Old and new evidence for neuropeptide involvement in Alzheimer's disease

Alzheimer's disease (AD) is an irreversible degenerative disorder characterized by degeneration of neurons in different brain areas and by progressive cognitive and functional decline. Various deranged mechanisms play a role in the disease process all inducing neuronal death, the inevitable event occurring in AD. Novel therapeutic approaches using disease-modifying treatment are being investigated with the intention of influencing multiple pathways involved in AD. Because of their putative roles as neurotransmitters, neuromodulators, and neuroregulators in the central nervous system, neuropeptides have been object of considerable research. Postmortem studies have provided evidence that several neuropeptide-containing neurons are pathologically altered in brain areas of AD patients, as well as in the brain of animal models of AD. In addition, altered levels of neuropeptides have been found in cerebrospinal fluid (CSF) of AD patients, getting insights into the potential role of neuropeptides in the pathophysiology of AD and offering the possibility to identify novel biomarkers of this pathology. The role exerted by neuropeptides seems particularly interesting since they are generally neuroprotective and widely distributed in brain areas responsible for learning and memory processes. The present review summarizes the recent findings on neuropeptides involvement in AD, with a focus on the contribution of thyrotrophin releasing hormone, cholecystokinin, bradykinin and chromogranin/secretogranin family, describing brain distribution and role played in AD and in cognitive functions, as well as their neuroprotective properties. Convincing evidence has been provided for the protective role of these neuropeptides against neurodegeneration observed in AD, both in vitro and in vivo, identifying neuropeptide receptors as potential therapeutic targets.