Neuroprotection by dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide-1 analogs via the modulation of AKT-signaling pathway in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common reason for progressive dementia in the elderly. It has been shown that disorders of the mammalian/mechanistic target of rapamycin (mTOR) signaling pathways are related to the AD. On the other hand, diabetes mellitus (DM) is a risk factor for the cognitive dysfunction. The pathogenesis of the neuronal impairment caused by diabetic hyperglycemia is intricate, which contains neuro-inflammation and/or neurodegeneration and dementia. Glucagon-like peptide-1 (GLP1) is interesting as a possible link between metabolism and brain impairment. Modulation of GLP1 activity can influence amyloid-beta peptide aggregation via the phosphoinositide-3 kinase/AKT/mTOR signaling pathway in AD. The GLP1 receptor agonists have been shown to have favorable actions on the brain such as the improvement of neurological deficit. They might also exert a beneficial effect with refining learning and memory on the cognitive impairment induced by diabetes. Recent experimental and clinical evidence indicates that dipeptidyl-peptidase-4 (DPP4) inhibitors, being currently used for DM therapy, may also be effective for AD treatment. The DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models. Although further studies for mTOR, GLP1, and DPP4 signaling pathways in humans would be intensively required, they seem to be a promising approach for innovative AD-treatments. We would like to review the characteristics of AD pathogenesis, the key roles of mTOR in AD and the preventive and/ or therapeutic suggestions of directing the mTOR signaling pathway.

In silico approach of 2,5-Diketopiperazines from marine organisms to neurodegenerative diseases

“…These enzymes are responsible for the regulation of dopamine (MAO-A/B) as well as the formation of the amyloid peptide (β/γ-Secretease) and prostaglandin E2 (COX-1/2), giving a multifaceted regimen according to the effect levels and selectivity of the protein inhibition, denoting the potential of DKPs derivatives against neurodegenerative diseases. [ 53,54] The results of molecular docking with the selected enzymes (Table 2) demonstrate the aforementioned latent potential of the DKPs, in purple the better than reference inhibitors and in green better than the endogenous substrates, observing multitarget inhibition by the DKPs, particularly DKP4, DKP23 and DKP25 have the potential to inhibit all the enzymes under study, proposing an increase in dopamine levels and a decrease in β-amyloids and PGG2, proposing a decrease in the progression of neurodegenerative diseases. DKP8 and DKP11 inhibit the secretase and COX pathways selectively.…”

The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer’s diseases

“…In addition, endogenous GLP-1 levels decrease Aβ peptide and tau phosphorylation in the AD rat models [ 151 ]. Furthermore, GLP1 receptor agonists have also been shown as possessing neuroprotective effects in AD, which seem to improve nearly all neuropathological features as well as cognitive functions of AD [ 152 ]. For example, NFTs, amyloid plaques, and neuro-inflammations in the hippocampus have been reduced in AD model mice [ 153 ].…”

Neuroprotective Properties of Peptides

“…Neurofibrillary tangles, which are shaped by hyperphosphorylated tau protein and can build up into oligomers and/or Aβ plaques, are one of the neuro-pathological characteristics of AD. Aβ buildup in AD has the potential to damage synapses and cause neuroinflammation by triggering astroglia and microglia cells [4,52,53].…”