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.

Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease

“…However, increasing BDNF bioavailability in the CNS clinically has been met with a number of significant challenges. Peripheral delivery of exogenous BDNF to patients has resulted in inconsistent results and is only minimally effective because of its low penetrance in crossing the blood–brain barrier (BBB; Gascon et al, 2021; Lu et al, 2013; Nagahara & Tuszynski, 2011; Palasz et al, 2020). It had been thought that the BBB was compromised in AD patients, which would substantially increase permeability of therapeutic agents into the brain.…”

“…Experimental blockade of BDNF in animal models results in significant impairment of AMPAR trafficking and learning, whereas BDNF application promotes trafficking and learning and memory (Keifer & Zheng, 2010). Therefore, therapeutic treatments aimed at increasing levels of BDNF in the brain to alleviate progression of neurodegenerative disease have been advanced in both humans and animal models with promising results (Bartlett et al, 2016; Gascon et al, 2021; Lu et al, 2013; Nagahara & Tuszynski, 2011; Sun et al, 2019; Walsh et al, 2020). However, their application in a clinical setting for patient treatment has been limited in spite of the strong research supporting them.…”

Getting Into the Brain: The Intranasal Approach to Enhance the Delivery of Nerve Growth Factor and Its Painless Derivative in Alzheimer’s Disease and Down Syndrome

“…One approach to overcome the limits of NGF administration might be the use of small molecules that could cross the blood brain barrier and mimic NGF action, improving survival of target cells [ Pediaditakis et al (2016a , b) and reviewed in Gascon et al (2021) ]. Currently one of these small-molecule NGF mimetics, the P75 NTR binding molecule LM11A-31, is under evaluation in clinical trials in Alzheimer’s disease ( Yang et al, 2008 , 2020 ).…”

A Review of Molecular Interplay between Neurotrophins and miRNAs in Neuropsychological Disorders

“…There are functional connections between NTs, TFs, and their transcriptional targets [13]. Enhancement of NT expression in the brain could protect neuronal tissues against a variety of pathological insults, such as ischemic and traumatic events as well as neurodegenerative processes [14,15]. NTs and their receptors are also involved in neuropsychiatric disorders [16].…”