Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration

Abstract

Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

“…DPP-4 inhibitors increase GLP-1 ( Deacon, 2019 ), the natural GLP-1RA, which crosses the BBB. These antidiabetic drugs possibly ameliorate neurodegenerative disease in some patients ( Mehan et al, 2022 ), but a potential contribution of Klotho, to our knowledge, has not been examined.…”

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

“…Although the mechanisms underlying the neuroprotective effects of GLP-1 are not completely clear, the activation of GLP-1 receptor signaling is important for glucose homeostasis in the brain [ 70 ]. GLP-1 binds to the GLP-1 receptor in the brain and activates the PI3K/AKT pathway [ 71 , 72 ]. The activation of PI3K/AKT pathways prevents tau phosphorylation, synuclein aggregation, and amyloid β aggregation, which are important pathological changes in neurodegeneration.…”

“…The activation of PI3K/AKT pathways prevents tau phosphorylation, synuclein aggregation, and amyloid β aggregation, which are important pathological changes in neurodegeneration. Simultaneously, GLP-1 receptor signaling increases cellular levels of cAMP and then activates protein kinase A (PKA), resulting in the promotion of proliferation and differentiation of neuronal cells and synaptic plasticity [ 71 , 72 ].…”

Role of macrophage polarization in osteoarthritis (Review)

“…The GLP-1 analogue liraglutide is a human GLP-1 applied in the patients with diabetes ( 36 ). New data suggest that liraglutide inhibits ROS generation, pro-inflammatory cytokine secretion ( 37 ).…”