New research shows how GLP-1 receptor drugs, known for treating diabetes and obesity, also protect the brain’s vital neurovascular system, offering hope for tackling cognitive decline and neurodegenerative diseases such as Alzheimer’s.
Judgement: GLP-1 programs the neurovascular landscape. Image credits: Juan Gaertner / Shutterstock
In a recent review published in the journal Cell metabolisma group of authors investigated how Glucagon-Like Peptide-1 receptor (GLP-1R) agonism shapes the neurovascular unit (NVU), potentially linking improvements in metabolic health to better brain health.
Background
Overconsumption of readily available, nutrient-dense foods has created an environment of overnutrition, leading to health problems such as obesity and metabolic syndrome. Chronic low-grade inflammation, often associated with obesity, contributes to neurodegenerative diseases. GLP-1R agonists have emerged as effective tools for weight management by influencing appetite and addressing metabolic dysfunctions. GLP-1R agonism not only helps with weight management, but also appears to have neuroprotective effects, including reducing neuroinflammation and improving brain health. Further research is needed to clarify whether GLP-1R agonism affects brain health directly or through improved metabolic function.
The role of GLP-1 in metabolic regulation
GLP-1 is a hormone that is produced in both the intestines and the brain. It plays a key role in maintaining glucose homeostasis by increasing insulin secretion and decreasing glucagon levels after meals. This incretin hormone also slows stomach emptying, slowing glucose absorption and preventing sharp increases in insulin levels. In addition to its metabolic functions, GLP-1 is involved in regulating several behaviors, including feeding, fluid intake, and even motivated behaviors such as drug use. Importantly, GLP-1 receptors are found not only in neurons but also in glial cells, which mediate its effects on brain health by regulating energy balance and maintaining neural circuits.
GLP-1R agonists in the treatment of obesity
GLP-1R agonists, such as semaglutide, liraglutide, and tirzepatide, have gained prominence in the treatment of obesity. These drugs work by mimicking the action of endogenous GLP-1, but in supraphysiological doses, resulting in stronger and longer lasting effects on appetite suppression. While endogenous GLP-1 has a short half-life and limited ability to act on remote organs, exogenous GLP-1R agonists have proven highly effective in reducing food intake and promoting weight loss.
Obesity is a major risk factor for a range of chronic conditions, including type 2 diabetes and cardiovascular disease. Individuals with obesity often experience chronic, low-grade inflammation, which not only affects peripheral tissues but also has detrimental effects on brain health, linking obesity to neurodegenerative diseases.
Chronic inflammation, obesity and brain health
Chronic inflammation, a hallmark of obesity, is associated with an increased risk of developing neurological disorders, including cognitive decline and neurodegeneration. The inflammatory state extends to the brain and contributes to conditions such as Alzheimer’s disease (a neurodegenerative disorder characterized by progressive memory loss and cognitive decline). This inflammatory process involves the activation of microglia and astrocytes – glial cells that are crucial for immune responses in the brain. The neuroinflammatory processes observed in obesity are similar to those in neurodegenerative diseases, in which microglial activation, reactive astrogliosis and insulin resistance play a key role.
Neuroprotective effects of GLP-1R agonism
In addition to their role in weight management, GLP-1R agonists have shown neuroprotective and neurotrophic properties, offering potential benefits in reducing neuroinflammation. GLP-1R signaling in microglia helps reverse the polarization of these immune cells from a pro-inflammatory state to an anti-inflammatory state, thereby reducing neuroinflammation. GLP-1R agonism has been observed to reduce microglial activation, a key driver of neuroinflammation, and protect against neuronal damage. In addition, these agonists can improve brain insulin sensitivity, reduce oxidative stress, and promote neuron survival.
Recent studies suggest that GLP-1R agonists may affect the neurovascular unit (NVU), the critical interface where neurons, glial cells, and blood vessels work together to maintain brain function. The NVU plays a crucial role in ensuring proper blood flow to the brain, regulating nutrient supply and removing waste products. Dysfunction in the NVU is associated with both metabolic disorders and cognitive decline.
GLP-1 and the NCE
GLP-1 receptors are expressed on several cell types within the NVU, including neurons, astrocytes, microglia, and endothelial cells. Activation of these receptors by GLP-1R agonists has been shown to protect against microvascular damage, especially in models of diabetic retinopathy and stroke. Given the similarities between the vascular systems of the brain and the retina, these findings suggest that GLP-1R agonism could also protect the brain microvasculature, thereby maintaining the integrity of the blood-brain barrier and improving cerebral blood flow.
In models of high-fat diet-induced obesity, GLP-1R agonism has demonstrated the ability to enhance neurovascular coupling, thereby improving the relationship between neuronal activity and brain blood flow. This can counteract the neurovascular dysfunction caused by chronic overnutrition. These findings suggest that GLP-1R agonists may help counteract the adverse effects of overnutrition on brain health.
Implications for neurodegenerative diseases
The potential of GLP-1R agonism to protect the brain and improve cognitive function has sparked interest in its use as a therapeutic strategy for neurodegenerative diseases such as Alzheimer’s disease. Preclinical studies have shown that GLP-1R agonists can reduce the accumulation of amyloid plaques, a hallmark of Alzheimer’s disease, and improve synaptic function. Additionally, GLP-1R agonists have been observed to improve the health of endothelial cells in the brain, promoting vascular remodeling, which may further support cognitive function.
Furthermore, the ability of GLP-1R agonists to modulate NVU and reduce neuroinflammation suggests that they may slow the progression of neurodegenerative diseases. By improving the health of the brain’s vascular system and reducing inflammatory responses, GLP-1R agonists may help preserve cognitive function in individuals with metabolic disorders or neurodegenerative disorders.
Conclusions
In summary, the link between metabolic and cognitive health highlights the communication between brain and body, redefining some disorders as neurometabolic. Repurposing antidiabetic drugs such as GLP-1 mimetics for neurological diseases is gaining interest because metabolic disorders pose a significant risk for neurodegeneration. GLP-1 mimetics show promise due to their anti-inflammatory, neuroprotective, and neurotrophic properties. The expression of GLP-1R on various cell types and its impact on the neurovascular unit (NVU), including neurons, glial cells, and endothelial cells, make GLP-1 a strong candidate for bridging brain-body crosstalk.