ReviewPeptides Acting as Cognitive Enhancers
Introduction
Cognitive enhancement is defined as the improvement in cognitive function of animals and human beings that can be achieved by a broad range of biomedical technologies that vary from pharmaceutical drugs to technological devices for brain stimulation. Although this concept has been commonly applied to healthy individuals, much research has been done in diverse neurological diseases that involve cognitive impairment, such as Alzheimer's disease (AD), schizophrenia and depression. As knowledge on the molecular and cellular mechanisms underlying learning and memory accumulates and understanding of the mechanisms leading to cognitive impairment grows, specific manipulations of cognitive processes aiming to enhance cognitive function are becoming possible. To develop new potential pharmacological cognitive enhancers identifying the molecular signaling pathways of learning and memory can help us search for specific compounds that modulate such pathways. Among the possible targets are protein kinases, phosphatases and a variety of receptors. Manipulations of these targets may modulate the expression or the activity of synaptic components. Recent basic research using transgenic mice has established the importance of a number of synaptic signaling pathways in enhancing cognitive function (Lee and Silva, 2009). In fact, a large number of mutations have been associated to changes in the activity of specific synaptic pathways, and crucially, the vast majority of these mutations are related to two synaptic plasticity mechanisms that have been suggested to be strongly related to learning and memory mechanisms: long-term potentiation (LTP) and long-term depression (LTD). In addition, the activation of neuronal repair mechanisms could lead to an enhancement of the cognitive function by preventing or reversing neurodegenerative processes (Nelson et al., 2015). In this article, we have selected examples of peptides that enhance learning and memory by modulating synaptic function. Peptides are highly specific to their targets and this feature reduces the probability of adverse effects (Sato et al., 2006). A series of new technologies that improve peptide permeability and stability have opened new opportunities for their exploitation as viable drugs (Vlieghe et al., 2010). Here we will discuss the logic behind the development of such peptides, their mechanisms of action and their possible utilities.
Section snippets
FGL: NCAM mimetic peptide
The neural cell adhesion molecule (NCAM) is expressed in the surface of most neural cells and plays an important role in synaptic plasticity (Schachner, 1997, Rønn et al., 2000). NCAM is involved in cell to cell adhesion, and acts as a ligand for the fibroblast growth factor receptor (FGFR) expressed on the surface of the interacting cell, promoting its activation and thus triggering FGFR-related signaling mechanisms. The extracellular region of NCAM is made up of five immunoglobulin-like (Ig)
PI3K activating peptide PTD4-PI3KAc
The phosphoinositide 3-kinase (PI3K) signaling pathway, is involved in the control of many cellular functions, including cell growth, proliferation, differentiation and survival. PI3K appears to be altered in many pathological conditions, including cancer (Samuels et al., 2004) and neurodegenerative diseases (Enriquez-Barreto and Morales, 2016). PI3Ks are classified into three different groups (I, II and II) of which Class IA is the best characterized. Class IA PI3K consists of heterodimers
PTEN-PDZ peptide
In LTD, synaptic strength is reduced in an experience-dependent manner. LTD has a crucial role in some types of learning and memory and in situations in which cognitive demands require a flexible response (Collingridge et al., 2010). In recent years it has been established that NMDA-dependent LTD requires the proper activity of PTEN. Indeed, PTEN-deficient mice are incapable of expressing hippocampal LTD (Wang et al., 2006) whereas pharmacological inhibition of PTEN with bpV(HO)pic, reduces LTD
Concluding remarks
Here we present examples of three peptides that may be used to achieve cognitive enhancement by improving synaptic function. Although the final goal in the development of cognitive enhancers is frequently to improve cognitive function in AD, of the three peptides described here, only the PTEN-PDZ peptide was specifically designed to overcome a specific pathological defect evident in AD models. Indeed, this peptide drug does not affect WT mice with intact cognitive function (Knafo et al., 2016).
Acknowledgments
The original work from the authors contributing to this review has been supported by grants from the Ministerio de Economía y Competitividad (SAF2016-78071-R and SAF2015-62540-ERC, Spain) from the Alzheimer’s Association (NIRG-13-279533), the Basque Ministry of Health (2013111138), Basque Business Development Agency (SPRI-Elkartek), the University of the Basque Country (EHUrOPE14/03), and the Ikerbasque Foundation.
References (43)
- et al.
Solid lipid nanoparticles as a drug delivery system for peptides and proteins
Adv Drug Deliv Rev
(2007) - et al.
NCAM-mimetic, FGL peptide, restores disrupted fibroblast growth factor receptor (FGFR) phosphorylation and FGFR mediated signaling in neural cell adhesion molecule (NCAM)-deficient mice
Brain Res
(2010) - et al.
Synaptic incorporation of AMPA receptors during LTP Is controlled by a PKC phosphorylation site on GluR1
Neuron
(2006) - et al.
Stimulation of mitogenesis by a cell-permeable PI 3-kinase binding peptide
Biochem Biophys Res Commun
(1998) - et al.
CAM-FGF receptor interactions: a model for axonal growth
Mol Cell Neurosci
(1996) - et al.
Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP
Structure
(2003) - et al.
A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala
Neuron
(2001) - et al.
Chapter 2 – Signaling pathways involved in cognitive enhancement
- et al.
The neural cell adhesion molecule in synaptic plasticity and ageing
Int J Dev Neurosci
(2000) - et al.
Therapeutic peptides: technological advances driving peptides into development
Curr Opin Biotechnol
(2006)
Neural recognition molecules and synaptic plasticity
Curr Opin Cell Biol
A neural cell adhesion molecule–derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention
Neuroscience
Effect of an NCAM mimetic peptide FGL on impairment in spatial learning and memory after neonatal phencyclidine treatment in rats
Behav Brain Res
Synthetic therapeutic peptides: science and market
Drug Discov Today
Ras and Rap control AMPA receptor trafficking during synaptic plasticity
Cell
NMDA receptor function and physiological modulation A2 – squire
Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers
Clin Pharmacokinet
PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane
Nat Neurosci
Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments
Hippocampus
A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation
J Neurosci
Long-term depression in the CNS
Nat Rev Neurosci
Cited by (11)
Applications in medicine: Mental health
2021, Biologically Active Peptides: From Basic Science to Applications for Human HealthNeuropharmacology of attention
2018, European Journal of PharmacologyCitation Excerpt :Additionally, the hypocretin/orexin system can also impact attentional performance (Fadel and Burk, 2010). A challenge for future research will be to establish how these neuropeptide systems integrate with well-established neural pathways involved in attention (Asua et al., 2018). For example, these neuropeptides may have trans-synaptic effects on attention by affecting the activity of subcortical areas that then influence cortical neurotransmission.
Editorial on the Special Issue: Molecules and Cognition
2018, NeuroscienceFORTIS: a live-cell assay to monitor AMPA receptors using pH-sensitive fluorescence tags
2021, Translational Psychiatry
- †
These authors contributed equally to this work.