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The foundation of the laboratory's effort are the discoveries, made between 1992-1994, that the major proteins implicated in Alzheimer's disease (AD), Aß and the amyloid protein precursor (APP), are copper/zinc metalloproteins whose physicochemical properties (e.g. solubility) are profoundly influenced by interaction with these metal ions. Our in vitro data is supported by findings that zinc, copper and iron are enriched in AD neocortex, and especially in the amyloid plaque deposit. In more recent years, the interaction of Aß with redox active metals iron and copper has been shown by us to engender a series of pernicious radical-mediated reactions that could be of importance to the oxidative lesions that typify AD brain damage. My laboratory has demonstrated that Aß possesses superoxide dismutase (SOD)-like activity, and therefore ß-amyloid, the classical neuropathological lesion of AD, may represent a corrupted antioxidant. In this regard, Aß resembles SOD since they are both copper/zinc superoxide scavengers, that form aggregates that are associated with neurodegeneration. My laboratory discovered that when binding iron or copper, Aß produces hydrogen peroxide, and can be disaggregated and rendered redox-inert by copper/iron complexing agents. Therefore, coordination of the metal binding sites on Aß by small molecules may the basis for a therapeutic, and this approach has lead to successful studies of novel chemotherapeutic agents in treating amyloid lesions in animal models, one of which is currently in Phase 2 clinical trials in Alzheimer patients.

Based upon our research into the biochemistry of AD, my laboratory has adopted a general hypothesis that dysregulation of the inorganic milieu of tissues, generating small increases in available redox-active metal ions (principally copper and iron), is one of the most important upstream components in the pathogenesis of age-related degenerative disorders. We have found interactions between copper or iron and other target proteins implicated in degenerative disorders, that resemble the interactions between copper or iron and Aß. Specifically, alpha-crystallin, implicated in cataractogenesis, was found to be specifically cross-linked by copper; PrPc, implicated in Creutzfeld-Jakob disease and other prion disorders, was found to reduce copper and generate reactive oxygen species (ROS); antipsychotics, which cause tardive dyskinesia through mechanisms that are thought to involve oxidation stress, strongly reduce copper and generate ROS; and we are also exploring copper-mediated oxidation in familial amyotrophic lateral sclerosis mediated by mutant superoxide dismutase. These reactions are specific for their target proteins, and all generate ROS which may further damage surrounding tissue. We are currently pursuing a mechanistic understanding of these provocative reactions using in vivo experimentation.


Jack Rogers, M.D.
Program Director
Assistant Professor of Psychiatry, Harvard Medical School
Massachusetts General Hospital-East
149 Thirteenth Street, Rm 2618
Charlestown, MA 02129
Phone:(617)726-8838; fax(617)724-1823
Publications by Dr. Rogers

Xudong Huang, PhD, Assistant Professor of Psychiatry (pending)
Jennifer Coccia, BS, Technician
Julien Muffat, BS, PhD, Student
Seichii Nagano, MD PhD, Postodoctoral Research Fellow

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Laboratory for Neurochemistry