Barrow Neurological Institute Scientists Awarded NIA Grant to Illuminate Therapeutic Strategies in Alzheimer’s Disease

Drs. Andrew A. George and Ronald J. Lukas of the Barrow Neurological Institute have been awarded a National Institutes on Aging grant to investigate sites and mechanisms of oligomeric amyloid-β action at a unique α7β2-nicotinic acetylcholine receptor (α7β2-nAChR) subtype. Oligomeric amyloid-β is a suspected etiopathogenic agent in Alzheimer’s disease. Members of the nAChR family play a wide range of important roles in the brain, naturally responding to the chemical neurotransmitter, acetylcholine. They also are defined as “nicotinic” because they mediate responses to exogenously-delivered nicotine, typically from use of tobacco products. Basal forebrain cholinergic neurons, which naturally and uniquely express α7β2-nAChR, are part of the brain system critical to learning and memory, and are among the first to degenerate in Alzheimer’s disease. The demise of these neurons is thought to contribute to the decline in cognitive function characteristic of Alzheimer’s disease.

The National Institutes of Health award is based on a research report now in press at The Journal of Neuroscience and entitled “Implications of oligomeric amyloid-beta signaling through α7β2-nicotinic acetylcholine receptors on basal forebrain cholinergic neuronal intrinsic excitability and cognitive decline” by Andrew A. George, Jaime Vieira, Cameron Xavier-Jackson, Michael Gee, John Cirrito, Heather Bimonte-Nelson, Marina Picciotto, Ronald J. Lukas, and Paul Whiteaker.

Dr. George et al. report that sub region-specific, mouse basal forebrain cholinergic neurons exposed to oligomeric amyloid-β become electrically hyperexcitable and functionally unstable, ultimately leading to their death. This neuronal hyperexcitation is prevented in the presence of pharmacological agents that block the interaction between oligomeric amyloid-β and α7β2-nAChR. Oligomeric amyloid-β-induced basal forebrain cholinergic excitotoxicity does not occur if these neurons genetically lack the β2 nAChR subunit, a key building block necessary for the proper function of α7β2-nAChR. Furthermore, and importantly, Dr. George et al. have shown that oligomeric amyloid-β exposure activates function of the analogous, human α7β2-nAChR. This work supports the hypothesis that interactions of oligomeric amyloid-β with the unique α7β2-nAChR subtype in humans similarly causes abnormal activation and demise of basal forebrain cholinergic neurons.

One goal of the new study is define molecular domains of human α7β2-nAChR that interact with oligomeric amyloid-β but that are not involved in natural interactions with acetylcholine. A related goal is to identify new pharmacological tools that interact with those domains to block harmful effects of oligomeric amyloid-β exposure without altering physiological responses to acetylcholine.
Superior imaging and biomarker tools are being developed and used to identify individuals in early stages of Alzheimer’s disease or with higher risk for the condition. Especially by focusing on these individuals well before their disease process progresses too far, findings from the George-Lukas project could illuminate therapeutic strategies leveraging nicotinic drugs with already proven safety to abrogate earliest stages in the development of Alzheimer’s disease and its devastating memory compromise.

Posted in AZBio News.