Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer's disease

Rebecca Deering Brose, Elin Lehrmann, Yongqing Zhang, Roger H Reeves, Kirby D. Smith, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by accumulation of amyloid β-peptide (Aβ) plaques in the brain and decreased cognitive function leading to dementia. We tested if hydroxyurea (HU), a ribonucleotide reductase inhibitor known to activate adaptive cellular stress responses and ameliorate abnormalities associated with several genetic disorders, could protect rat hippocampal neurons against oxidative-, excitatory-, mitochondrial-, and Aβ-induced stress and if HU treatment could improve learning and memory in the APP/PS1 mouse model of AD. HU treatment attenuated the loss of cell viability induced by treatment of hippocampal neurons with hydrogen peroxide, glutamate, rotenone, and Aβ1–42. HU treatment attenuated reductions of mitochondrial reserve capacity, maximal respiration, and cellular adenosine triphosphate content induced by hydrogen peroxide treatment. In vivo, treatment of APP/PS1 mice with HU (45 mg/kg/d) improved spatial memory performance in the hippocampus-dependent Morris water maze task without reducing Aβ levels. HU provides neuroprotection against toxic insults including Aβ improves mitochondrial bioenergetics, and improves spatial memory in an AD mouse model. HU may offer a new therapeutic approach to delay cognitive decline in AD.

Original languageEnglish (US)
Pages (from-to)121-133
Number of pages13
JournalNeurobiology of Aging
Volume72
DOIs
StatePublished - Dec 1 2018

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Hydroxyurea
Alzheimer Disease
Neurons
Hydrogen Peroxide
Cell Respiration
Ribonucleotide Reductases
Rotenone
Inborn Genetic Diseases
Poisons
Spatial Memory
Amyloid
Neurodegenerative Diseases
Cognition
Energy Metabolism
Dementia
Glutamic Acid
Hippocampus
Cell Survival
Adenosine Triphosphate
Learning

Keywords

  • Alzheimer's disease
  • Amyloid beta
  • APP/PS1
  • Hormesis
  • Hydroxyurea
  • Mitochondria
  • Neurodegeneration

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer's disease. / Brose, Rebecca Deering; Lehrmann, Elin; Zhang, Yongqing; Reeves, Roger H; Smith, Kirby D.; Mattson, Mark P.

In: Neurobiology of Aging, Vol. 72, 01.12.2018, p. 121-133.

Research output: Contribution to journalArticle

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