By Talia Ogliore, Office of the UH Mānoa Vice Chancellor for Research
A research team at the University of Hawai‘i at Mānoa’s John A. Burns School of Medicine has published new research that highlights the potential role of specific target receptors on nerve cells for β-amyloid toxicity in the earliest stages of Alzheimer’s disease.
A major indicator of Alzheimer’s disease is the accumulation in brain tissue of a small, toxic peptide, known as β-amyloid (Aβ), in the form of dense deposits referred to as plaques. However, the levels of Aβ have been found to rise sharply as much as 10 years before a person is diagnosed with the disease.
The University of Hawai‘i study focused on key target receptors found on certain nerve cells in brain, which appear to be particularly sensitive to Aβ. These target receptors, normally activated by the neurotransmitter acetylcholine, appear to render these nerve cells highly vulnerable to accumulating Aβ, ultimately triggering their death.
“This study is the first of its kind to use a very tightly defined nerve cell system to attempt to better understand the impact of sustained exposure of Aβ on the regulation of cellular and synaptic function,” said Robert Nichols, UH Mānoa Professor of Cell and Molecular Biology and the principal investigator for this study. The results were published in the April 19 edition of The Journal of Biological Chemistry.
The researchers introduced a DNA vector into model nerve cells to express the target acetylcholine receptors, then exposed these altered nerve cells to soluble solutions of Aβ for several days before testing them for molecular and structural changes.
“Our data show disturbed calcium homeostasis, coupled with mitochondrial dysfunction and loss of neuronal integrity on prolonged exposure to Aβ,” said Nichols. “The results suggest that the presence of the receptors sensitizes neurons to the toxic actions of soluble oligomeric Aβ, perhaps contributing to the cholinergic deficit in Alzheimer’s disease.”
“A next step to consider is: Can we intervene and block the cell death?” Nichols asked.
Nichols conducted this research with an all-Hawai‘i team including recent JABSOM doctoral graduate and lead author Komal Arora, JABSOM doctoral candidate Naghum Alfulaij, recent JABSOM doctoral graduate Jason Higa, and Associate Researcher Jun Panee.
In Hawai‘i, there are approximately 31,000 individuals over age 65 who have Alzheimer’s disease, according to the State Task Force on Alzheimer’s Disease and Related Dementias (ADRD). One in eight adults 65 and older will develop Alzheimer’s disease, with the risk doubling every five years. One in two people age 85 will develop Alzheimer’s disease. This age group is the fastest growing segment of Hawai‘i’s population.
Arora, K. Alfulaij, N., Higa, J.K., Panee, J. and Nichols, R.A. (2013) Impact of Sustained Exposure to β-amyloid on Calcium Homeostasis and Neuronal Integrity in Model Nerve Cell System Expressing α4β2 Nicotinic Acetylcholine Receptors. J. Biol. Chem. 288, 11175-11190
Pictured: Nerve cells are highly sensitized to the toxic action (oxidative damage) of beta amyloid when target receptors (nicotinic receptors) are present.