Glucagon-Like Peptide-1 Cleavage Product GLP-1(9-36) Amide Rescues Synaptic Plasticity and Memory Deficits in Alzheimer's Disease Model Mice

Ma, Tao; Du, Xing; Pick, Joseph; Sui, Guangzhi; Brownlee, Michael; Klann, Eric

doi:10.1523/jneurosci.2107-12.2012

Cited by 94 publications

(83 citation statements)

References 45 publications

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“…In the pancreatic islets, the GLP-1 receptor is internalized after GLP-1-induced activation (20)(21)(22)(23) and passes through recycling endosomes before it appears in the plasma membrane again (23). The GLP-1 receptor is widely distributed in the brain (10, 16,24), including in the hippocampal CA3 pyramidal neurons (16,25), and GLP-1 and other agonists at the GLP-1 receptor have been reported to regulate food intake (26), be neuroprotective (27), anti-inflammatory (28), and modulate synaptic plasticity and memory formation (28)(29)(30)(31)(32).…”

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confidence: 99%

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

et al. 2014

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Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on g-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01-1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01-1 nmol/L GLP-1 and by 0.5-100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABA A signaling by pre-and postsynaptic mechanisms.In recent years, compelling evidence has emerged suggesting that diabetes mellitus increases the risk for cognitive impairments in the elderly (1-8). How this comes about is not resolved, but interestingly, the brain contains receptors for many metabolic hormones, among those receptors for insulin and the incretins. To date, with the exception of the hypothalamus, we know relatively little about how metabolic hormones affect neuronal activity and thereby brain function. The hippocampus is central for cognitive functions and is the center for memory and learning (9,10). It has prominent expression for receptors activated by metabolic hormones (10). Furthermore, via neurons in the septum, the hippocampus regulates the activity of a number of hypothalamic nuclei (11,12). Glucagon-like peptide-1 (GLP-1) is a gut hormone that is secreted by intestinal L cells in response to food intake, and the GLP-1 receptor is expressed in the hippocampus (10,13). GLP-1 crosses the blood-brain barrier, but it is also a neurotransmitter produced by neurons with cell bodies in the brainstem (12-15). The best known effects of GLP-1 are to stimulate insulin and inhibit glucagon secretion in a glucose-dependent manner in the pancreatic islets to regulate glucose homeostasis after a meal (13). Although the GLP-1 receptor is expressed in the hippocampus (10,16,17) and GLP-1 and its mimetics, e.g., exendin-4, liraglutide, might potentially be used to treat cognitive declines related to diabetes (6,7), to date not much is known about the effects of GLP-1 on neuronal signaling and, hence, how GLP-1 affects cognition and hippocampal regulation of metabolic homeostasis.

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confidence: 99%

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

et al. 2014

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“…Neuronal cell line studies and AD rodent models showed that GLP‐1 and GIP ameliorated oxidative stress‐induced injury76, 80, 85, 86, and protected against cell death induced by Aβ42, 88. Furthermore, various studies reported that D‐Ala 2 GIP reduced the inflammatory response in rodent AD models81, 83, 85.…”

Section: Type 2 Diabetes Mellitus Dementia and Incretin‐based Therapiesmentioning

confidence: 99%

“…In rodent models of AD, peripherally‐administered geniposide and D‐Ala 2 GIP reduced levels of Aβ plaque load81, 83, 84, 85. However, two other studies reported no reduction of both APP and Aβ levels, despite the fact that treatment did have beneficial effects on memory or LTP82, 86. Peripherally‐administered liraglutide reduced both Aβ and APP levels72, even in a late‐stage AD rodent model75.…”

Section: Type 2 Diabetes Mellitus Dementia and Incretin‐based Therapiesmentioning

confidence: 99%

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

Groeneveld

Kappelle

Biessels

2015

J of Diabetes Invest

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Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin‐based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin‐based therapies are currently available: the glucagon‐like‐peptide‐1 agonists and the dipeptidyl peptidase‐4 ‐inhibitors. Independent of their glucose‐lowering effects, incretin‐based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin‐based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin‐based therapies on cognition, synaptic plasticity and metabolism of amyloid‐β and microtubule‐associated protein tau. Preclinical studies on incretin‐based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin‐based therapies at improving the outcome of Alzheimer's disease and stroke through glucose‐independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact.

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“…When GLP-1 binds to GLP-1r it stimulates B cell proliferation, it inhibits apoptosis, favors glucose mediated insulin secretion, achieving glucose homeostasis, lowering food intake. Other functions of GLP-1 include the reduction in glucagon secretion, the inhibition of gastrointestinal motility, the inhibition of hepatic glucose production and release, inhibition of overall gluconeogenesis and glucogenolysis, acting at hypothalamic level to reduce appetite and increasing sensitivity to insulin, among others [10].…”

Section: Glp-1mentioning

confidence: 99%

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

Kunz-Martinez¹

2017

EMIJ

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Glucagon-Like Peptide-1 Cleavage Product GLP-1(9-36) Amide Rescues Synaptic Plasticity and Memory Deficits in Alzheimer's Disease Model Mice

Cited by 94 publications

References 45 publications

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

GLP-1 and Exendin-4 Transiently Enhance GABAA Receptor–Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

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