Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta-induced pathology

Oksana Dmytriyeva; Amor Belmeguenai; Laurent Bezin; Katia Soud; David Paul Drucker Woldbye; Casper René Gøtzsche; Stanislava Pankratova

doi:10.1016/j.neurobiolaging.2019.05.003

Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta-induced pathology

Neurobiol Aging. 2019 Sep:81:88-101. doi: 10.1016/j.neurobiolaging.2019.05.003. Epub 2019 May 13.

Authors

Oksana Dmytriyeva¹, Amor Belmeguenai², Laurent Bezin², Katia Soud³, David Paul Drucker Woldbye³, Casper René Gøtzsche³, Stanislava Pankratova⁴

Affiliations

¹ Laboratory of Neural Plasticity, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark; Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
² Lyon Neuroscience Research Center, TIGER Team, Bron, France; Epilepsy Institute IDÉE, Bron, France.
³ Laboratory of Neural Plasticity, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
⁴ Laboratory of Neural Plasticity, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark; Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address: stasya@sund.ku.dk.

PMID: 31255922
DOI: 10.1016/j.neurobiolaging.2019.05.003

Abstract

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the irreversible neuronal loss and memory impairment, and current treatments are merely symptomatic. Erythropoietin (EPO) has been shown to possess neurotrophic, neuroprotective, anti-inflammatory, and memory-enhancing effects, which could be therapeutically beneficial in the different aspects of AD. However, the hematopoietic effect of EPO has hampered its potential as a neuroprotective and procognitive agent. In this study, we characterized a novel small peptide, NL100, derived from a conserved C-helix region of EPO. NL100 was shown to bind to the EPO receptor, induce neuritogenesis, and protect hippocampal neurons from oxidative- and Aβ_25-35-induced neurodegeneration in vitro. Importantly, long-term NL100 treatment did not induce hematopoiesis, overcoming this challenge associated with EPO. Memory-enhancing effects were demonstrated after NL100 treatment in social recognition test for short-term memory, in both healthy rats and rats challenged centrally with Aβ_25-35 peptide, and in the Morris water maze test for spatial memory. Moreover, NL100 was shown to reverse Aβ_25-35-induced hippocampal degeneration and gliosis as well as pilocarpine-induced suppression of long-term potentiation in rats. In conclusion, NL100 is a novel EPO-derived nonhematopoietic peptide with neuroprotective and memory-enhancing effects and could therefore be a potential candidate for the development of new treatments for neurodegenerative disorders and dementia.

Keywords: Beta amyloid peptide(25-35); Erythropoietin-derived peptide; Hippocampus; Memory; Neurite outgrowth; Neuroprotection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / metabolism*
Animals
Dementia / drug therapy*
Dementia / etiology*
Erythropoietin* / chemistry
Female
Hippocampus / metabolism
Hippocampus / pathology
Long-Term Potentiation / drug effects*
Male
Memory / drug effects*
Mice, Inbred BALB C
Neurodegenerative Diseases / drug therapy*
Neurodegenerative Diseases / etiology*
Neuronal Outgrowth / drug effects
Neuroprotective Agents*
Peptides / pharmacology*
Peptides / therapeutic use*
Rats, Sprague-Dawley
Rats, Wistar

Substances

Amyloid beta-Peptides
Neuroprotective Agents
Peptides
Erythropoietin