title: Metal dyshomeostasis and inflammation in Alzheimer's and Parkinson's diseases: possible impact of environmental exposures.
abstract: A dysregulated metal homeostasis is associated with both Alzheimer's (AD) and Parkinson's (PD) diseases; AD patients have decreased cortex and elevated serum copper levels along with extracellular amyloid-beta plaques containing copper, iron, and zinc. For AD, a putative hepcidin-mediated lowering of cortex copper mechanism is suggested. An age-related mild chronic inflammation and/or elevated intracellular iron can trigger hepcidin production followed by its binding to ferroportin which is the only neuronal iron exporter, thereby subjecting it to lysosomal degradation. Subsequently raised neuronal iron levels can induce translation of the ferroportin assisting and copper binding amyloid precursor protein (APP); constitutive APP transmembrane passage lowers the copper pool which is important for many enzymes. Using in silico gene expression analyses, we here show significantly decreased expression of copper-dependent enzymes in AD brain and metallothioneins were upregulated in both diseases. Although few AD exposure risk factors are known, AD-related tauopathies can result from cyanobacterial microcystin and β-methylamino-L-alanine (BMAA) intake. Several environmental exposures may represent risk factors for PD; for this disease neurodegeneration is likely to involve mitochondrial dysfunction, microglial activation, and neuroinflammation. Administration of metal chelators and anti-inflammatory agents could affect disease outcomes.
authors.affiliation: Division of Environmental Medicine, Department of Chemicals and Radiation, The Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, 0403 Oslo, Norway.
authors.forename: Oddvar
authors.initials: O
authors.lastname: Myhre
authors.forename: Hans
authors.initials: H
authors.lastname: Utkilen
authors.forename: Nur
authors.initials: N
authors.lastname: Duale
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brunborg
authors.forename: Tim
authors.initials: T
authors.lastname: Hofer
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004781:Environmental Exposure; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008670:Metals / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008670:Metals