SLF molecule carrying pyrroline nitroxide blocks AβO formation and reduces Aβ toxicity and inflammation.
Scientists have developed a type of modified fluorene compound that blocks the formation of amyloid beta (Aβ) aggregates and could potentially represent a new class of drug for treating Alzheimer disease (AD). The University of California, Davis (UCD)-led team synthesized a spin-labeled fluorine (SLF) compound containing a oxygen radical-scavenging pyrroline nitroxide group, which allowed the molecules to be imaged using electron paramagnetic resonance (EPR) spectroscopy.
They found that the SLF compound was as potent as a model fluorene in terms of preventing Aβ oligomer (AβO) aggregation and protecting against AβO toxicity but was also much better at free radical scavenging. The team says that the ability to detect the SLF by EPR indicates that as well as having therapeutic potential, such molecules could represent a sensitive diagnostic tool for detecting Aβ plaques in patients with AD.
John C. Voss, Ph.D., and colleagues report on their work in PLoS One in a paper titled “The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide.”
The UCD researchers had previously developed a series of amyloid imaging compounds based on a rigid tricyclic fluorene ring and demonstrated that two of their compounds could in addition disrupt AβO assembly in solution, were capable of penetrating the brain, and reduced amyloid burden in mouse models. In their current work, the investigators have modified these compounds further to generate a pyrroline nitroxide-containing SLF, which they designated HO-4160 (7-bromo-N-methyl-N –[(2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl]-9H-fluoren-2-amine radical).
Their in vitro studies showed that HO-4160 bonds to and disaggregated Aβ in amyloid precursor protein (APP)-expressing cultured neurons. This led to a reduction in AβO accumulation and the toxic effects of Aβ production, while increasing cell viability. The reactive oxygen-scavenging moiety on HO-4160 also lowered inflammation.
“The spin-labeled fluorenes demonstrated a number of extremely important qualities,” Dr. Voss notes. “This makes them potentially useful in the areas of research, diagnostics, and treatment of Alzheimer’s disease.” The UCD team next plans to study the safety of SLF compounds and evaluate them in preclinical models of AD.