Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation.
Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.
Sheng
J G
JG
The Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA.
Jones
R A
RA
Zhou
X Q
XQ
McGinness
J M
JM
Van Eldik
L J
LJ
Mrak
R E
RE
Griffin
W S
WS
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000378:metabolism
D007375:Interleukin-1; D012333:RNA, Messenger; D016875:tau Proteins; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases