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Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer’s disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days in vitro (DIV) to examine the effect of different stressors on H3K9me3 across neuron ages. We found that the oxidative stressor hydrogen peroxide (H2O2) does not induce H3K9me3 in 12 DIV neurons. Inhibiting BDNF signaling via TrkB-Fc elevated H3K9me3 in 12 and 21 DIV neurons compared to 6 DIV neurons. Antioxidant treatment prevented H3K9me3 elevation in 12 DIV neurons treated with TrkB-Fc and H2O2. H2O2 elevated the epigenetic regulator SIRT1 in 6 DIV neurons but did not increase H3K9me3 levels. Our findings demonstrate that inhibiting BDNF signaling elevates hippocampal H3K9me3 in a manner dependent on in vitro age and oxidative stress.

Histone modifications are key contributors to the cognitive decline that occurs in aging and Alzheimer's disease. Our lab has previously shown that elevated H3K9me3 in aged mice is correlated with synaptic loss, cognitive impairment and a reduction in brain derived neurotrophic factor (BDNF). However, the mechanism of H3K9me3 regulation remains poorly understood. In this study, we investigated the role of age-associated stressors on H3K9me3 regulation and examined if changes in H3K9me3 were age dependent. We used cultured hippocampal neurons at 6, 12, and 21 days

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of “molecular memory” for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.

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.

Introduction We have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I–V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer's disease (AD) subjects. Methods Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays. Results The microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6 . Discussion Our findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.

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.

We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.

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.

Using a novel microfluidic chamber that allows the isolation of axons without contamination by nonaxonal material, we have for the first time purified mRNA from naive, matured CNS axons, and identified the presence of >300 mRNA transcripts. We demonstrate that the transcripts are axonal in nature, and that many of the transcripts present in uninjured CNS axons overlap with those previously identified in PNS injury-conditioned DRG axons. The axonal transcripts detected in matured cortical axons are enriched for protein translational machinery, transport, cytoskeletal components, and mitochondrial maintenance. We next investigated how the axonal mRNA pool changes after axotomy, revealing that numerous gene transcripts related to intracellular transport, mitochondria and the cytoskeleton show decreased localization 2 d after injury. In contrast, gene transcripts related to axonal targeting and synaptic function show increased localization in regenerating cortical axons, suggesting that there is an increased capacity for axonal outgrowth and targeting, and increased support for synapse formation and presynaptic function in regenerating CNS axons after injury. Our data demonstrate that CNS axons contain many mRNA species of diverse functions, and suggest that, like invertebrate and PNS axons, CNS axons synthesize proteins locally, maintaining a degree of autonomy from the cell body.

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.

We investigated the possibility that estrogen and exercise interact in the hippocampus and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippocampal BDNF mRNA and protein levels. However, the exercise effect on BDNF up-regulation is reduced in the absence of estrogen, in a time-dependent manner. In addition, voluntary activity itself is stimulated by the presence of estrogen. In exercising animals, estrogen deprivation reduced voluntary activity levels, while estrogen replacement restored activity to normal levels. In sedentary animals, estrogen deprivation (ovariectomy) decreased baseline BDNF mRNA and protein, which were restored by estrogen replacement. Despite reduced activity levels in the ovariectomized condition, exercise increased BDNF mRNA levels in the hippocampus after short-term (3 weeks) estrogen deprivation. However, long-term estrogen-deprivation blunted the exercise effect. After 7 weeks of estrogen deprivation, exercise alone no longer affected either BDNF mRNA or protein levels. However, exercise in combination with long-term estrogen replacement increased BDNF protein above the effects of estrogen replacement alone. Interestingly, protein levels across all conditions correlated most closely with mRNA levels in the dentate gyrus, suggesting that expression of mRNA in this hippocampal region may be the major contributor to the hippocampal BDNF protein pool. The interaction of estrogen, physical activity and hippocampal BDNF is likely to be an important issue for maintenance of brain health, plasticity and general well-being, particularly in women.

In this study, we examined whether experimental alterations of circulating estrogen levels are associated with changes in the expression of bcl-x, an inhibitor of apoptosis. We report that bcl-x mRNA expression in rat hippocampus significantly decreases after reduction of estrogen levels resulting from ovariectomy. Exposure of ovariectomized rats to 17beta-estradiol for either 5 or 28 days restored bcl-x mRNA expression to levels at or above those observed in sham-ovariectomized control animals. These data demonstrate that physiological levels of estrogen regulate hippocampal expression of bcl-x, an important modulator of neuronal apoptosis. Estrogen-mediated regulation of bcl-x may be relevant to the maintenance of neuronal viability and may contribute to the mechanism of estrogen neuroprotection.

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.

The central nervous system (CNS) possesses a well-known capacity for circuitry rearrangement, or “plasticity,” which is maintained throughout life. Two well-studied categories of CNS plasticity are the circuitry rearrangement which occurs in response to injury and that which occurs in response to normal environmental stimuli. In an injury response, such as that which follows partial denervation of the hippocampus by unilateral removal of the entorhinal cortex, undamaged fibers in the denervated zone sprout and form new connections to replace lost synapses. In addition, rearrangement of circuitry also takes place in nondenervated zones which are functionally associated with the denervated circuitry. These observations indicate that the CNS is capable of major remodeling of neuronal circuitry, both in response to an injury as well as in the absence of a direct insult. Importantly, such plasticity reactions after injury appear to mediate recovery of lost function in hippocampal-dependent learning. Plasticity can also occur in response to relatively subtle stimuli, such as are found in an enriched environment or with exercise. Even tightly structured repetitive exercise, such as wheel-running by rats, drives plasticity responses in brain regions such as the hippocampus, cortex, and cerebellum. Plasticity in response to injury and environmentally driven plasticity share similar molecular features, such as activation of growth factors, suggesting that some molecular events and mechanisms driving circuitry remodeling are common to all forms of plasticity. In this review, these two categories of CNS plasticity are discussed, using in vivo models to illustrate remodeling occurring after damage, as well as environmentally driven plasticity. MRDD Research Reviews 1998; 4:223–230 © 1998 Wiley-Liss, Inc.

Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5-/- mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.

Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aβ accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aβ, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON – control environment/control diet, AOX– control environment/antioxidant diet, ENR – enriched environment/control diet, AOX/ENR– enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging.

While aging is associated with modest declines in certain aspects of cognitive function (memory, executive function, processing speed), many cognitive domains can remain relatively stable until late in life. In contrast to the mild decline observed in normal aging, pathological aging such as Alzheimer’s disease (AD) affects global cognitive function – impairing memory, language, thinking, and reasoning, and interferes substantially with daily living capacity. Changes in the structural integrity of the brain underlie the cognitive declines that occur in both aging and AD, however different brain structures are affected. In healthy aging, mild functional changes are predominantly detected in the prefrontal cortex and basal ganglia, while in AD, pathology initially accumulates and disrupts function in the medial temporal lobe (disrupting memory), progresses to cortical structures, and eventually globally impacts the brain. Cognitive decline with normal and pathological aging is mediated by a complex interaction of multiple factors that include genetic and nongenetic risk factors that determine the age of onset as well as the rate of decline. Importantly, the progression and decline can be prevented or slowed by certain lifestyle factors (exercise participation, stress management) and pharmaceutical interventions (statins, hormone replacement therapy for postmenopausal women). While most individuals will experience some degree of cognitive decline with aging, conversion to MCI or AD is not an inevitable consequence of aging. It is likely that additional strategies to promote healthy brain aging will be uncovered in the next years that will further contribute to successful brain aging and will help to maintain a high quality of living through the last decades of life.

Human and other animal studies demonstrate that exercise targets many aspects of brain function and has broad effects on overall brain health. The benefits of exercise have been best defined for learning and memory, protection from neurodegeneration and alleviation of depression, particularly in elderly populations. Exercise increases synaptic plasticity by directly affecting synaptic structure and potentiating synaptic strength, and by strengthening the underlying systems that support plasticity including neurogenesis, metabolism and vascular function. Such exercise-induced structural and functional change has been documented in various brain regions but has been best-studied in the hippocampus - the focus of this review. A key mechanism mediating these broad benefits of exercise on the brain is induction of central and peripheral growth factors and growth factor cascades, which instruct downstream structural and functional change. In addition, exercise reduces peripheral risk factors such as diabetes, hypertension and cardiovascular disease, which converge to cause brain dysfunction and neurodegeneration. A common mechanism underlying the central and peripheral effects of exercise might be related to inflammation, which can impair growth factor signaling both systemically and in the brain. Thus, through regulation of growth factors and reduction of peripheral and central risk factors, exercise ensures successful brain function.

Although exercise has long been equated with better physical health, there is now extensive research showing that it has substantial benefits for the brain as well. From an Alzheimer's disease (AD) standpoint, one of the most important effects of exercise is on cognition. Exercise not only improves cognitive function in normal individuals, but it has been associated with a lower risk for AD and other types of dementia. Studies in animal models also suggest that exercise might attenuate some of the cognitive symptoms and pathophysiology of dementia. Recent research has attempted to identify molecular and cellular changes in the central nervous system elicited by physical activity. Work in animal models has identified several key responses, including up-regulation of growth factors, increased neurogenesis, and improved learning and memory, which might be key to improved cognition in response to exercise.

Exercise is an important facet of behavior that enhances brain health and function. Increased expression of the plasticity molecule brain-derived neurotrophic factor (BDNF) as a response to exercise may be a central factor in exercise-derived benefits to brain function. In rodents, daily wheel-running exercise increases BDNF gene and protein levels in the hippocampus. However, in humans, exercise patterns are generally less rigorous, and rarely follow a daily consistency. The benefit to the brain of intermittent exercise is unknown, and the duration that exercise benefits endure after exercise has ended is unexplored. In this study, BDNF protein expression was used as an index of the hippocampal response to exercise. Both daily exercise and alternating days of exercise increased BDNF protein, and levels progressively increased with longer running duration, even after 3 months of daily exercise. Exercise on alternating days was as effective as daily exercise, even though exercise took place only on half as many days as in the daily regimen. In addition, BDNF protein remained elevated for several days after exercise ceased. Further, after prior exercise experience, a brief second exercise re-exposure insufficient to cause a BDNF change in naive animals, rapidly reinduced BDNF protein to levels normally requiring several weeks of exercise for induction. The protein reinduction occurred with an intervening “rest” period as long as 2 weeks. The rapid reinduction of BDNF by an exercise stimulation protocol that is normally subthreshold in naive animals suggests that exercise primes a molecular memory for BDNF induction. These findings are clinically important because they provide guidelines for optimizing the design of exercise and rehabilitation programs, in order to promote hippocampal function.

Available evidence suggests that regular, moderate-intensity exercise has beneficial effects on neural health, perhaps including neuroprotection. To evaluate this idea further, we compared the severity of kainate-induced neuronal loss in exercised versus sedentary female rats. Stereological estimations of neuron number revealed that rats in the exercise condition exhibited significantly greater neuron loss in hippocampal region CA2/3, suggesting that high levels of physical activity may increase neuronal vulnerability to excitotoxicity.

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