Summary: Study reveals long term use of anticholinergic drugs, such as those used to treat allergies, can increase the risk of developing Alzheimer’s disease later in life.
Source: University of Western Ontario.
A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine – a target for anticholinergic drugs – results in dementia-like changes in the brain.
“There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia,” said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western’s Schulich School of Medicine & Dentistry. “So the question we asked is ‘why?'”
For this study, published in the journal Cerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer’s disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer’s-like pathology in mice.
“We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer’s pathology,” said Prado.
Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory. Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer’s disease.
“We demonstrated that in order to keep neurons healthy you need acetylcholine,” said Prado. “So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer’s disease.” Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.
The study, conducted at Western’s Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes. The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.
“When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well,” said Kolisnyk.
The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.
Funding: The researchers were supported by CIHR, Brain Canada and NSERC and the work was done in collaboration with researchers at the UCL Institute of Neurology, The Hebrew University of Jerusalem and McMaster University.
Source: Crystal Mackay – University of Western Ontario
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer’s-Like Pathology” by Benjamin Kolisnyk, Mohammed Al-Onaizi, Lilach Soreq, Shahar Barbash, Uriya Bekenstein, Nejc Haberman, Geula Hanin, Maxine T. Kish, Jussemara Souza da Silva, Margaret Fahnestock, Jernej Ule, Hermona Soreq, Vania F. Prado, and Marco A. M. Prado in Cerebral Cortex. Published online June 16 2016 doi:10.1093/cercor/bhw177
[cbtabs][cbtab title=”MLA”]University of Western Ontario. “Long Term Use of Anticholinergic Drugs Increases Alzheimer’s Risk.” NeuroscienceNews. NeuroscienceNews, 22 June 2016.
<https://neurosciencenews.com/alzheimers-brain-chemical-changes-4539/>.[/cbtab][cbtab title=”University of Western Ontario”]University of Western Ontario. (2016, June 22). Long Term Use of Anticholinergic Drugs Increases Alzheimer’s Risk. NeuroscienceNews. Retrieved June 22, 2016 from https://neurosciencenews.com/alzheimers-brain-chemical-changes-4539/[/cbtab][cbtab title=”Chicago”]University of Western Ontario. “Long Term Use of Anticholinergic Drugs Increases Alzheimer’s Risk.” https://neurosciencenews.com/alzheimers-brain-chemical-changes-4539/ (accessed June 22, 2016).[/cbtab][/cbtabs]
Abstract
Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer’s-Like Pathology
The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer’s disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aβ1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer’s-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.
“Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer’s-Like Pathology” by Benjamin Kolisnyk, Mohammed Al-Onaizi, Lilach Soreq, Shahar Barbash, Uriya Bekenstein, Nejc Haberman, Geula Hanin, Maxine T. Kish, Jussemara Souza da Silva, Margaret Fahnestock, Jernej Ule, Hermona Soreq, Vania F. Prado, and Marco A. M. Prado in Cerebral Cortex. Published online June 16 2016 doi:10.1093/cercor/bhw177
