C-terminal fragment of amyloid precursor protein induces astrocytosis.
One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.
Bach
J H
JH
Department of Anatomy, College of Medicine, BioGrand Inc., and MRC, Chung-Ang University, 221 Huksuk-dong, Dongjak-ku, Seoul 156-756, Korea.
Chae
H S
HS
Rah
J C
JC
Lee
M W
MW
Park
C H
CH
Choi
S H
SH
Choi
J K
JK
Lee
S H
SH
Kim
Y S
YS
Kim
K Y
KY
Lee
W B
WB
Suh
Y H
YH
Kim
S S
SS
D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004790:Enzyme Induction; D005911:Gliosis / Q000139:chemically induced*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D016328:NF-kappa B; D009498:Neurotoxins; D010446:Peptide Fragments; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases