The remarkable benefits of amylin protein as a treatment for Alzheimer’s disease
Alzheimer’s disease (AD) is known to be a multifactorial disease. [2] That is, several factors contribute to the pathogenic development of this disorder. However, amyloid beta (Aβ) accumulation in the brain is highlighted as critical in developing the disease. [2,3] Recent studies have shown that long before the onset of symptoms of the disease, the accumulation of the Aβ protein forms plaques between neurons which turn out to be very toxic to neurons. [2,3] In addition, it has been exposed that these plaques are responsible for progressive cognitive impairment. [1,2,3] The accumulation of Aβ induces neuronal cells to die. Aβ plaques constantly induce neuroinflammation, so it, in turn, causes injury to nerve cells affecting memory and other cognitive factors. [2,3]
Representation of the hallmarks of AD in the brain.
Countless studies have found a protein with Aβ like characteristics called amylin. [1,2,3,5] These two proteins generate soluble forms of oligomeric form intermediates, which have been found to have potent cytotoxicity. [2,6] This cytotoxicity affects cell membranes and organelles, inducing inflammatory responses, causing reactive oxygen species, and overloading the protein-splitting. [1,2] These two proteins are so similar that their oligomers can even interact with each other accumulating in the brain in the same way as Aβ alone. [1,2] Amylin accumulation in the brain of AD rat models has been found to contribute significantly to brain damage caused by the illness. [2,6]In addition to AD, amylin has been found in high concentrations in the brain of patients with dementia and type 2 diabetes(T2DM). [2]
Amylin receptors (AMY receptors) are expressed in critical central nervous system (CNS) cells, such as neurons, glial cells, and endothelial cells. [2,5] These cells play a fundamental role in the pathogenesis of the disease. In addition, AMY receptors contribute to the mediation of synaptic dysfunction, loss of neurons, activation of the local immune system of the brain, and activation of inflammatory response cascades, among others. [1,5,6] For this reason, scientists have seen these receptors as a unique opportunity to develop of therapies to combat AD. [1,2,5] Recent studies indicate that the development of antagonists (inhibitors) and agonists (controlled activation for therapeutic purposes) of AMY receptors achieving significant advances in AD patients and AD mice models such as (see APPENDIX FIGURE 2):[1,2,5]
• Reduction of endothelial cells degeneration
• Increase of Aβ clearance
• Decrease of neuronal inflammation
• Decrease microglia activation (cells of the local immune system of the brain) • Increased synaptic connection
• Decreased neuronal dystrophy
• Decreased apoptosis (cell death)
• Increased cognitive functions
• Weight loss
• Decreased in the formation of Aβ plaques
• Decreased cytotoxicity caused by the accumulation of both Aβ and amylin protein
• Capacity to cross the blood-brain barrier
• Decreases the induction of oxidative stress
AMY receptors are involved in long-term potentiation (LTP) neuronal activity.[2] LTP consists of the persistence of strengthening signal transmission between neurons.[2] This process is essential for neurons to maintain their synaptic connection constantly and vigorously for long periods. Several investigations have exposed that LTP is strongly affected by the cytotoxicity and accumulation of both Aβ and amylin protein. [1,2] On the other hand, investigators discovered the use of antagonists in AD models of mice, a partial improvement in cognitive response and LTP. [6] In addition, recent studies have revealed that using amylin protein analogs has been well implemented for treatments to combat obsessiveness and as a supplement for weight loss. [4] These amylin protein analogs are considered highly efficient and safe. [4] Several clinical studies show that combining amylin with the GLP-1 agonist has a greater impact on achieved more significant weight loss. [4] GLP-1 is a glucagon-like peptide agonist of type 1. An essential fact is that the GLP-1 peptide has already been well-researched and has indicated a good potential to be used as a treatment for AD as it improves learning and memory, reduces the accumulation of Aβ, and prevents the formation of tau tangles, which together with the aggregation of Aβ plaques are the main responsible for the progression of AD pathogenesis. [4]
Lastly, researchers from the University of Alberta developed two peptides due to the fragmentation of a novel amylin receptor called AC253.[1,6] The AC253 can decrease the cytotoxicity of Aβ. [1,6] In addition, AC253 prevents Aβ accumulation by blocking specific receptors related to this process. [1,6] However, the AC253 molecule is enormous, so the scientists chose to fragment the AC253 molecule into two peptides shortening its size. [1,6] The use of these peptides was a success since the studies have proven that when the two peptides are administered, they rejoin once they reach the brain forming AC253 again. [1,6] The research results revealed the ability of these peptides to improve the memory of mice used as AD models after being injected daily for five weeks. [1,6] In addition, peptides reduce the physical changes in the brain that are associated with AD disease. [1,6] All this research demonstrates the remarkable ability of the amylin protein as a potential therapy for AD. Amylin protein is critical for the development of new AD treatments.
References
Appendix
FIGURE 2: Targeting AMY receptors for AD treatment.
FIGURE 3: Shows the benefits of amylin in the human body.
