Elsevier

Neuroscience

Volume 159, Issue 1, 3 March 2009, Pages 183-195
Neuroscience

Molecular Neuroscience
Cognitive performance and age-related changes in the hippocampal proteome

https://doi.org/10.1016/j.neuroscience.2008.12.004Get rights and content

Abstract

Declining cognitive performance is associated with increasing age, even in the absence of overt pathological processes. We and others have reported that declining cognitive performance is associated with age-related changes in brain glucose utilization, long-term potentiation and paired-pulse facilitation, protein expression, neurotransmitter levels, and trophic factors. However, it is unclear whether these changes are causes or symptoms of the underlying alterations in dendritic and synaptic morphology that occur with age. In this study, we examined the hippocampal proteome for age- and cognition-associated changes in behaviorally stratified young and old rats, using two-dimensional in-gel electrophoresis and MS/MS. Comparison of old cognitively intact with old cognitively impaired animals revealed additional changes that would not have been detected otherwise. Interestingly, not all age-related changes in protein expression were associated with cognitive decline, and distinct differences in protein expression were found when comparing old cognitively intact with old cognitively impaired rats. A large number of protein changes with age were related to the glycolysis/gluconeogenesis pathway. In total, the proteomic changes suggest that age-related alterations act synergistically with other perturbations to result in cognitive decline. This study also demonstrates the importance of examining behaviorally-defined animals in proteomic studies, as comparison of young to old animals regardless of behavioral performance would have failed to detect many cognitive impairment–specific protein expression changes evident when behavioral stratification data were used.

Section snippets

Animals and behavioral testing

Fisher 344xBrown Norway (F1) male rats (10 and 27 months of age) were obtained from the NIA colony at Harlan Industries (Indianapolis, IN, USA). Animals were singly housed in polycarbonate cages with food (Purina Mills, Richmond, IN, USA) and water was available ad libitum. The animal rooms were kept at a constant temperature and humidity and maintained on a 12-h light/dark cycle. The animal facilities were fully accredited by the American Association for Accreditation of Laboratory Animal Care

Behavioral results

Animals were subdivided from a cohort of 15 animals (5 Young and 10 Old animals) based on their performance on the training blocks and probe trial phases of the Morris water maze and the absence of gross, peripheral underlying age-related pathology (i.e. tumors, cardiovascular hypertrophy, enlarged kidneys) observed at necropsy. This assessment was necessary since the presence of peripheral disease may influence behavioral results. The absence of significant gross pathology in the experimental

Discussion

Age is a primary risk factor for cognitive decline in rodents, non-human primates and humans, indicated by increasingly impaired performance in tasks of learning and memory. Although the etiology of age-related cognitive decline, and specifically impaired hippocampally-dependent learning and memory, remains unclear, cognitive decline is associated with impaired function of many cellular processes, including, but not limited to, decreased glucose metabolism and blood flow as well as alterations

Acknowledgments

The authors wish to thank the Penn State Mass Spectrometry Facility for technical assistance, Joseph Freeman for editorial assistance, and Tracy Marrow for illustration preparation. This work was supported by R01AG026607 and P01AG11370 (to W.E.S.).

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