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Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59years), cognitively intact aging (73-95years) and age-matched AD cases. To identify "anti-aging/AD" transcription patterns associated with physical activity, probesets significantly associated with both physical activity and aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2210 probesets significant in both data sets, nearly 95% showed opposite transcription patterns with physical activity compared with aging/AD. The majority (>70%) of these anti-aging/AD genes showed increased expression with physical activity and decreased expression in aging/AD. Enrichment analysis of the anti-aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling, and spine plasticity. Anti-aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function (notably negative regulation of transcription). These data reveal that physical activity is associated with a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer’s disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20–99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.

The aged canine is a higher animal model that naturally accumulates β-amyloid (Aβ) and shows age-related cognitive decline. However, profiles of Aβ accumulation in different species (40 vs. 42), its assembly states, and Aβ precursor protein (APP) processing as a function of age remain unexplored. In this study, we show that Aβ increases progressively with age as detected in extracellular plaques and biochemically extractable Aβ40 and Aβ42 species. Soluble oligomeric forms of the peptide, with specific increases in an Aβ oligomer migrating at 56kDa, also increase with age. Changes in APP processing could potentially explain why Aβ accumulates, and we show age-related shifts towards decreased total APP protein and non-amyloidogenic (α-secretase) processing coupled with increased amyloidogenic (β-secretase) cleavage of APP. Importantly, we describe Aβ pathology in the cingulate and temporal cortex and provide a description of oligomeric Aβ across the canine lifespan. Our findings are in line with observations in the human brain, suggesting that canines are a valuable higher animal model for the study of Aβ pathogenesis.

While it is well established that exercise can improve cognitive performance, it is unclear how long these benefits endure after exercise has ended. Accordingly, the effects of voluntary exercise on cognitive function and brain-derived neurotrophic factor (BDNF) protein levels, a major player in the mechanisms governing the dynamics of memory formation and storage, were assessed immediately after a 3-week running period, or after a 1-week or 2-week delay following the exercise period. All exercised mice showed improved performance on the radial arm water maze relative to sedentary animals. Unexpectedly, fastest acquisition (fewest errors and shortest latency) occurred in animals trained following a 1-week delay, while best memory performance in the probe trial was observed in those trained immediately after the exercise period. Assessment of the time course of hippocampal BDNF availability following exercise revealed significant elevations of BDNF immediately after the exercise period (186% of sedentary levels) and at 1 and 2 weeks after exercise ended, with levels returning to baseline by 3–4 weeks. BDNF protein levels showed a positive correlation with cognitive improvement in radial water maze training and with memory performance on day 4, supporting the idea that BDNF availability contributes to the time-dependent cognitive benefits of exercise revealed in this study. Overall, this novel approach assessing the temporal endurance of cognitive and biochemical effects of exercise unveils new concepts in the exercise-learning field, and reveals that beneficial effects of exercise on brain plasticity continue to evolve even after exercise has ended.

Over the past few decades, the average age at time of spinal cord injury (SCI) has increased. Here we examined locomotor recovery and myelin pathology in both young and aged adult rats following contusion SCI. Our assessment indicates that the rate of locomotor recovery following SCI is significantly delayed in aged rats as compared to young rats, and is associated with a greater degree of pathology and demyelination. Additionally, we examined the effect of voluntary exercise, pre- and post-injury, on locomotor recovery and myelin pathology following contusion SCI. Our data indicate that exercise improves the locomotor recovery of injured aged rats such that it is comparable to the recovery rate of injured young rats, and is associated with a decreased area of pathology and amount of demyelination. Interestingly, the rate of locomotor recovery and myelin pathology in the aged exercised rats was similar to that of the young sedentary rats after injury, indicating that exercise attenuates the delayed recovery of function and associated histopathology in aged rats. These data indicate that there is an age-related delay in locomotor recovery following SCI, and an age-related increase in histopathology following SCI. Importantly, our data indicate that exercise attenuates these age-related deficits following SCI.

Brain-derived neurotrophic factor (BDNF) is involved in activity-dependent plasticity and interacts with the neurotransmitter glutamate. Glutamate N-methl-D-aspartate (NMDA) receptor activation increases BDNF expression, while BDNF facilitates NMDA activity, with both involved in spatial learning. Administration of the NMDA receptor antagonist MK-801 can impair this leaning. The interaction between NMDA and BDNF in learning is examined in this study. Adult male Sprague-Dawley rats received either i.p. MK-801 or saline and were trained to locate a submerged water maze platform. Sedentary and activity yoked groups were included for biochemical comparisons. Control rats quickly learned the platform location while MK-801-treated rats learned at a significantly slower rate (P < 0.0001). In situ hybridization for hippocampal BDNF mRNA indicated significant increases in the yoked and learning groups. However, MK-801 attenuated the BDNF mRNA increase in the learning and activity-yoked conditions (P < 0.05). Administration of MK-801 to the sedentary group did not alter baseline mRNA levels. These data suggest that BDNF expression is important for NMDA-dependent learning and memory. Interestingly, learning still occurs across trials independent of the NMDA and BDNF interaction. Increases in BDNF and NMDA activity may be significant components in learning and memory, and modulation of these systems may be beneficial for developing strategies to improve cognitive function.

Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.

Endogenous expression levels of brain-derived neurotrophic factor (BDNF) mRNA were assessed using in situ hybridization to investigate whether there is a natural diurnal fluctuation in BDNF mRNA expression in the hippocampus of rats housed with a normal (12:12 h) light/dark cycle. BDNF expression was increased during lights out (dark-cycle) to 134%-158% of light-cycle levels in hippocampal regions CA1, CA3, and hilus. In addition, expression levels of the four BDNF transcript forms, exons I-IV, were assessed to evaluate whether expression of specific BDNF transcripts exhibited differential endogenous fluctuation. All exons had lowest levels of expression at either noon or 6 p.m. Significant correlations were found between exon expression level and time, with elevated expression occurring at dark-cycle timepoints. The exon III transcript showed the greatest diurnal change in expression in all hippocampal fields, with dark-cycle expression elevated to 219-419% of light-cycle expression level. In addition to exon III, dark-cycle exon II mRNA levels were elevated in all hippocampal subfields, to 140-180% of light-cycle levels, suggesting that the endogenous fluctuation in BDNF expression results predominantly from activation of the promoters linked to exons II and III. Previously we have shown that physical activity increases BDNF expression. The naturally occurring rise in BDNF expression during the dark-cycle, the time when rats are most physically active, may be due to increased activity and arousal levels. Because BDNF has a role in plasticity, the increase in BDNF expression during the time that a rat is maximally interacting with its surroundings may be part of an ongoing stimulus-encoding mechanism, or may be a mechanism to maximize information storage about the environment.

Previous results from our laboratory indicate that two nights of voluntary wheel running upregulates brain-derived neurotrophic factor (BDNF) mRNA expression in the hippocampus. In order to investigate the time-course of the BDNF response and to examine how physical activity preferentially activates particular transcriptional pathways, the effects of 6 and 12 h of voluntary wheel running on BDNF and exons I-IV mRNA expression were investigated in rats. Hippocampal full-length BDNF mRNA expression was rapidly influenced by physical activity, showing significant increases in expression levels as soon as 6 h of voluntary wheel running. Moreover, there was a strong positive correlation between distance run and BDNF mRNA expression. Exon I mRNA expression was significantly upregulated after 6 h of running and was maintained or enhanced by 12 h of voluntary running. Exon II had a slower time-course and was significantly upregulated after 12 h, selectively in the CA1 hippocampal region. Exon III and Exon IV showed no significant increase in expression level after 6 or 12 h of running in the paradigm studied. It is significant that the rapid neurotrophin response is demonstrated for a physiologically relevant stimulus, as opposed to the extreme conditions of seizure paradigms. Furthermore, exercise-induced upregulation of BDNF may help increase the brain's resistance to damage and neurodegeneration that occurs with aging.

Most histories of senile dementia commence with Alois Alzheimer's description in 1906 of the first case of Alzheimer's disease, yet the history of senile dementia before 1906 is quite rich, dating back to the ancient Greek and Roman philosophers and physicians. Over the 2500 years since ancient times, the concept of senile dementia has evolved from a rather vague notion that mental decline occurred inevitably in old age, to become defined today by a distinct set of clinical and pathological features with the potential for treatment and prevention within grasp. Throughout history, many elderly individuals with unpredictable behavior were sequestered in institutions, and the line between mental disorders and senile dementia was hazy at best. The identification of Alzheimer's disease at the onset of the 20th century was a turning point for the understanding of senile dementia, and the concepts and histological findings presented by the early researchers of Alzheimer's disease remain relevant still today. Indeed, these early findings are proving to be a continuing source of insight, as many of the issues debated at the turn of the century remain unresolved still today. This paper thus traces the history of the evolution of our current conceptualization of Alzheimer's disease from the amorphous Greco-Roman concept of age-associated dementia.

Erratum to “Spatial learning is delayed and brain-derived neurotrophic factor mRNA expression inhibited by administration of MK-801 in rats” [Neurosci. Lett. 353 (2003) 95–98] J. Patrick Kesslaka,b,∗, Kenneth R. Chuanga, Nicole C. Berchtolda, C.W. Cotmana a Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697-4540, USA b Department of Neurology, University of California, Irvine, CA 92697-4540, USA