PORTO, PORTUGAL — The hallmark amyloid accumulation in Alzheimer's disease may actually be the body's response to neuronal oxidative stress, according to data presented at the Fourth International Congress on Vascular Dementia.
Attempts to remove amyloid plaque may have the unintended effect of increasing neuronal oxidative damage, said Dr. Akihiko Nunomura of Asahikawa (Japan) Medical College.
Evaluation of immunoreactions in the hippocampal regions of the brains of patients with Alzheimer's disease (AD) has revealed an inverse relationship between amyloid-β 42—the protein believed to be responsible for the formation of amyloid plaques in the brain—and the nucleoside 8-hydroxyguanosine—a product of RNA oxidation that serves as a biomarker of neuronal oxidative stress, he said.
Dr. Nunomura and his colleagues evaluated postmortem tissue samples from the hippocampal region of 16 subjects (aged 65–93 years at time of death) previously diagnosed with AD using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria.
Optical density measurements were done on tissue samples that had been immunochemically stained for 8-hydroxyguanosine, amyloid-β 40, and amyloid-β 42.
Intraneuronal amyloid-β 42 and 8-hydroxyguanosine immunoreactions were observed in the hippocampal pyramidal neurons in all of the subjects. Neurons positive for 8-hydroxyguanosine were more widely distributed compared with those positive for amyloid-β 42. However, immunoreaction of intraneuronal amyloid-β 40 was faint in most of the subjects, compared with that of amyloid-β 42.
“When we focused on the relationship between intraneuronal 8-hydroxyguanosine and amyloid-β 42 immunoreactivities, we found several cases with high 8-hydroxyguanosine and low amyloid-β 42, as well as [several cases with] low 8-hydroxyguanosine and high amyloid-β 42,” said Dr. Nunomura.
Relative optical density measurements confirmed the inverse relationship between 8-hydroxyguanosine and amyloid-β 42 immunoreactivities but there was no significant relationship between 8-hydroxyguanosine and amyloid-β 40.
The inverse relationship between 8-hydroxyguanosine and amyloid-β42 suggests “that extra- and intraneuronal accumulation of amyloid-β 42 is related to a compensatory response to neuronal oxidative stress in AD,” said Dr. Nunomura.
While the mechanism at work is unclear, the researchers hypothesize that amyloid-β 42 accumulates as a response to oxidative stress and that 8-hydroxyguanosine is also downregulated, coauthor George Perry, Ph.D., said in an interview. Dr. Perry is a professor of pathology and neurosciences and Case Western Reserve University in Cleveland.
The researchers previously reported an inverse relationship between percent area of amyloid-β 42 plaque burden and immunointensity of neuronal 8-hydroxyguanosine in subjects with Down syndrome. In addition, both intraneuronal amyloid-β accumulation and oxidative stress precede amyloid-β deposition both in patients with Down syndrome and in transgenic mice models of AD.
Taken together with previous data, these findings suggest that excessive removal of amyloid-β may lead to increased neuronal oxidative damage in AD, said Dr. Nunomura.
The researchers are now focusing on better understanding the mechanism behind the amyloid-β/8-hydroxyguanosine relationship, said Dr. Perry.
Faint intraneuronal A-β 42 immunoreactivity in the hippocampus is shown in an 82-year-old AD patient (left). Intense intraneuronal A-β 42 immunoreactivity in a 77-year-old patient with AD (right). Arrow indicates extraneuronal A-β deposition. Photos courtesy Dr. Akihiko Nunomura
