Role of liraglutide in Alzheimer’s disease pathology

Abstract

Background The described relationship between Alzheimer’s disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology. Main body Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve β cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer’s Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date. Conclusion The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients.

Glucagon-like Peptide-1 Receptor in the Human Hypothalamus Is Associated with Body Mass Index and Colocalizes with the Anorexigenic Neuropeptide Nucleobindin-2/Nesfatin-1

“…Although research has primarily focused on GLP-1R’s metabolic role, it is becoming increasingly obvious that GLP-1R activation has additional functions [ 2 ]. Experimental models and preclinical studies show beneficial effects of GLP-1R agonism on Alzheimer’s disease’s neuropathological features, including cholinergic basal forebrain nuclei degeneration and cognition [ 40 , 41 , 42 ]. Recent reports suggest that brain–gut peptides, including GLP-1 and nesfatin-1, share neuroprotective properties and might have therapeutic potential for neurodegenerative disorders [ 43 , 44 , 45 ].…”

A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro

“…We reasoned that an allosteric ligand acting on the Akt/PDK-1/mTORC2 interaction complex could normalize insulin sensitivity and restore the imbalance in Akt activity. Promising results from early clinical trials in MCI and mild AD of insulin sensitizers (metformin, [82]), GLP-1 receptor agonist/ incretin analogs (liraglutide, [83]), intranasal (IN) insulin [84,85] and insulin-sensitizing PPAR-γ agonists that target genes such as IRS-1, GLUT-4 and PI3K [86,87] (Rosiglitazone, [88]; Pioglitazone, [89]), support finding druggable targets in this pathway and several relevant ongoing trials: Metformin (phase 3, NCT04098666), liraglutide (phase2b, NCT 01843075, [90]) and semaglutide (phase 3, NCT 04777396). However, some phase 3 trials have not met their primary endpoints or been terminated for lack of efficacy, e.g.…”

Liraglutide attenuate central nervous inflammation and demyelination through AMPK and pyroptosis‐related NLRP3 pathway

“…In our study, GLP‐1R also decreased during the acute phase of EAE and unsignificantly restored by GLP‐1R activation. Lira is demonstrated to ameliorate neuroinflammation, improve memory function, and reduce amyloid‐β deposition and oxidative injury in Alzheimer's disease animal model, 53 , 54 , 55 and the mechanisms include but not limited to facilitating insulin signaling pathways, activating cAMP/PKA pathways, and PI3K/Akt pathways, thus restored GLP‐1R level might benefit to exert neuroprotective roles.…”