Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation

• Published in: Brain research Vol. 842; no. 1; pp. 224 - 229
• Main Authors: Zhu, Haiyan, Guo, Qing, Mattson, Mark P
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 18.09.1999; Amsterdam Elsevier; New York, NY
• Subjects: Alzheimer; Alzheimer Disease - genetics; Animals; Apoptosis; Biological and medical sciences; Body Weight - physiology; Calorie restriction; Cell Death - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diet; Eating - physiology; Excitatory Amino Acid Agonists - toxicity; Excitotoxicity; Hippocampus - cytology; Hippocampus - physiology; Hyroxynonenal; Kainate; Kainic Acid - toxicity; Lipid Peroxidation - drug effects; Medical sciences; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Neurology; Oxidative stress; Presenilin-1; Oxidative stress; Kainate; Hyroxynonenal; Excitotoxicity; Calorie restriction; Alzheimer; Apoptosis; Nervous system diseases; Rat; Alzheimer disease; Rodentia; Central nervous system; Presenilin; Cerebral disorder; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Degenerative disease; Mutation; Hippocampus; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)01827-2

Alzheimer's disease (AD) is an age-related disorder that involves degeneration of synapses and neurons in brain regions involved in learning and memory processes. Some cases of AD are caused by mutations in presenilin-1 (PS1), an integral membrane protein located in the endoplasmic reticulum. Previous studies have shown that PS1 mutations increase neuronal vulnerability to excitotoxicity and apoptosis. Although dietary restriction (DR) can increase lifespan and reduce the incidence of several age-related diseases in rodents, the possibility that DR can modify the pathogenic actions of mutations that cause AD has not been examined. The vulnerability of hippocampal neurons to excitotoxic injury was increased in PS1 mutant knockin mice. PS1 mutant knockin mice and wild-type mice maintained on a DR regimen for 3 months exhibited reduced excitotoxic damage to hippocampal CA1 and CA3 neurons compared to mice fed ad libitum; the DR regimen completely counteracted the endangering effect of the PS1 mutation. The magnitude of increase in levels of the lipid peroxidation product 4-hydroxynonenal following the excitotoxic insult was lower in DR mice compared to mice fed ad libitum, suggesting that suppression of oxidative stress may be one mechanism underlying the neuroprotective effect of DR. These findings indicate that the neurodegeneration-promoting effect of an AD-linked mutation is subject to modification by diet.