Caveolae with GLP-1 and NMDA Receptors as Crossfire Points for the Innovative Treatment of Cognitive Dysfunction Associated with Neurodegenerative Diseases

Abstract

Some neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that encompasses memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative diseases that are characterized by deficits of cognition and alterations of behavior. Despite the huge efforts against Alzheimer's disease, there has yet been no successful treatment for this disease. Interestingly, several possible risk genes for cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes, and/or caveolae formation, suggesting that caveolae may be a therapeutic target for cognitive dysfunctions. Interestingly, the modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptor signaling may offer a novel approach to preventing and alleviating cognitive dysfunction. A paradigm showing that both GLP-1 and NMDA receptors at caveolae sites may be promising and crucial targets for the treatment of cognitive dysfunctions has been presented here, which may also be able to modify the progression of Alzheimer's disease. This research direction may create the potential to move clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.

Keywords: Alzheimer’s disease; NMDA; autophagy; caveolae; caveolin; cognitive dysfunction; glucagon-like peptide-1; mitophagy.

Figure 1

An illustrative representation of caveolae associated with caveolin proteins. Caveolae may be a kind of platform for various signaling molecules including GLP-1 and NMDA receptors as well as even for the development of certain exosomes, which may be interrelated to the scaffold domain of caveolins. Note that some critical pathways for the development of various disease-related signaling have been omitted for clarity. Abbreviation: GLP-1, glucagon-like peptide-1; NMDA, N-methyl-d-aspartate.

Figure 2

Several modulator molecules linked to the signaling of GLP-1 receptor within the PI3K/AKT/mTOR pathway are demonstrated. Example molecules known to act on an AMPK/mTOR pathway are also shown. The activation of GLP-1 receptor results in the stimulation of adenylyl cyclase (AC) that transforms adenosine triphosphate (ATP) into 3-5-cyclic adenosine monophosphate (cAMP), which then activates the cAMP-dependent protein kinase (PKA) as well as the following AMPK for the modification of autophagy/mitophagy. Some example factors including fasting, starvation, and/or metformin known to act on the autophagy/mitophagy signaling are also shown. Note that some critical pathways such as that for insulin induction have been omitted for clarity. Arrowhead means stimulation whereas hammerhead represents inhibition. Abbreviation: GLP-1, glucagon-like peptide-1; AMPK, adenosine monophosphate-activated protein kinase; mTOR, mammalian/mechanistic target of rapamycin; PI3K, phosphoinositide-3 kinase; PKA, protein kinase A; PTEN, phosphatase and tensin homologue deleted on chromosome 10.

Figure 3

Schematic depiction of NMDA receptor signaling pathway along with a GTP-binding protein-coupled receptor (GPCR) signaling pathway for autophagy/mitophagy. NMDA receptors may require the binding of several amino acid molecules of glycine, glutamate, and/or aspartate, which could modulate the receptor function. For example, glutamate is in the glutamate-binding site and glycine is in the glycine-binding site within the NMDA receptor subunit. The stimulation of NMDA receptors may allow Ca²⁺ entry into the cytoplasm of neurons, which may contribute to long-term potentiation (LTP) or long-term depression (LTD) as well as to a phase of excito-toxicity and/or apoptosis. Stimulatory effects are indicated with arrows.

Figure 4

The plausible tactics for neuroprotection and/or against cognitive impairment have been shown. The ideal approach might be to utilize agonists of GLP-1 receptors and/or antagonists of NMDA receptors to halt the neuron-damaging process for neuroprotection. Note that several important activities such as inflammatory reaction, autophagy initiation, and reactive oxygen species (ROS) production have been omitted for clarity. Stimulatory effects are indicated with arrows; inhibitory effects with a line ending in a hammerhead. Broken lines indicate possible mechanism of action. “?” means author speculation.