Accumulation of beta-amyloid in the brain microvessels accompanies increased hyperphosphorylated tau proteins following microsphere embolism in aged rats.
To define mechanisms underlying neurovascular injury following brain embolism-induced neurodegeneration, we investigated temporal and spatial pathological changes in brain microvessels up to 12 weeks after microsphere embolism (ME) induction in aged male rats. Mild ME upregulated endothelial nitric oxide synthase (eNOS) and protein tyrosine nitration in brain microvessels. Strong beta-amyloid immunoreactivity coincident with increased eNOS immunoreactivity was observed in microvessels. Immunoblotting of purified brain microvessels revealed that beta-amyloid accumulation significantly increased 1 week after ME induction and remained elevated for 12 weeks. Importantly, beta-amyloid accumulation in brain parenchyma was also observed in areas surrounding injured microvessels at 12 weeks. Levels of Alzheimer's-related hyperphosphorylated tau proteins also concomitantly increased in neurons surrounding regions of beta-amyloid accumulation 12 weeks after ME induction, as did glycogen synthase kinase (GSK3beta) (Tyr-216) phosphorylation. Taken together, ME-induced aberrant eNOS expression and subsequent protein tyrosine nitration in microvessels preceded beta-amyloid accumulation both in microvessels and brain parenchyma, leading to hyperphosphorylation of neuronal tau proteins through GSK3beta activation.
Han
F
F
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
Ali Raie
A
A
Shioda
N
N
Qin
Z-H
ZH
Fukunaga
K
K
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology*; D002196:Capillaries / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D004617:Embolism / Q000378:metabolism*; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008863:Microspheres; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D030421:Peroxynitrous Acid / Q000378:metabolism; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D030421:Peroxynitrous Acid; D011064:Poly Adenosine Diphosphate Ribose; D052250:Nitric Oxide Synthase Type III; D038362:Glycogen Synthase Kinase 3