My research focuses on development of potential therapeutics to target protein-misfolding disorders, in particular Alzheimer’s disease.
Stemming from the basic research of protein-lipid interactions, my laboratory identified a family of naturally occurring compounds that inhibit the formation of toxic soluble aggregates in Alzheimer’s disease.
These molecules underwent preclinical studies to demonstrate efficacy and are now in Phase II clinical trials.
This work is being expanded to examine other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Huntington’s and Parkinson’s disease in order to investigate the possibility of a universal anti-aggregant small molecule. Further, since amyloid formation and disease progression cannot be monitored at present, we are attempting to develop a diagnostic based on compounds that bind amyloid but are not effective therapeutics.
Our latest endeavors include characterization of novel therapeutics that might be used in combination with small molecule therapies to fully recover functioning in Alzheimer’s disease.
This work is based on the premise that strategies in clinical trials to date will have some beneficial effects in stabilizing disease progression, yet to achieve optimal cognitive functioning combination therapies that address other targets will be necessary.
Previous work that contributed to drug discovery investigated the role of aging in neurodegeneration and the age-specific factors, which leads to susceptibility to injury within the CNS.
CNS immune mechanisms are altered during aging, the role in neurodegeneration was and is being investigated.
The principle goal was to investigate processes, which lead to the formation of β-amyloid (Aβ) and deposition in Alzheimer’s disease, and the mechanisms by which Aβ deposition leads to tissue damage.
The mechanism of amyloid-β peptide toxicity with respect to the apparent increased susceptibility of aged cells to amyloid fibril deposition were also investigated to identify downstream physiological and biochemical events which occur after binding of Aβ to the cell surface. Further, the mechanism of β−amyloid peptide (Aβ) toxicity in Alzheimer's disease remained controversial.
Pathological and in vitro studies demonstrated the association of senile plaques with neuronal and microglial membranes, although their specific mode of interaction was not well understood. I examined the interaction of Aβ fibrils with lipids membranes. The Aβ peptides form a β-structure that folds into the toxic fibril, it is speculated that this is the species involved in neuronal toxicity.
We speculated that intermediates along the pathway to fibril formation also possess toxic effects.
Investigations into the ability of species other than the fibril to cause membrane disruption or damage were investigated.