Title:Inhibition of Early Upstream Events in Prodromal Alzheimer’s Disease by Use of Targeted Antioxidants
VOLUME: 7 ISSUE: 2
Author(s):Kedar N. Prasad and Stephen C. Bondy
Affiliation:Occupational & Environmental Medicine, Department of Medicine, University of California, Irvine, Irvine, CA 92697-1830, USA.
Keywords:Alzheimer's disease, antioxidants, free radicals, inflammation, neurodegenerative disease, oxidative stress.
Abstract:A link between Alzheimer's disease (AD) and an excess presence of oxidant free radicals in the brain has frequently
been reported. It is generally assumed that such oxidative stress and related cellular damage is caused by inflammatory
changes in the brain and is consequent to amyloid deposition. This review makes the argument that elevated oxidative
stress in AD is an early causal event in the initiation and advancement of this disease. Oxidative stress can be decreased
by enhancing antioxidant enzymes through activation of the cytoplasmic transcriptional factor (Nrf2)/ARE (antioxidant
response element) pathway, and by dietary and endogenous antioxidant chemicals. Reduction in the binding ability
of Nrf2 to ARE lowers antioxidant enzyme levels. Decreased levels of Nrf2 and augmentation of oxidative stress in
AD suggest that the ROS-dependent mechanism of activating the Nrf2/ARE pathway has become unresponsive. A combination
of agents that can either activate the Nrf2-ARE pathway by ROS-independent mechanisms, or by acting directly as
antioxidant chemicals, may be necessary to reduce oxidative stress in AD. Earlier shortcomings of using individual antioxidants
may be due to consideration of antioxidants as pharmacological agents, ignoring the fact that individual antioxidants
can be transmuted in the highly oxidant milieu that is present in AD. Interactions between various cellular compartments
may require simultaneous examination of more than one agent. The clinical utility of such a more integrative
method can reveal interactive effects such as those found in nutritional research and this can compensate for any mechanistic
shortcomings of simultaneous testing of more than a single agent.
