Michael W. Marlatt

Running throughout middle‐age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice

Age‐related memory loss is considered to commence at middle‐age and coincides with reduced adult hippocampal neurogenesis and neurotrophin levels. Consistent physical activity at midlife may preserve brain‐derived neurotrophic factor (BDNF) levels, new cell genesis, and learning. In the present study, 9‐month‐old female C57Bl/6J mice were housed with or without a running wheel and injected with bromodeoxyuridine (BrdU) to label newborn cells. Morris water maze learning, open field activity and rotarod behavior were tested 1 and 6 months after exercise onset. Here we show that long‐term running improved retention of spatial memory and modestly enhanced rotarod performance at 15 months of age. Both hippocampal neurogenesis and mature BDNF peptide levels were elevated after long‐term running. Thus, regular exercise from the onset and during middle‐age may maintain brain function.

Subcellular and metabolic examination of amyloid-β peptides in Alzheimer disease pathogenesis: Evidence for Aβ25–35

Amyloid-beta peptide (Abeta) is a central player in the pathogenesis and diagnosis of Alzheimer disease. It aggregates to form the core of Alzheimer disease-associated plaques found in coordination with tau deposits in diseased individuals. Despite this clinical relevance, no single hypothesis satisfies and explicates the role of Abeta in toxicity and progression of the disease. To explore this area, investigators have focused on mechanisms of cellular dysfunction, aggregation, and maladaptive responses. Extensive research has been conducted using various methodologies to investigate Abeta peptides and oligomers, and these multiple facets have provided a wealth of data from specific models. Notably, the utility of each experiment must be considered in regards to the brain environment. The use of Abeta(25-35) in studies of cellular dysfunction has provided data indicating that the peptide is indeed responsible for multiple disturbances to cellular integrity. We will review how Abeta peptide induces oxidative stress and calcium homeostasis, and how multiple enzymes are deleteriously impacted by Abeta(25-35). Understanding and discussing the origin and properties of Abeta peptides is essential to evaluating their effects on various intracellular metabolic processes. Attention will also be specifically directed to metabolic compartmentation in affected brain cells, including mitochondrial, cytosolic, nuclear, and lysosomal enzymes.

The cell cycle in Alzheimer disease : A unique target for neuropharmacology

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

ALZHEIMER’S DISEASE: CEREBROVASCULAR DYSFUNCTION, OXIDATIVE STRESS, AND ADVANCED CLINICAL THERAPIES

Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimers disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and blood-brain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.

Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer's disease.

Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimers disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we tested whether activity and pharmacological stimulation could prevent memory deficits and modify neurogenesis and/or neuropathology in the 3xTg model backcrossed to the C57Bl/6 strain. We chronically administered the antidepressant fluoxetine to one group of mice, allowed access to a running wheel in another, and combined both treatments in a third cohort. All treatments lasted for 11 months. The female 3xTg mice failed to exhibit any deficits in spatial learning and memory as measured in the Morris water maze, indicating that when backcrossed to the C57Bl/6 strain, the 3xTg mice lost the behavioral phenotype that was present in the original 3xTg mouse maintained on a hybrid background. Despite this, the backcrossed 3xTg mice expressed prominent intraneuronal amyloid beta (Aβ) levels in the cortex and amygdala, with lower levels in the CA1 area of the hippocampus. In the combined cohort, fluoxetine treatment interfered with exercise and reduced the total distance run. The extent of Aβ neuropathology, the tau accumulations, or BDNF levels, were not altered by prolonged exercise. Thus, neuropathology was present but not paralleled by spatial memory deficits in the backcrossed 3xTg mouse model of AD. Prolonged exercise for 11 months did improve the long-term survival of newborn neurons generated during middle-age, whereas fluoxetine had no effect. We further review and discuss the relevant literature in this respect.

Estrogen bows to a new master : The role of gonadotropins in alzheimer pathogenesis

Abstract: Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Womens Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic‐pituitary‐gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle‐stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood‐brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

Therapeutic opportunities in Alzheimer disease: one for all or all for one?

In recent years, Alzheimer disease (AD) has received great attention as an incurable and fatal disease that threatens the lives of aging individuals. Debates regarding areas of research and treatment designs have made headlines as scientists in the field question ongoing work. Despite these academic quarrels, significant insights concerning the cellular and molecular basis of AD have illuminated the potential causes and consequences of AD pathogenesis in the human brain. Additionally, assigning relationships among scientific evidence is difficult due to the nature of the disease. It is crucial to note that all findings do not constitute causality as AD has many stages of progression, and therefore a particular finding may reflect disease epiphenomenon. Determining the primary causes of disease are even more problematic when considering that a succinct timeline in which a normal aging brain develops AD-like changes due to a single cause may not be appropriate, as increasing lines of evidence indicate that multiple factors likely contribute to the clinical manifestation of AD. Implications for therapeutic strategies are dramatically affected by viewing AD as a multi-factorial disease state, one specific treatment may not be able to prevent or reverse AD if this is indeed the case. In this regard, the current focus on individual therapeutic targets may prove to be ineffective in the successful treatment of AD; however, if taken in combination, these singular therapies may likely result in the global suppression of AD. In this review, the scientific basis for common AD therapeutics as well as the efficacy of these treatments will be discussed.

Proliferation in the Alzheimer hippocampus is due to microglia, not astroglia, and occurs at sites of amyloid deposition

Microglia and astrocytes contribute to Alzheimers disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

Distinct structural plasticity in the hippocampus and amygdala of the middle-aged common marmoset (Callithrix jacchus)

Adult neurogenesis in the primate brain is generally accepted to occur primarily in two specific areas; the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. Hippocampal neurogenesis is well known to be downregulated by stress and aging in rodents, however there is less evidence documenting the sensitivity of neuroblasts generated in the SVZ. In primates, migrating cells generated in the SVZ travel via a unique temporal stream (TS) to the amygdala and entorhinal cortex. Using adult common marmoset monkeys (Callithrix jacchus), we examined whether i) adult-generated cells in the marmoset amygdala differentiate into doublecortin-positive (DCX+) neuroblasts, and ii) whether lasting changes occur in DCX-expressing cells in the DG or amygdala when animals are exposed to 2 weeks of psychosocial stress. A surprisingly large population of DCX+ immature neurons was found in the amygdala of these 4-year-old monkeys with an average density of 163,000 DCX+ cells per mm(3). Co-labeling of these highly clustered cells with PSA-NCAM supports that a subpopulation of these cells are migratory and participate in chain-migration from the SVZ to the amygdala in middle-aged marmosets. Exposure to 2 weeks of isolation and social defeat stress failed to alter the numbers of BrdU+, or DCX+ cells in the hippocampus or amygdala when evaluated 2 weeks after psychosocial stress, indicating that the current stress paradigm has no long-term consequences on neurogenesis in this primate.

Presenilin mouse and zebrafish models for dementia: Focus on neurogenesis

Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimers disease (AD), a neurological disorder pathologically characterized by intraneuronal accumulation and extracellular deposition of amyloid-β in plaques and intraneuronal, hyperphosphorylated tau aggregation in neurofibrillary tangles. Presenilins (PS/PSENs) are part of the proteolytic γ-secretase complex, which cleaves substrate proteins within the membrane. Cleavage of the amyloid precursor protein (APP) by γ-secretase releases amyloid-β peptides. Besides its role in the processing of APP and other transmembrane proteins, presenilin plays an important role in neural progenitor cell maintenance and neurogenesis. In this review, we discuss the role of presenilin in relation to neurogenesis and neurodegeneration and review the currently available presenilin animal models. In addition to established mouse models, zebrafish are emerging as an attractive vertebrate model organism to study the role of presenilin during the development of the nervous system and in neurodegenerative disorders involving presenilin. Zebrafish is a suitable model organism for large-scale drug screening, making this a valuable model to identify novel therapeutic targets for AD.