P4‐298: The histidine analogue hydraide reduces BETA‐AMYLOID 42 levels and gamma‐secretase activity in a model of Alzheimer's disease

Abstract

Membrane lipid peroxidation product 4-hydroxynonenal (HNE) is important therapeutic target for several neurodegenerative diseases because it is neurotoxic and has been implicated in the pathogenesis of alzheimer's disease, Parkinson's diease, amyotrophic lateral sclerosis, and stroke. We recently reported that a histidine analogue (AG/01), which is highly effective in scavenging HNE and significantly protects against focal ischemia-induced brain damage. We now report that anti-amyloidogenic and neuroprotective ability of the histidine analogue was investigated in the triple-transgenic Alheimer's disease model mice (3xTg-AD mice). HNE-mediated beta-secretase and gamma-secretase activities, abeta production, and modification of gamm-secretase activities, Abeta production, and modification of gamma-secretase were reduced in the presence of the histidine analogue. The histidine analogue histidyl hydraide was also effective in reducing Abeta42 levels, gamma-secretase activity, and HNE modification of gamma-secretase substrate receptor Nicastrin in the brains of 3xTg-AD mice. These findings suggest a therapeutic potential for HNE-scavenging agents in the treatment of alzheimer's disease. Western blot Animals and treatment with the histidine analog histidyl hydrazide (AG/01) The histidine analog histidyl hydrazide (AG/01) reduces the Aβ42/Aβ40 ratio, γ-secretase activity, and HNE-modified Nct in the brains of AD mice. These findings suggest a therapeutic potential for HNE-scavenging agents in the treatment of alzheimer's disease.