Advances in Alzheimer's Research

Volume: 2

Indexed in: EBSCO, Ulrich's Periodicals Directory

Alzheimer’s disease (AD) is currently recognized as an untreatable, progressive, degenerative and terminal disease that is global – afflicting over 36 million people worldwide, with the number ...
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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

Abstract

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.

Keywords:

Aging, alzheimer disease, astrocyte, heme oxygenase-1, iron, metalloporphyrin, mitochondria, neuroprotection, OB-24, oxidative stress.

Affiliation:

Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, Quebec, H3T 1E2 Canada.