APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer's disease.
Up-regulated expression of amyloid precursor protein (APP) occurs early in the cascade of events that leads to amyloid plaque formation in the human brain. APP gene up-regulation, mediated by activated NF-kappaB, is a response to stress from nM concentrations of aluminum ions, aluminum-disregulated iron ions, reactive-oxygen species, cytokines, and physical trauma. We examined in vivo effects of aluminum on APP in aged rats, obtained from previously-reported longitudinal studies, that chronically ingested aluminum in amounts equivalent to total dietary aluminum levels that Americans routinely ingest. These rats exhibited two outcomes: one group remained cognitively-intact, scoring as well on a memory-discrimination task in old age as in middle age. The other developed cognitive deterioration, obtaining significantly lower mean performance scores in old age than in middle age and exhibiting abnormal behaviors associated with dementia. We compared the expression, distribution and accumulation of APP in hippocampal and cortical tissue of these two rat groups. Compared to results from cognitively-intact rats, hippocampal and cortical tissue from the cognitively-deteriorated rats showed elevated APP gene expression, significantly more dense APP deposits in cytoplasm of neural cells, and APP-immunoreactive neurites that were swollen and varicose. This study shows aluminum routinely derived from chronic oral ingestion, that gradually accumulates in brain regions important for memory-processing, is sufficient to increase APP levels in neural cells of those regions. Aluminum may thus launch the cascade that results in the formation of amyloid plaques in human brain.
Walton
J R
JR
Australian Institute for Biomedical Research, Sydney NSW, Australia. j.walton@unsw.edu.au
Wang
M-X
MX
D000284:Administration, Oral; D000535:Aluminum / Q000633:toxicity*; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008137:Longitudinal Studies; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D000535:Aluminum