Drugs like Wegovy and Ozempic (semaglutide) and Zepbound (tirzepatide) may offer benefits that go beyond weight loss in people with type 2 diabetes or obesity, suggests a recent review probing how they might also offer neuroprotective benefits.
Because obesity can cause chronic inflammation, including inflammation in the brain, it can also raise the risk of developing neurodegenerative diseases like Alzheimer’s disease.
The study examines how these GLP-1 medications reduce brain inflammation, and how they might be able to strengthen the blood-brain barrier.
It examines how GLP-1 drugs can balance the neurovascular unit – the part of the brain that regulates blood flow within the brain – thereby creating the possibility of improving cognitive functioning, reports Medical News Today.
How obesity affects cognitive function
Obesity can increase the risk for issues including heart disease, sleep apnoea and type 2 diabetes, as well as chronic low-grade inflammation – which affects the entire body, including the brain, and contributes to insulin resistance, fatigue and an aching body.
As far as the brain is concerned, chronic low-grade inflammation can also affect cognitive functioning.
Obesity and chronic low-grade inflammation are a “pathway” to developing Alzheimer’s disease. As scientists continue trying to find ways to prevent and slow the progression of neurodegenerative diseases, the category of GLP-1 drugs has become a major focus of research.
Researchers describe GLP-1 as a hormone naturally produced in the gut and the brain. Physicians treating people with either type 2 diabetes or obesity may offer GLP-1 receptor agonist drugs (GLP-1 drugs) to assist with weight loss.
These slow down gastric emptying, lowering blood sugar levels, and improving satiety. They also help improve metabolism, and with the weight loss resulting from the medication, there is generally improved heart health, and a lesser risk of developing cancer.
How GLP-1 drugs may protect the brain
More studies are revealing that GLP-1 drugs can also improve brain health.
Chronic low-grade inflammation can affect the brain by affecting glial cell functioning. Glial cells include:
• astrocytes, which perform neuroprotective tasks and form the blood-brain barrier
• microglia, which are immune cells that sustain the blood-brain barrier and remove damaged cells, but changes in which can lead to neurodegeneration.
The blood-brain barrier is especially important as it protects the brain from harmful substances and infection. Inflammation in obese people may result in reductions in their blood-brain barriers.
The review, published in Cell Metabolism, addresses how research shows that cell signalling from GLP-1 drugs may interact with these cells and provide brain health benefits.
The authors noted that a study in mouse models showed the GLP-1 drug liraglutide (Victoza) increased the number of astrocytes.
According to the review, “(GLP-1 receptor) signalling in astrocytes regulates both central and peripheral metabolism, extending from energy balance to neuroplasticity”.
This signalling also enhances neuron growth, and an increase in astrocytes also increases neuron survival.
Another study tested a GLP-1 medication on mice with glaucoma, and found a reduction in astrocyte transformation and retinal ganglion cell death.
With microglia, the review shows that some studies believe GLP-1 receptor signalling can reverse inflammation.
“GLP-1R signalling on microglia attenuates neuroinflammation by suppressing the polarisation of microglia to a pro-inflammatory state,” wrote the authors.
If inflammation in the brain could be reversed, this could be especially helpful in neurodegenerative diseases.
The review authors noted that further research is needed into the potential brain benefits of GLP-1 medications but they are optimistic about the future of these drugs in how they may boost brain health.
Is treating Alzheimer’s with semaglutide on the horizon?
David Hunter, MD, an associate professor of neurology at UTHealth Houston, not involved in this review, said decades of research into Alzheimer’s have shown that inflammation is a key step in disease pathology.
Various trials were testing to see how effectively GLP-1 drugs can help treat Alzheimer’s, and the drug “closest to FDA approval is semaglutide”.
Hunter expected that UTHealth’s own EVOKE trial would announce results on the use of semaglutide for Alzheimer’s early next year.
José Morales, MD, a vascular neurologist and neurointerventional surgeon at Providence Saint John’s Health Centre in California, also not involved in the review, told MNT that “microglia’s effect on the neurovascular unit has been associated with dementia”.
“(GLP-1 drugs) could potentially modulate inflammation to reduce the propensity for developing dementias like Alzheimer’s, particularly in the setting of metabolic syndrome.”
He added that in people with glycaemia or type 2 diabetes, inflammation of the blood-brain barrier could “lead to progressive damage to the brain over longer periods”.
He noted that trials combining neuroimaging techniques, which measure the blood-brain barrier and GLP-1 treatment, are needed and could prove these drugs have neuroprotective benefits.
Study details
GLP-1 programmes the neurovascular landscape
Bandy Chen, Xiaofei Yu, Claudia Horvath-Diano et al.
Published in Cell Metabolism on 1 October 2024
Summary
Readily available nutrient-rich foods exploit our inherent drive to over-consume, creating an environment of over-nutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.
Cell Metabolism article – GLP-1 programmes the neurovascular landscape (Open access)
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