Aβ12-28P, which is homologous to residues 12-28 of native Aβ, can block the binding of apoE to Aβ. This binding has been shown to cause Aβ toxicity and fibril formation, which can effectively be reduced with this novel peptide. This effect is likely not caused by an antibody clearance response as no antibodies are detected in blood samples from treated mice, indicating the mechanism lies elsewhere. This project will expand the investigation into Aβ12-28P as a viable treatment option in humans, testing its efficacy in transgenic mice which express human ApoE isoforms or ApoE knockout.
K08AG020747 Vaccine and Magnetic Resonance Imaging Approaches for AD
With the success of anti-Aβ vaccination in Alzheimer’s Disease model mice, a potential treatment for humans is worthy of further exploration. As previous preparations of the vaccine have relied on elements that are toxic to humans, this project aims to use Aβ homologue peptides which are non-fibrillogenic and non-toxic. Testing will also involve an intranasal application of this vaccine. Finally, due to the increased likelihood of efficacy in early-stage Alzheimer’s patients, developing techniques for detecting preclinical onset of AD is an additional aim of this project.
Gadolinium, used for contrast in MRIs, may be able to bind Aβ when co-injected with mannitol or putrescine and can act as a contrast agent for amyloid lesions in a brain MRI.