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Drug developed for diabetes could treat Alzheimer's
"With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer's. It's imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer's and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to people who need them. Although the benefits of these 'triple agonist' drugs have so far only been found in mice, other studies with existing diabetes drugs (liraglutide) have shown real promise with Alzheimer's, so further development is crucial."
This is the first time a triple receptor drug has been tested against brain degeneration. The drug combinines three growth factors: GLP-1, GIP and Glucagon to amplify its affect. Growth factor signalling is known to be impaired in Alzheimer's patients.
Mice used in the study are transgenic as they were grown infused with human genes mutated to cause Alzheimer's. These genes are found in people with an inherited form of Alzheimer's. The mice receiving the drug were advanced in age, with advanced neurodegeneration.
Tests showed these mice improved in:
Type 2 diabetes is a known risk factor for Alzheimer's as impaired insulin has been linked to cerebral degenerative processes. Insulin desensitisation has also been observed in diseased Alzheimer's brains. Insulin is normally a growth factor with neuroprotective properties until diabetes, specifically, impairs its affect. Glucagon, by stimulating the liver to release glucose through glycogenolysis and gluconeogenesis, has the opposite effect of insulin. The secretion of insulin and glucagon into the blood in response to blood glucose concentrations is the primary mechanism of glucose homeostasis.
Professor Holscher: "These very promising outcomes demonstrate the efficacy of these novel multiple receptor drugs that originally were developed to treat type 2 diabetes, but, have shown consistent neuro- protective effects in several studies. Clinical studies with an older version of this drug type already showed very promising results in people with Alzheimer's disease or with mood disorders. Here we show that a novel triple receptor drug shows promise as a potential treatment for Alzheimer's but further dose-response tests and direct comparisons with other drugs have to be conducted in order to evaluate if this new drug is superior to previous ones."
• A novel triple GLP-1/GIP/glucagon receptor agonist has been developed.
• The drug improves memory formation in a mouse model of Alzheimer’s disease.
• Amyloid plaque load, inflammation and oxidative stress is reduced by the drug.
• Neurogenesis, BDNF expression and synapse numbers are increased in the brain.
Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10?nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of ?-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD.
Authors: Jingjing Tai, Weizhen Liu, Yanwei Li, Lin Lia, Christian Hölscher.
This research was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of General Medical Sciences, the Wellcome Trust Sanger Institute, a research fund from University of Maryland Baltimore, a Shandong Provincial Education Association for International Exchanges visiting professorship, the Carnegie Institution for Science Endowment, and the G. Harold and Leila Y. Mathers Charitable Foundation.
The research was supported by the National Institutes of Health's (NIH) National Institute of Diabetes and Digestive and Kidney Diseases, the NIH's National Center for Advancing Translational Sciences and Massachusetts General Hospital's Clafin Distinguished Scholar Award.
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One in 3 people will develope Alzheimer's. And now, a drug developed for diabetes could treat Alzheimer's. Scientists found it 'significantly reversed memory loss' in mice through a triple method of actions combining three growth factors. This is the first time a triple receptor drug has been used that acts in multiple ways to protect the brain from degeneration. Image credit: Lancaster University