Metal chelation as a potential therapy for Alzheimer's disease.
Alzheimer's disease is a rapidly worsening public health problem. The current lack of effective treatments for Alzheimer's disease makes it imperative to find new pharmacotherapies. At present, the treatment of symptoms includes use of acetylcholinesterase inhibitors, which enhance acetylcholine levels and improve cognitive functioning. Current reports provide evidence that the pathogenesis of Alzheimer's disease is linked to the characteristic neocortical amyloid-beta deposition, which may be mediated by abnormal metal interaction with A beta as well as metal-mediated oxidative stress. In light of these observations, we have considered the development of drugs that target abnormal metal accumulation and its adverse consequences, as well as prevention or reversal of amyloid-beta plaque formation. This paper reviews recent observations on the possible etiologic role of A beta deposition, its redox activity, and its interaction with transition metals that are enriched in the neocortex. We discuss the effects of metal chelators on these processes, list existing drugs with chelating properties, and explore the promise of this approach as a basis for medicinal chemistry in the development of novel Alzheimer's disease therapeutics.
Cuajungco
M P
MP
Laboratory for Oxidation Biology, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.
Fagét
K Y
KY
Huang
X
X
Tanzi
R E
RE
Bush
A I
AI
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D018384:Oxidative Stress; D015032:Zinc / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D003300:Copper; D007501:Iron; D015032:Zinc