期刊
NEUROBIOLOGY OF AGING
卷 72, 期 -, 页码 121-133出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2018.08.021
关键词
Hydroxyurea; Amyloid beta; Alzheimer's disease; APP/PS1; Neurodegeneration; Mitochondria; Hormesis
资金
- National Institute on Aging
- PHS award [R01HD038384]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD038384] Funding Source: NIH RePORTER
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by accumulation of amyloid beta-peptide (A beta) 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 A beta-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 A beta(1-42). 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 A beta levels. HU provides neuroprotection against toxic insults including A beta, 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. Published by Elsevier Inc.
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