Induction of NADPH cytochrome P450 reductase by the Alzheimer β‐protein. Amyloid as a ‘foreign body’

A large body of data suggests that the Alzheimer's amyloid peptide (Aβ) causes degeneration and death of neurons by mechanisms that involve reactive oxygen species. The pathways involved in Aβ‐mediated oxidative injury are only partially understood. We theorized that abnormal microaggregates and/or pathological conformations of Aβ peptides may behave as xenobiotics and trigger the induction of NADPH cytochrome P450 reductase (CP450r), an enzyme which, if induced by non‐physiological substrates (such as xenobiotics like drugs or other ‘foreign molecules’), is known to cause oxidative stress. In order to test this hypothesis, i.e. that Aβ can increase the expression of CP450r, SK‐N‐SH human neuroblastoma cells were exposed to Aβ25‐35 and Aβ1‐42 and then examined for induction of this enzyme in immunoblots, using specific antibodies. Following exposure to Aβ peptides, neuroblastoma cells showed a clear‐cut induction of CP450r. To determine whether this mechanism is operational in vivo , we investigated the expression 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 immunoreactivity for CP450r, surrounding amyloid deposits. The pattern of expression of CP450r was similar to that exhibited by neuritic and oxidative stress markers. Sections from non‐transgenic mice showed no detectable immunoreactivity. Immunostaining of sections from four brains with neuropathologically confirmed AD showed a pattern of abnormality different from transgenic mice that was characterized by abnormal immunoreactivity for CP450r within the cytoplasm of cortical neurons. No labeling was seen in sections from aged‐matched control brains. The data showed that CP450r is induced by Alzheimer amyloid peptide and that such a response must be considered as one possible mechanism whereby Aβ causes oxidative stress.