Glial HO-1 Suppression as a Neuroprotective Strategy in Alzheimer’s Disease
Pp. 214-229 (16)
Hyman M. Schipper, Ajay Gupta and Walter A. Szarek
The mechanisms responsible for oxidative damage, pathological brain iron
deposition and mitochondrial insufficiency in Alzheimer disease (AD) remain
enigmatic. Heme oxygenase-1 (HO-1) is a 32 kDa stress protein that catabolizes heme
to biliverdin, free iron and carbon other tissues in various models of disease and trauma.
Our laboratory demonstrated that 1) HO-1 protein is significantly over-expressed in
AD-affected temporal cortex and hippocampus relative to neurohistologically-normal
control preparations, 2) in cultured astrocytes, HO-1 up-regulation by transient
transfection of the human ho-1 gene, or stimulation of endogenous HO-1 expression by
exposure to β-amyloid, TNFα or IL-1β, promotes intracellular oxidative stress, opening
of the mitochondrial permeability transition pore and accumulation of non-transferrin
iron in the mitochondrial compartment, and 3) the glial iron sequestration renders cocultured
neuron-like PC12 cells prone to oxidative injury (reviewed in Schipper HM. J
Neurochem 110: 469-85, 2009). Induction of the astroglial ho-1 gene may constitute a
‘common pathway’ leading to pathological brain iron deposition, intracellular oxidative
damage and bioenergetic failure in AD and other human CNS disorders. Hypothesis:
Targeted suppression of glial HO-1 hyperactivity may prove to be a rational and
effective neurotherapeutic intervention in AD and related neurodegenerative disorders.
To begin testing this hypothesis, studies have been initiated to determine whether
systemic administration of a novel, selective and brain-permeable inhibitor of HO-1
activity ameliorates cognitive dysfunction and neuropathology in a transgenic mouse
model of AD.
Aging, alzheimer disease, astrocyte, heme oxygenase-1, iron,
metalloporphyrin, mitochondria, neuroprotection, OB-24, oxidative stress.
Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, Quebec, H3T 1E2 Canada.