APLP1, Alzheimer's-like pathology and neurodegeneration in the frontal cortex of manganese-exposed non-human primates.
Chronic manganese (Mn) exposure produces a neurological syndrome with psychiatric, cognitive and parkinsonian features. Gene expression studies in the frontal cortex of Cynomolgus macaques exposed to different doses of Mn showed gene expression changes associated with cell cycle regulation, DNA repair, apoptosis, ubiquitin-proteasome system, protein folding, cholesterol homeostasis, axonal/vesicular transport and inflammation. Amyloid-beta (A-beta) precursor-like protein 1 (APLP1), a member of the amyloid precursor family, was the most highly up-regulated gene. Immunohistochemistry confirmed increased APLP1 expression and revealed the presence of A-beta diffuse plaques. Cortical neurons and white matter fibers from Mn-exposed animals exhibited accumulation of silver grains indicative of on-going degeneration. Cortical neurons also expressed nuclear hypertrophy, intracytoplasmic vacuoles, and apoptotis stigmata. The levels of p53 were increased in neurons and glial cells in Mn-exposed tissue. Analysis of another amyloidogenic protein, alpha-synuclein, also exhibited aggregation in the gray and white matter from Mn-exposed animals. In summary, chronic Mn exposure in non-human primates produces a cellular stress response leading to neurodegenerative changes, diffuse A-beta plaques and alpha-synuclein aggregation in the frontal cortex. These changes may help explain the cognitive and working memory deficits expressed by these animals.
Guilarte
Tomás R
TR
Neurotoxicology & Molecular Imaging Laboratory, Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, 615 N. Wolfe St. Rm E6622, Baltimore, MD 21205, USA. tguilart@jhsph.edu
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008252:Macaca fascicularis; D008345:Manganese / Q000633:toxicity*; D020149:Manganese Poisoning / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016622:Silver Staining / Q000379:methods
D016564:Amyloid beta-Protein Precursor; D008345:Manganese