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.

Keywords: GLP-1 activators; dementia; insulin signaling; neurodegeneration.

Figure 1

Impaired insulin signaling/ secretion involved in the progression of dementia This schematic diagram depicts both normal and abnormal insulin signaling in the brain. Insulin activates signaling pathways such as AKT, PI3K, JNK, NF-KB, GLUT4 and GSK3. Synaptic plasticity and memory are both linked to the PI3K pathway. The PI3K pathway is linked to synaptic plasticity and memory. As a result, aberrant insulin binding can cause neuroinflammation by activating proinflammatory cytokines and lowering cognitive capacities via JNK and NF-KB. Long-term memory loss is caused by oxidative stress, mitochondrial dysfunction, and inflammation caused by GSK3 and its hyperphosphorylation. It also elevates the expression of caspase-3 and 9, which ultimately leads to neuronal cell death.

Figure 2

Insulin resistance in dementia is represented schematically by mitochondrial dysfunction, which leads to synaptic damage and neurodegeneration, glycosylated haemoglobin in intoxicated cognitive function due to failure in glucose transport for neurons, oxidative stress-induced amyloid beta and phosphorylated tau lineups via advanced glycation end products, inflammation caused by mitochondrial dysfunction and toxicities of amyloid-beta and glycation end products. Additionally, in both normal and impaired insulin signaling, Tau hyperphosphorylation was also observed, stimulates AKT, and inhibits tau hyperphosphorylation by inactivating GSK-3. Furthermore, the TOR pathway was also active for cellular growth and kept autophagy at a low level for cellular function. Black normal flow lines represent normal working mechanism; dotted red lines show inhibition of the pathway, and normal dark red flow lines show the overall cause of dementia.