Induction of NADPH cytochrome P450 reductase by the Alzheimer beta-protein. Amyloid as a 'foreign body'

Citation
Ma. Pappolla et al., Induction of NADPH cytochrome P450 reductase by the Alzheimer beta-protein. Amyloid as a 'foreign body', J NEUROCHEM, 78(1), 2001, pp. 121-128
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
0022-3042 → ACNP
Volume
78
Issue
1
Year of publication
2001
Pages
121 - 128
Database
ISI
SICI code
0022-3042(200107)78:1<121:IONCPR>2.0.ZU;2-B
Abstract
A large body of data suggests that the Alzheimer's amyloid peptide (A beta) causes degeneration and death of neurons by mechanisms that involve reacti ve oxygen species. The pathways involved in A beta -mediated oxidative inju ry are only partially understood. We theorized that abnormal microaggregate s and/or pathological conformations of A beta peptides may behave as xenobi otics and trigger the induction of NADPH cytochrome P450 reductase (CP450r) , an enzyme which, if induced by non-physiological substrates (such as xeno biotics like drugs or other 'foreign molecules'), is known to cause oxidati ve stress. In order to test this hypothesis, i.e. that A beta can increase the expression of CP450r, SK-N-SH human neuroblastoma cells were exposed to A beta 25-35 and A beta1-42 and then examined for induction of this enzyme in immunoblots, using specific antibodies. Following exposure to A beta pe ptides, neuroblastoma cells showed a clear-cut induction of CP450r. To dete rmine whether this mechanism is operational in vivo, we investigated the ex pression of CP450r in a transgenic mouse model of Alzheimer's disease (AD) and in brains from patients afflicted with AD, using an immunocytochemical approach. Tissue sections from brains of transgenic mice exhibited strong i mmunoreactivity for CP450r, surrounding amyloid deposits. The pattern of ex pression of CP450r was similar to that exhibited by neuritic and oxidative stress markers. Sections from non-transgenic mice showed no detectable immu noreactivity. Immunostaining of sections from four brains with neuropatholo gically confirmed AD showed a pattern of abnormality different from transge nic mice that was characterized by abnormal immunoreactivity for CP450r wit hin the cytoplasm of cortical neurons. No labeling was seen in sections fro m aged-matched control brains. The data showed that CP450r is induced by Al zheimer amyloid peptide and that such a response must be considered as one possible mechanism whereby A beta causes oxidative stress.