An aluminum-based rat model for Alzheimer's disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration.
In Alzheimer's disease (AD), oxidative damage leads to the formation of amyloid plaques while low PP2A activity results in hyperphosphorylated tau that polymerizes to form neurofibrillary tangles. We probed these early events, using brain tissue from a rat model for AD that develops memory deterioration and AD-like behaviors in old age after chronically ingesting 1.6 mg aluminum/kg bodyweight/day, equivalent to the high end of the human dietary aluminum range. A control group consumed 0.4 mg aluminum/kg/day. We stained brain sections from the cognitively-damaged rats for evidence of amyloid plaques, neurofibrillary tangles, aluminum, oxidative damage, and hyperphosphorylated tau. PP2A activity levels measured 238.71+/-17.56 pmol P(i)/microg protein and 580.67+/-111.70 pmol P(i)/microg protein (p<0.05) in neocortical/limbic homogenates prepared from cognitively-damaged and control rat brains, respectively. Thus, PP2A activity in cognitively-damaged brains was 41% of control value. Staining results showed: (1) aluminum-loading occurs in some aged rat neurons as in some aged human neurons; (2) aluminum-loading in rat neurons is accompanied by oxidative damage, hyperphosphorylated tau, neuropil threads, and granulovacuolar degeneration; and (3) amyloid plaques and neurofibrillary tangles were absent from all rat brain sections examined. Known species difference can reasonably explain why plaques and tangles are unable to form in brains of genetically-normal rats despite developing the same pathological changes that lead to their formation in human brain. As neuronal aluminum can account for early stages of plaque and tangle formation in an animal model for AD, neuronal aluminum could also initiate plaque and tangle formation in humans with AD.
Australian Institute for Biomedical Research, Sydney, NSW, Australia. j.walton@unsw.edu.au
J R
JR
Walton
D000535:Aluminum / Q000633:toxicity*; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D016874:Neurofibrillary Tangles; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D014617:Vacuoles / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D000535:Aluminum; D010749:Phosphoprotein Phosphatases