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 r...

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Published in:Journal of neurochemistry 2001-07, Vol.78 (1), p.109-120
Main Authors: Bach, Jae‐Hyung, Chae, Hee Sun, Rah, Jong Choel, Lee, Myoung Woo, Park, Cheol Hyoung, Choi, Se Hoon, Choi, Jeong Kyu, Lee, Sang Hyung, Kim, Yong Sik, Kim, Kyung Yong, Lee, Won Bok, Suh, Yoo‐Hun, Kim, Sung Su
Format: Article
Language:English
Subjects:
amyloid
Amyloid beta-Protein Precursor - pharmacology
Animals
astrocyte
Astrocytes - drug effects
Astrocytes - metabolism
astrocytosis
Biological and medical sciences
Cells, Cultured
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Enzyme Induction
Gliosis - chemically induced
Humans
Medical sciences
Mitogen-Activated Protein Kinases - physiology
mitogen‐actovated protein kinase
Neurology
Neurotoxins - pharmacology
NF-kappa B - physiology
NF‐κB
nitric oxide
Nitric Oxide - metabolism
Nitric Oxide Synthase - metabolism
Nitric Oxide Synthase Type II
Peptide Fragments - pharmacology
Rats
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Summary: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‐κB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor‐kappa B (NF‐κB) activation. But inhibitors of NF‐κB 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‐κB‐dependent astrocytosis and iNOS induction.
ISSN:0022-3042
1471-4159
DOI:10.1046/j.1471-4159.2001.00370.x