Suppression of glial HO-1 activity as a potential neurotherapeutic intervention in AD.
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 monoxide. The HO-1 gene is exquisitely sensitive to oxidative stress and is induced in brain and 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 beta-amyloid, TNFalpha or IL-1beta, 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 co-cultured neuron-like PC12 cells prone to oxidative injury. 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.


OBJECTIVE
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.
Schipper
Hyman M
HM
Centre for Neurotranslational Research and Bloomfield Centre for Research in Aging, The Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada. hyman.schipper@mcgill.ca
Gupta
Ajay
A
Szarek
Walter A
WA
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress
D007501:Iron; D051547:Heme Oxygenase-1