P3–369: Intraneuronal amyloid–β42 may silence oxidative stress in Alzheimer's disease

A growing body of evidence suggests an initial role of intraneuronal accumulation of amyloid–β (Aβ) in the pathological cascade of Alzheimer's disease (AD), but on the other hand, we have reported that oxidative stress is one of the earliest events in vulnerable neurons of AD. Indeed, both intraneuronal Aβ accumulation and oxidative stress precede extraneuronal deposition of Aβ plaque in patients with Down syndrome and in transgenic mice models of AD, which suggests a possible connection between the two events. To investigate the relationship between the levels of intraneuronal Aβ accumulation and oxidative damage to RNA in AD brains, the latter of which was previously shown to parallel oxidative damage to protein. Immunocytochemically, Aβ40, Aβ42 and the oxidized RNA nucleoside, 8–hydroxyguanosine (8OHG) were identified in postmortem tissue sections of the hippocampal region from 16 cases of AD (age 65–93 years). Intraneuronal Aβ42 and 8OHG immunoreactions were observed in the hippocampal pyramidal neurons in all the subjects, while 8OHG–positive neurons were more widely distributed compared with Aβ42–positive neurons. Intraneuronal Aβ40 immunoreaction was faint in most of the subjects. The QCB42 antibody (Biosource) showed the same pattern and level of Aβ42 immunoreaction in the neuronal cytoplasm that the MBC42 antibody (H.Y.) showed, while the former recognizes both monomeric and oligomeric Aβ42 species and the latter recognizes mainly monomeric Aβ42. However, the antibody specific to Aβ oligomers (provided by Dr. C. Glabe) hardly immunostained the neuronal cytoplasm, suggesting that the neuronal cytoplasmic Aβ42 observed in this study might be mainly monomeric. Relative density measurements revealed an inverse relationship between intraneuronal Aβ42 and 8OHG immunoreactivities (r = − 0.61, p < 0.02), while there was no significant relationship between intraneuronal Aβ40 and 8OHG immunoreactivities. Together with recent evidence that Aβ possibly acts as an antioxidant through its capability to capture redox metal ions, these results suggest that intraneuronal accumulation of Aβ42, especially the monomeric form, is related to a compensatory response to neuronal oxidative stress in AD. We suggest that excessive removal of Aβ may lead to increased, rather than decreased, neuronal oxidative damage in AD.