J. Patrick Kesslak

Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome

Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimers disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that Abeta immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology. We find that Abeta deposits are cleared first and subsequently reemerge prior to the tau pathology, indicative of a hierarchical and direct relationship between Abeta and tau. The clearance of the tau pathology is mediated by the proteasome and is dependent on the phosphorylation state of tau, as hyperphosphorylated tau aggregates are unaffected by the Abeta antibody treatment. These findings indicate that Abeta immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course.

Physical activity-antidepressant treatment combination : impact on brain-derived neurotrophic factor and behavior in an animal model

The mechanism of antidepressant action, at the cellular level, is not clearly understood. It has been reported that chronic antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and that physical activity (voluntary running) enhances this effect. We wished to investigate whether BDNF expression brought about by these interventions may overcome deficits caused by acute stress, and might impact behavior in an animal model. In this report, we have tested the hypothesis that the combination of the antidepressant, tranylcypromine, and physical exercise could lead to decreased neurotrophin deficits and enhanced swimming time in animals that have been forced to swim in an inescapable water tank. Rats were either treated with tranylcypromine, engaged in voluntary running, or both for one week. After these treatments, the animals underwent a two-day forced swimming procedure. BDNF mRNA levels were significantly depressed in untreated animals subjected to forced swimming. Animals that either underwent prior activity or received antidepressant showed BDNF mRNA levels restored to baseline. Animals receiving the combined intervention showed an increase in hippocampal BDNF mRNA well above baseline. Swimming time during a five-minute test was significantly enhanced in animals receiving the combined intervention over untreated animals. Swimming time was not significantly enhanced over that of animals receiving antidepressant alone, however. Enhanced swimming time correlated with increased levels of BDNF mRNA in one hippocampal sub-region (CA4-hilus). These results suggest that the combination of exercise and antidepressant treatment may have significant neurochemical, and possibly behavioral, effects. In addition, these results support the possibility that the enhancement of BDNF expression may be an important element in the clinical response to antidepressant treatment. The induction of BDNF expression by activity/pharmacological treatment combinations could represent an important intervention for further study, to potentially improve depression treatment and management.

Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus

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.

Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance?

Brain-derived neurotrophic factor (BDNF) promotes neuron survival, enhances sprouting, protects neurons against insult, and may be involved in several aspects of learning and memory. In this study, rats trained to locate a submerged platform in a water maze had elevated levels of BDNF messenger ribonucleic acid (mRNA) in the hippocampus (p < .05), a structure associated with spatial memory. BDNF mRNA expression increased after 3 and 6 days but not after 1 day of training in the water maze. A yoked control group that swam without the platform present, to control for physical activity, showed a trend for elevated BDNF mRNA at an intermediate level between the learning and sedentary groups. Other cortical and subcortical areas did not show a significant increase in BDNF mRNA after learning or activity (p > .05). These findings suggest that learning can impact BDNF mRNA expression localized to the brain areas involved in the processing of spatial information. Furthermore, behaviors such as physical activity and learning may help maintain and protect neurons at risk in aging and neurodegenerative disease via increased BDNF expression.

Transplants of purified astrocytes promote behavioral recovery after frontal cortex ablation

Ablation of the medial frontal cortex produces a learning deficit on a reinforced alternation task. Recovery from this deficit was significantly accelerated in rats by transplantation of either cultured purified astrocytes or Gelfoam that had remained the previous 5 days in a brain wound in another animal (wound-Gelfoam). Cell-free extracts of wound-Gelfoam did not enhance behavioral recovery. Embryonic frontal cortex was effective only if transplanted with a delay after ablation. It appears from these results that transplants can facilitate functional recovery by more than one mechanism, including promotion of survival and reactive synaptogenesis of host neurons, stabilization of the damaged environment and replacement of lost neurons. In this study, glial cells were capable of facilitating recovery from central nervous system damage to the same extent as neuronal transplants.

Lesions of the rat postsubiculum impair performance on spatial tasks.

Previous studies have identified a population of neurons in the postsubiculum that discharge as a function of the rats head direction in the horizontal plane (Taube, Muller, & Ranck, 1990a). To assess the contribution of these cells in spatial learning, Long-Evans rats were tested in a variety of spatial and nonspatial tasks following bilateral electrolytic or neurotoxic lesions of the postsubiculum. Compared to unlesioned control animals, lesioned animals were impaired on two spatial tasks, a radial eight-arm maze task and a Morris water task, although the performance scores of both lesion groups improved over the course of behavioral testing. In contrast, lesioned animals were unimpaired on two nonspatial tasks, a cued version of the water maze task and a conditioned taste-aversion paradigm. In addition, lesioned animals showed transient hyperactivity in an open-field activity test. These results support the concept that neurons in the postsubiculum are part of a neural network involved in the processing of spatial information.

Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.

Brain‐derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise‐dependent gene upregulation of this neurotrophin. Focal lesions were produced by medial septal infusion of the saporin‐linked immunotoxins 192‐IgG‐saporin or OX7‐saporin. 192‐IgG‐saporin produced a selective and complete loss of medial septal cholinergic neurons with no accompanying GABA loss. Baseline BDNF mRNA was reduced in the hippocampus of sedentary animals, but exercise‐induced gene upregulation was not impaired, despite complete loss of septo‐hippocampal cholinergic afferents. OX7‐saporin produced a graded lesion of the medial septum characterized by predominant GABA neuron loss with less reduction in the number of cholinergic cells. OX7‐saporin lesion reduced baseline hippocampal BDNF mRNA and attenuated exercise‐induced gene upregulation, in a dose‐dependent manner. These results suggest that combined loss of septal GABAergic and cholinergic input to the hippocampus may be important for exercise‐dependent BDNF gene regulation, while cholinergic activity on its own is not sufficient. These results are discussed in relation to their implications for aging and Alzheimers disease.

Effects of conditioning lesions on transplant survival, connectivity, and function. Role of neurotrophic factors.

Are there mechanisms intrinsic to the brain that can be drawn upon to promote functional repair after central nervous system (CNS) injury? Brain transplants provide a powerful approach for investigating this question. The successful grafting of neurons into damaged brain depends not only on the type of neurons transplanted but on the ability of the host brain to support and integrate these cells. In cell culture, for example, neurons will grow only if provided the proper medium and substrate. Similarly, the mature brain must provide the proper environment and be sufficiently adaptable to incorporate fetal neurons into its circuits. One of the first clues to the nature of intrinsic mechanisms came from the observation that introducing a delay between the time of injury and transplantation could significantly enhance the survival and integration of grafted neurons. This effect is correlated with the production and accumulation of trophic factors in the brain in response to injury. Thus, transplanted neurons may depend upon the establishment of proper “conditions” to enhance survival, integration, and behavioral function.

Roles of Metabotropic Glutamate Receptors in Brain Plasticity and Pathology

In summary, the mGluRs are a large family of receptor subtypes with diverse properties in terms of transduction coupling, pharmacology, and anatomical distribution. Many divergent studies have demonstrated that activation of these receptors can result in either neuroprotection or neuropathology. We hypothesized that the mGluRs of astrocytes may have a role in determining the response following administration of mGluR agonists in vivo, and we have defined a suitable in vitro model for the study of these receptors. The experimental plasticity demonstrated in the astrocyte culture model may represent a more general principle that conditions in the microenvironment may differentially alter mGluR subtype expression as part of development, functional specialization, or pathology. This astrocyte model of receptor regulation provides a system suitable for studying the effects of specific growth factors, neurotrophins, cytokines, and other substances released by neurons and glia that may act in both autocrine and paracrine fashions. Alteration in the ratios of receptors by such variables could then modify future signaling properties and neuroglial interactions, a form of conditioning of the astrocytic response that would alter the physiological output following glutamate release. One measure of the value of this model will be its usefulness in stimulating the generation of hypotheses that can be tested in vivo. For example, the morphology of the astrocytes when cultured in the defined medium has similarities to the morphology of astrocytes undergoing reactive gliosis in pathological states. It is also interesting to note that treatments that have been reported to increase excitatory amino acid-stimulated PI hydrolysis in ex vivo brain slices (lesions, ischemia, and kindling) are accompanied by reactive gliosis. Those findings combined with the present in vitro results lead us to speculate that mGluR5 expression may also be altered in vivo during reactive gliosis. If so, it will be important to examine the functional consequences of such a change with regard to the astrocytic response to injury and maintaining the balance between excitatory transmission and excitotoxicity.

Exercise increases the vulnerability of rat hippocampal neurons to kainate lesion.

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.