About This Project

Ask the Scientists

What is the context of this research?

The amyloid-β (Aβ) peptide is generated in the brain, however in many individuals Aβ initiates a cascade of events that over decades leads to neurotoxicity and ultimately Alzheimer’s disease (AD). The Aβ peptide forms aggregates, ranging from small soluble clusters (oligomers) to the large insoluble amyloid plaque deposits. While the presence of amyloid and disease has proved confounding, genetics strongly point to Aβ's causative role in AD. Mutations resulting in early onset AD drive increased Aβ production, and mutations that lower Aβ production are associated with a decreased risk for AD. Evidence now points to the oligomer form of Aβ as central to driving AD. Unfortunately, current imaging capabilities lack the ability to detect and localize oligomeric Aβ in the brain.

What is the significance of this project?

Because considerable brain damage has already occurred before a definitive diagnosis of dementia can be made, it is imperative to develop methods capable of detecting the AD process at the earliest possible stage. MRI imaging of oligomeric and amyloid Aβ in the brain would provide a non-invasive, practical method to detect the early disease process. However, this requires the devolvement of a contrast agent with a high affinity for Aβ and permeability across the blood brain barrier. Gadolinium chelates are ordinarily used to provide contrast in MRI, but have chemical limitations and pose a significant risk for adverse reactions in humans. We have devised a compound with a demonstrated affinity for Aβ amyloid and oligomers as well as the magnetic property enabling contrast in MRI imaging.

What are the goals of the project?

The innovative compound we wish to develop for detecting harmful Aβ at the earliest stages of the Alzheimer's process is called a spin-labeled fluorene (SLF). This is a bi-functional molecule, with the one part responsible for targeting the compound to Aβ and the other portion of the molecule containing the paramagnetic species responsible for producing contrast in MRI. The contrast portion utilizes a nitroxide spin label and the targeting portion contains a fluorene chemical species (thus the name SLF).
Project Goals:
1) Demonstrate in a synthetic experiment that SLF binds to Aβ at a density sufficient to produce contrast enhancement in MRI.
2) Demonstrate that SLF specifically localizes to Aβ-enriched regions in brain tissue.