Peptides Derived from Growth Factors to Treat Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood-brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

Keywords: MAPK; PI3K/AKT; amyloid-β peptide; bone morphogenetic proteins; cholinergic neurons; metabolic pathway; neurotrophin; tau protein.

Figure 1

Structure of (A) mNGF (PDB ID: 1 BET) monomer [60]. The exposed β-turn loops L1 (residues 28-36), L2 (residues 42-49), L3 (residues 59-67) and L4 (residues 91-99) were used to design peptides. (B) The mNGF dimer (red and blue)-TrkA extracellular domain (black) binding sites (PDB ID: 2IFG [61]) [58,62].

Figure 2

The NGF and BDNF signaling pathways and their roles in healthy and AD brains [70,71,72,73,74,75]. CAM: calmodulin kinase; DAG: diacylglycerol; mBDNF: mature form of BDNF (monomer); mNGF: mature form of NGF (monomer); RSK: ribosomal S6 kinase; TRAF: TNFR-associated factors. The figure was created using Servier Medical Art (https://smart.servier.com; 30 April 2021).

Figure 3

FGF-2 and BMP-9 signaling pathways and their roles in healthy and AD brains [106,185,188,189,190,191,192]. GAB1: Grb2-associated binder-1; SOS: salt overly sensitive; TAB1/2/3: TAK1 binding protein 1/2/3; TAK: transforming growth factor β-activated kinase 1; XIAP: X-linked inhibitor of apoptosis. The figure was created using Servier Medical Art (https://smart.servier.com; 30 April 2021).

Figure 4

Signaling pathways activated by peptides derived from growth factors and their effect in vitro and/or in vivo [232,239,243,244,245]. The figure was created using Servier Medical Art (https://smart.servier.com; 30 April 2021).