Incretin and insulin signaling as novel therapeutic targets for Alzheimer's and Parkinson's disease

Abstract

Despite an ever-growing prevalence and increasing economic burden of Alzheimer's disease (AD) and Parkinson's disease (PD), recent advances in drug development have only resulted in minimally effective treatment. In AD, along with amyloid and tau phosphorylation, there is an associated increase in inflammation/glial activation, a decrease in synaptic function, an increase in astrocyte activation, and a state of insulin resistance. In PD, along with α-synuclein accumulation, there is associated inflammation, synaptic dysfunction, dopaminergic neuronal loss, and some data to suggest insulin resistance. Therapeutic strategies for neurodegenerative disorders have commonly targeted individual pathological processes. An effective treatment might require either utilization of multiple drugs which target the individual pathological processes which underlie the neurodegenerative disease or the use of a single agent which could influence multiple pathological processes. Insulin and incretins are compounds with multiple effects on neurodegenerative processes. Preclinical studies have demonstrated that GLP-1 receptor agonists reduce neuroinflammation, reduce tau phosphorylation, reduce amyloid deposition, increase synaptic function, and improve memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. Currently, phase 2 and phase 3 trials are underway in AD and PD populations. Here, we provide a comprehensive review of the therapeutic potential of incretin mimetics and insulin in AD and PD.

Fig. 1. GLP-1 structure and cerebral cell signaling.

a shows structure of GLP-1 analogues exenatide, lixisenatide, liraglutide, albiglutide, semaglutide and dulaglutide. b displays downstream signaling pathways from GLP-1 activation. Abbreviations: Fc fragment crystallizable, GLP-1 glucagon-like peptide-1, IgG immunoglobulin G, AC adenylyl cyclase, ADP adenosine diphosphate, Akt murine thymoma viral oncogene homologue, B-Raf B-regulation of alpha-fetoprotein, cAMP cyclic adenosine monophosphate, ERK extracellular signal-regulated kinase, GEFs guanine-nucleotide-exchange factors, GLP-1 glucagon-like peptide-1, GLP-1R glucagon-like peptide-1 receptor, LTP long-term potentiation, MAPK mitogen-activated protein kinases, MEK MAPK kinase, PDK phosphatidylinosite dependent kinase, PI3K phosphatidylinositol- 4,5-bisphosphate 3-kinase, PKA protein kinase A, PKB protein kinase B, PKC protein kinase C, Rap1A Ras-related protein Rap-1A.

Fig. 2. Neuroprotective effects of GLP-1 and insulin signaling in the brain.

a shows downstream signaling pathways depicting the influence GLP-1 on Parkinson’s disease pathogenesis. b Insulin signaling in neurons. b demonstrates the action of insulin in the neuron and activation of downstream pathway. Abbreviations: Bcl-2 B cell lymphoma 2, BAD (Bcl-2) antagonist of death, Bcl-XL B cell lymphoma 2 extra-large, cAMP cyclic AMP, CREB cAMP response element-binding protein, FoxO1/O3 Forkhead box O1/O3, GLP-1 glucagon-like peptide-1, GSK-3B glycogen synthase 3 beta, LTP long-term potentiation, MAPK mitogen-associated protein kinase, mTOR mammalian target of rapamycin, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, PI3K phophoinositide 3-kinase, TNF tumor necrosis factor, Akt/PKB protein kinase B complex, CPD3B cyclic phosphodiesterase 3 beta, Grb2/SOS Growth factor receptor binding protein 2/son of sevenless protein, IRS insulin receptor substrates that get phosphorylated after activation, NRF1 nuclear respiratory factor-1, PGC-1α peroxisome proliferator-activated receptor γ coactivator 1-α, PDK phosphatidylinosite dependent kinase, PPAR peroxisome proliferator-activated receptor family, Raf regulation of alpha-fetoprotein, Ras rat sarcoma virus peptide, Shc Src homology collagen peptide.