Oxidative stress resulting from advanced glycation end products (AGEs) is one of the leading causes of Alzheimer’s disease (AD) pathogenesis. An efficient address is provided by supplementation of the glutathione-dependent glyoxalase enzyme activity to neutralize causative reactive dicarbonyls. Given the metabolic instability and thus, limited bioavailability of glutathione, we have developed a metabolically stable glutathione analogue, ψ-GSH, for restoration of glyoxalase function. In recent evaluations using APP/PS1 mice, wherein ψ-GSH treatment was initiated after established AD pathology, demonstrated attenuation of disease progression. Biochemical analysis of brain tissues displayed marked reduction in oxidative stress indices and confirmed glyoxalase engagement as judged by reduction in substrate methylglyoxal and elevation in product D-lactate concentrations. Quantitative neuropathological analysis also showed significant reduction in Aβ plaque burden, and neuroinflammation. Ψ-GSH affected progressive neurodegeneration as gauged by TH+ fiber density, cell volume and count in the locus coeruleus. One shortcoming of ψ-GSH, however, is limited oral bioavailability. We have successfully created orally bioavailable prodrugs of ψ-GSH by masking the labile aliphatic thiol. Assessment of plasma and tissue metabolic stability demonstrated advantage of this design approach. Oral administration of the lead prodrug in intracerebroventricularly injected Aβ1-42 mouse model highlighted its benefits in behavioral and biochemical outcomes over ψ -GSH. Collectively, this data support utility of ψ-GSH-based treatment options in reversing/retarding the progression of AD-like pathology and further preclinical exploration of the glyoxalase pathway for therapeutic development.

Supplementation of glyoxalase 1 activity: A promising strategy for development of Alzheimer’s therapeutics

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.