GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight

Abstract

Defects in brain energy metabolism and proteopathic stress are implicated in age-related degenerative neuronopathies, exemplified by Alzheimer’s disease (AD) and Parkinson’s disease (PD). As the currently available drug regimens largely aim to mitigate cognitive decline and/or motor symptoms, there is a dire need for mechanism-based therapies that can be used to improve neuronal function and potentially slow down the underlying disease processes. In this context, a new class of pharmacological agents that achieve improved glycaemic control via the glucagon-like peptide 1 (GLP-1) receptor has attracted significant attention as putative neuroprotective agents. The experimental evidence supporting their potential therapeutic value, mainly derived from cellular and animal models of AD and PD, has been discussed in several research reports and review opinions recently. In this review article, we discuss the pathological relevance of derangements in the neurovascular unit and the significance of neuron–glia metabolic coupling in AD and PD. With this context, we also discuss some unresolved questions with regard to the potential benefits of GLP-1 agonists on the neurovascular unit (NVU), and provide examples of novel experimental paradigms that could be useful in improving our understanding regarding the neuroprotective mode of action associated with these agents.

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“…In addition, GLP-1RA has been shown, in animal studies, to improve cognitive function, reduce cerebral accumulation of amyloid-b peptide in Alzheimer’s disease, influence dopamine levels in Parkinson’s disease and demonstrated beneficial effects on brain ischaemia. Therefore, there is the potential of these agents to maintain neuronal integrity and improve neurodegenerative diseases in humans [ 154 ]. The effect of these new therapies on skeletal muscles and muscle function needs future investigation.…”

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“…Treatment of Liraglutide in a T-cell driven adoptive transfer colitis mouse model upregulated expression of IL-33, mucin 5b, and CCL20 in murine Brunner’s glands and improved colitis ( Bang-Berthelsen et al, 2016 ). GLP-1RAs have shown promising efficacies in cellular and animal neurodegenerative models including Alzheimer’s disease and Parkinson’s disease (reviewed in Monti et al, 2022 ). Retrospective analysis of pooled clinical trials of GLP-1RAs in T2D patients for 3.6 years, including LEADER, SUSTAIN 6 and PIONEER 6, indicated that the incidence of dementia in T2D patients treated with Liraglutide or Semaglutide was 53% less than patients on placebo ( Norgaard et al, 2022 ).…”

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“…In T2DM, the GLP-1 receptor (GLP-1R) is responsible for the genes’ regulatory elements involved in neuronal survival and function. As GLP-1 agonists, they are used as targets in neurological disorders [ 10 ]. Some studies have shown that GLP-R is activated via the cAMP (cellular levels of cyclic AMP)/PKA (Protein Kinase A) pathways and is involved in neuroprotective action.…”