Abstract
Vasoactive peptides constitute a heterogenous family of mediators exerting various physiological functions, mostly studied for their vasotropic effects and role as peripheral neurotransmitters/neuromodulators, mainly involved in nociceptive transmission modulation. They have been divided into vasodilatory or vasoconstrictive peptides, according to their predominant effects on vascular tone. Recent research has shown in the Central Nervous System effects as transmitters and "growth factor-like" signals. Therefore, deregulation of their signaling systems has been thought to play a role in neural cell death and in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, since these peptides can regulate neuronal stress signaling, survival cascades, synaptic plasticity. This review considers evidence about the implication of neuropeptide systems in Alzheimer's disease while focusing mainly on calcitonin gene-related peptide-alpha. In vitro and in vivo studies have shown potential implications in its pathogenesis. It has been possibly proposed as a neuroprotective agent, considering not only its pleiotropic actions on blood vessels, neurovascular coupling, energy metabolism, but also its potential actions on neuronal, glial, and immune system stress signaling, which might also derive from its structural homology to amylin. Amylin signaling is thought to be disrupted in Alzheimer's disease, and amylin itself takes part in the composition of senile plaques. Calcitonin gene-related peptide-containing systems seem more closely related to Alzheimer's disease pathogenesis than other neuropeptidergic systems, and their regulation might represent an interesting mechanism in developing novel therapeutic approaches.
Highlights
Vasoactive peptides constitute a heterogenous family of mediators exerting various physiological functions, mostly studied for their vasotropic effects and role as peripheral neurotransmitters/neuromodulators, mainly involved in nociceptive transmission modulation
This review considers evidence about the implication of neuropeptide systems in Alzheimer's disease while focusing mainly on calcitonin gene-related peptide-alpha
In vitro and in vivo studies have shown potential implications in its pathogenesis. It has been possibly proposed as a neuroprotective agent, considering its pleiotropic actions on blood vessels, neurovascular coupling, energy metabolism, and its potential actions on neuronal, glial, and immune system stress signaling, which might derive from its structural homology to amylin
Summary
This review highlights the potential roles of vasoactive peptides in the pathogenesis of Alzheimer’s disease (AD) It is a complex neurodegenerative disease whose most prominent features, on a neuropathological basis, are thought to be atrophy and neuron loss as well as the accumulation in several cortical areas of pathologic elements like senile plaques, mainly composed of amyloid-beta 1–42 and amylin, and neurofibrillary tangles, mainly composed of hyperphosphorylated tau [1, 2]. The DIAN-TU-001 trial, investigating the effectiveness of gantenerumab and solanezumab, monoclonal antibodies targeting mainly senile plaques and amyloid-beta oligomers (ABOs), in symptomatic and presymptomatic autosomal dominant AD mutation carriers has failed to meet its clinical efficacy endpoints It has been stopped before its completion [28]. Drugs, such as memantine, which are thought to ameliorate abnormal glutamatergic signaling, have elicited a moderate, albeit temporary, symptom relief [31,32,33]
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