C-terminal fragment of amyloid precursor protein induces astrocytosis

One of the pathophysiological features of Alzheimer's disease is astrocytos is around senile plaques. Reactive astrocytes may produce proinflammatory m ediators, nitric oxide, and subsequent reactive oxygen intermediates such a s peroxynitrites. In the present study, we investigated the possible role o f the C-terminal fragment of amyloid precursor protein (CT-APP), which is a nother constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinan t C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis mo rphologically 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 nitr ic oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whe reas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxi city and pretreatment with NO and peroxynitrite scavengers attenuated its t oxicity. These suggest that CT-APP may participate in Alzheimer's pathogene sis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.