Activity- and pharmacology-dependent modulation of adult neurogenesis in relation to Alzheimer’s disease

In de hersenen van een volwassen mens zijn stamcellen aanwezig. Deze delen zich om nieuwe neuronen te produceren. Dit proces heet neurogenese, en speelt een belangrijke rol bij verschillende hersenprocessen. De vraag is echter of stamcellen therapeutisch kunnen worden ingezet voor de behandeling van bijvoorbeeld de ziekte van Alzheimer, een ziekte waarbij neuronen vroegtijdig afsterven. Michael Marlatt laat zien dat lichaamsbeweging bij muizen ervoor zorgt dat neurogenese in de hersenen toeneemt. Daarnaast voorkomt lichaamsbeweging een leeftijd-gerelateerde afname van ruimtelijk geheugen. Ook bevestigt de aanwezigheid van neurogenese in de amygdala, een hersengebied dat een belangrijke rol speelt bij emoties. Zijn bevindingen zijn bemoedigend voor de toekomstige behandeling van de ziekte van Alzheimer. Mogelijk kan lichaamsbeweging of medicijnen de geheugenproblemen die met de ziekte geassocieerd worden, terugdraaien

Neurogenesis and Alzheimer's disease: biology and pathophysiology in mice and men

The hippocampus is critical for learning and memory and heavily affected in dementia. The presence of stem cells in this structure has led to an increased interest in the phenomenon of adult neurogenesis and its role in hippocampal functioning. Not surprising, investigators of Alzheimer's disease have also evaluated adult neurogenesis due to its responsiveness to hippocampal damage. Although causal relationships have not been established, many factors known to impact neurogenesis in the hippocampus, are implicated in the pathogenesis of AD. Also, adult neurogenesis has been proposed to reflect a "neurogenic reserve" that may determine vulnerability to hippocampal dysfunction and neurodegeneration. Since neurogenesis is modifiable, stimulation of this process, or the potential use of stem cells, recruited endogenously or implanted by transplantation, has been speculated as a possible treatment of neurodegenerative disorders. As the structural and molecular mechanisms governing adult neurogenesis are important for evaluating therapeutic strategies, we will here review collective literature findings and speculate about the future of this field with a focus on findings from Alzheimer's mouse models. Continued research in this area and use of these models is critical for evaluating if neurogenesis based therapeutic strategies will indeed have the potential to aid those with degenerative conditions

Comparison of neurogenic effects of fluoxetine, duloxetine and running in mice

Hippocampal neurogenesis can be regulated by extrinsic factors, such as exercise and antidepressants. While there is evidence that the selective serotonin reuptake inhibitor (SSRI) fluoxetine enhances neurogenesis, the new dual serotonergic-noradrenergic reuptake inhibitor (SNRI) duloxetine has not been evaluated in this context. In addition, it is unclear whether effects of antidepressants and running on cell genesis and behavior are of similar magnitude in mice. Here, we assessed neurogenesis and open-field behavior in 2-month-old female C57Bl/6 mice after 28 days of treatment with either fluoxetine (18 mg/kg), duloxetine (2, 6 or 18 mg/kg) or exercise. New cell survival, as measured by 5-bromo-2′-deoxyuridine (BrdU)-labeled cells, was enhanced by 200% in the running group only. Both running and fluoxetine, but not duloxetine, increased the percentage of new cells that became neurons. In the open-field test, animals treated with either drug spent less time in the center than controls and runners. In addition, fluoxetine treatment resulted in reduced locomotor activity. Together, these data show that the neurogenic response to exercise is much stronger than to antidepressants and imply a low likelihood that anxiolytic effects of these drugs are mediated by adult neurogenesis in C57Bl/6 mice

Alzheimer’s disease and adult neurogenesis—Are endogenous stem cells part of the solution?

The human brain produces new neurons that mediate hippocampal plasticity but also have a potential role in hippocampal-related disorders, such as Alzheimer’s disease and dementia. Factors such as stress and aging that reduce adult neurogenesis also serve as independent risk factors for Alzheimer’s disease. Causality between loss of neurogenesis and hippocampal dysfunction has not been established; however, neurogenesis is an attractive research avenue for therapy since it is readily modifiable. Activities such as running and enrichment increase the proliferation of neural stem cells and survival of nascent neuroblasts. Adult neurogenesis may alternatively reflect capacity to overcome age-dependent insults and neurodegeneration in the hippocampus. This collectively indicates that stimulation of endogenous cells or transplantation of neural stem cells are potential pathways reversing the behavioral changes associated with neurodegenerative disorders by augmenting structural plasticity of the hippocampus. Continued research in this area and in appropriate animal models of disease is critical for evaluating whether neurogenesis-based therapeutic strategies will have the potential to aid those with degenerative conditions

Subcellular and metabolic examination of amyloid-beta peptides in Alzheimer disease pathogenesis: evidence for Abeta(25-35).

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

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

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 Alzheimer's 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

Presenilin mouse and zebrafish models for dementia: Focus on neurogenesis

Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimer's 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