Neurogenesis in Alzheimer's disease

It is widely acknowledged that neural stem cells generate new neurons through the process of neurogenesis in the adult brain. In mammals, adult neurogenesis occurs in two areas of the CNS: the subventricular zone and the subgranular zone of the dentate gyrus of the hippocampus. The newly generated cells display neuronal morphology, generate action potentials and receive functional synaptic inputs, their properties being equivalent to those of mature neurons. Alzheimer's disease (AD) is the widespread cause of dementia, and is an age-related, progressive and irreversible neurodegenerative disease that results in massive neuronal death and deterioration of cognitive functions. Here, we overview the relations between adult neurogenesis and AD, and try to analyse the controversies in the field. We also summarise recent data obtained in the triple transgenic model of AD that show time- and region-specific impairment of neurogenesis, which may account for the early changes in synaptic plasticity and cognitive impairments that develop prior to gross neurodegenerative alterations and that could underlie new rescue therapies.     

Newborn granule cells in the ageing dentate gyrus

The dentate gyrus of the hippocampus generates neurons throughout life, but adult neurogenesis exhibits a marked age-dependent decline. Although the decrease in the rate of neurogenesis has been extensively documented in the ageing hippocampus, the specific characteristics of dentate granule cells born in such a continuously changing environment have received little attention. We have used retroviral labelling of neural progenitor cells of the adult mouse dentate gyrus to study morphological properties of neurons born at different ages. Dendritic spine density was measured to estimate glutamatergic afferent connectivity. Fully mature neurons born at the age of 2 months display ∼2.3 spines μm⁻¹ and maintain their overall morphology and spine density in 1-year-old mice. Surprisingly, granule cells born in 10-month-old mice, at which time the rate of neurogenesis has decreased by ∼40-fold, reach a density of dendritic spines similar to that of neurons born in young adulthood. Therefore, in spite of the sharp decline in cell proliferation, differentiation and overall neuronal number, the ageing hippocampus presents a suitable environment for new surviving neurons to reach a high level of complexity, comparable to that of all other dentate granule cells.     

Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice

Age-related changes in neurogenesis and its modulation by caloric restriction (CR) were studied in C57BL/6 mice. To this end, bromodeoxyuridine (BrdU) labeling was used to assess neuronal and glial precursor proliferation and survival in the granular cell layer (GCL) and the hilus of the dentate gyrus of 2-, 12-, 18-, and 24-month-old mice. For both regions, we found an age-dependent decrease in proliferation but not in survival of newborn cells. Interestingly, the reduction in proliferation occurred between 2 and 18 months of age with no additional decline between 18- and 24-month-old mice. Phenotyping of the newborn cells revealed a decrease in the neuron fraction in the GCL between 2 and 12 months of age but not thereafter. The majority of BrdU cells in the hilus colocalized with astrocytic but none with neuronal markers. CR from 3 to 11 months of age had no effect on neurogenesis in the GCL, but had a survival-promoting effect on newly generated glial cells in the hilus of the dentate gyrus. In conclusion, C57BL/6 mice reveal a substantial reduction in neurogenesis in the dentate gyrus until late adulthood with no further decline with aging. Long-term CR does not counteract this age-related decline in neurogenesis but promotes survival of hilar glial cells.     

Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain

Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.     

Running wheel exercises accelerate neuronal turnover in mouse dentate gyrus

Neurogenesis continues throughout adulthood in mouse dentate gyrus, and is influenced by environmental, endocrine, and pharmacological conditions. Although running wheel exercises have been reported to enhance neurogenesis, the effects on neuronal death in dentate gyrus are not well understood. The precise control of the production and elimination of neurons is thought to be important for the maintenance of a relatively constant number of neurons in the adult nervous system and for the regulation of adult brain function. We report here that running wheel exercises enhance the death of pre-existing neurons as well as neurogenesis in dentate gyrus. In addition, we analyzed mice lacking an NMDA receptor varepsilon1 subunit, and found that the enhancement of the neuronal death by the exercises is suppressed in the varepsilon1 subunit knockout mice. These results suggest that running wheel exercises accelerate neuronal turnover in mouse dentate gyrus, through the activation of NMDA receptors.     

Pneumococcal cell wall-induced meningitis impairs adult hippocampal neurogenesis

Bacterial meningitis is a major infectious cause of neuronal degeneration in the hippocampus. Neurogenesis, a continuous process in the adult hippocampus, could ameliorate such loss. Yet the high rate of sequelae from meningitis suggests that this repair mechanism is inefficient. Here we used a mouse model of nonreplicative bacterial meningitis to determine the impact of transient intracranial inflammation on adult neurogenesis. Experimental meningitis resulted in a net loss of neurons, diminished volume, and impaired neurogenesis in the dentate gyrus for weeks following recovery from the insult. Inducible nitric oxide synthase (iNOS) immunoreactivity was prominent in microglia in nonproliferating areas of the dentate gyrus and hilus region after meningitis induction. Treatment with the specific iNOS inhibitor N6-(1-iminoethyl)-L-lysine restored neurogenesis in experimental meningitis. These data suggest that local central nervous system inflammation in and of itself suppresses adult neurogenesis by affecting both proliferation and neuronal differentiation. Repair of cognitive dysfunction following meningitis could be improved by intervention to interrupt these actively suppressive effects.     

Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus

Neurogenesis in the dentate gyrus (DG) declines severely by middle age, potentially because of age-related changes in the DG microenvironment. We hypothesize that providing fresh glial restricted progenitors (GRPs) or neural stem cells (NSCs) to the aging hippocampus via grafting enriches the DG microenvironment and thereby stimulates the production of new granule cells from endogenous NSCs. The GRPs isolated from the spinal cords of embryonic day 13.5 transgenic F344 rats expressing human alkaline phosphatase gene and NSCs isolated from embryonic day 9 caudal neural tubes of Sox-2:EGFP transgenic mice were expanded in vitro and grafted into the hippocampi of middle-aged (12 months old) F344 rats. Both types of grafts survived well, and grafted NSCs in addition migrated to all layers of the hippocampus. Phenotypic characterization revealed that both GRPs and NSCs differentiated predominantly into astrocytes and oligodendrocytic progenitors. Neuronal differentiation of graft-derived cells was mostly absent except in the dentate subgranular zone (SGZ), where some of the migrated NSCs but not GRPs differentiated into neurons. Analyses of the numbers of newly born neurons in the DG using 5'-bromodeoxyuridine and/or doublecortin assays, however, demonstrated considerably increased dentate neurogenesis in animals receiving grafts of GRPs or NSCs in comparison with both na?ve controls and animals receiving sham-grafting surgery. Thus, both GRPs and NSCs survive well, differentiate predominantly into glia, and stimulate the endogenous NSCs in the SGZ to produce more new dentate granule cells following grafting into the aging hippocampus. Grafting of GRPs or NSCs therefore provides an attractive approach for improving neurogenesis in the aging hippocampus. Disclosure of potential conflicts of interest is found at the end of this article.     

Raised circulating corticosterone inhibits neuronal differentiation of progenitor cells in the adult hippocampus

Neurons are added throughout life to the dentate gyrus of the hippocampus of the mammalian brain. Progenitors residing in the dentate gyrus progress through three distinct stages of adult neurogenesis: proliferation, survival and differentiation. One of the most potent factors which regulates adult neurogenesis is adrenal-derived glucocorticoids. Raised levels of glucocorticoids suppress progenitor division, while removal of glucocorticoids by adrenalectomy stimulates proliferation of these cells in the dentate gyrus. We have recently reported that both pre- and post-mitotic corticoid environments powerfully regulate survival of progenitor cells in a time-dependent manner. However, it is unknown if glucocorticoids alter the process of neuronal differentiation, since not all of the newly-formed cells acquire a neuronal fate during development. Here we employ triple immuno-fluorescence staining techniques to phenotype surviving progenitor cells 28 days after labeling. Results show that high levels of corticosterone (the major glucocorticoid in rodents) either before or after progenitor labeling discouraged the acquisition of neuronal fate. Similar to its effect on survival, post-mitotic corticosterone also regulates neuronal differentiation in a time-dependent fashion, but this action is most prominent from around 19-27 days after the cells were born. In contrast, a corticoid-free environment either before or after progenitor proliferation did not affect neuronal differentiation. Combining these data with previous survival data obtained from the same animals allowed us to estimate the total number of neurons formed resulting from different corticoid treatments. Raised corticosterone significantly reduced neuronal production while adrenalectomy resulted in significantly higher number of neurons in the adult male rat hippocampus.     

The aging hippocampus: a multi-level analysis in the rat

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.     

The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer's disease

Alzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that results in the loss of selected neurons throughout the basal forebrain, amygdala, hippocampus, and cortical area as well as progressive deficits of cognition and memory. The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is one of the regions where adult neurogenesis occurs in mammals, including humans and non-human primates. The new granule cells, which are the primary excitatory neurons in the DG, contribute to the processes of learning and memory. The changes in neurogenesis observed during the initial stages and progression of AD suggest that the modulation of the new production of neurons at neurogenic sites may exert profound effects on hippocampal function. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin contribute to the modulation of neurogenesis in the adult hippocampus, thereby affecting hippocampal function. This review focuses on the role of BMP4 and Noggin in the control of the stem and precursor cells in the adult hippocampus during AD and their potential as a possible therapeutic strategy for AD sufferers. It is helpful to extend the understanding of the control of stem cells in the normal and diseased hippocampus.     

Melatonin supplementation delays the decline of adult hippocampal neurogenesis during normal aging of mice

Melatonin modulates adult hippocampal neurogenesis in adult mice. Also, plasma melatonin levels and new neuron formation decline during aging probably causing cognitive alterations. In this study, we analyzed the impact of exogenous supplementation with melatonin in three key events of hippocampal neurogenesis during normal aging of mice. The analysis was performed in rodents treated with melatonin during 3, 6, 9 or 12 months. We found an increase in cell proliferation in the dentate gyrus of the hippocampus after 3, 6 and 9 months of treatment (>90%). Additionally, exogenous melatonin promoted survival of new cells in the dentate gyrus (>50%). Moreover, melatonin increased the number of doublecortin-labeled cells after 6 and 9 months of treatment (>150%). In contrast, melatonin administered during 12 months did not induce changes in hippocampal neurogenesis. Our results indicate that melatonin also modulates the neurogenic process in the hippocampus during normal aging of mice. Together, the data support melatonin as one of the positive endogenous regulators of neurogenesis during aging.     

Effect of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning

The dentate gyrus of the hippocampal formation produces new neurons throughout adulthood in mammalian species. Several experimental statuses and factors regulating to neurogenesis have been identified in the adult dentate gyrus. For example, exposure to an enriched environment enhances neurogenesis in the dentate gyrus and improves hippocampus-dependent spatial learning. Furthermore, serotonin is known to influence adult neurogenesis, and learning and memory. However, the effects of long-lasting depletion of serotonin over the developing period on neurogenesis have not been investigated. Thus, we examined the influence of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis and spatial memory performance. As reported previously, environmental enrichment significantly increased new neurons in the dentate gyrus. However, there was no improvement of the spatial learning test in adult rats in standard and in environmental enrichment housings. Intracisternal administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine, on postnatal day 3 apparently reduced serotonin content in the adult hippocampus without regeneration. This experimental depletion of serotonin in the hippocampus of rats housed in an enriched environment had no effect on spatial memory performance, but produced significant decreases in the number of bromodeoxyuridine-labeled new cells in the dentate gyrus. These findings indicate that newly generated cells stimulated by environmental enrichment are not critical for improvements in hippocampus-dependent learning. Furthermore, numbers of bromodeoxyuridine-labeled cells in the dentate gyrus of 5,7-dihydroxytryptamine-injected rats did not differ between 1 day and 4 weeks after bromodeoxyuridine injection. These data suggest that survival of newly generated dentate gyrus cells remains relatively constant under long-lasting serotonin depletion.     

Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia

The observed age-related decline in neurogenesis may result from reduced proliferation or increased death rate of neuronal precursor cells (NPCs). We found that caspase-3, but not caspase-6, -7, or -9, was activated in NPCs in neurogenic regions of young, young-adult, middle-aged and aged rat brains. The number of capase-3-immunoreactive cells was highest in young and lowest in aged rats. Surprisingly, intraventricular administration of a caspase-3 inhibitor failed to restore the number of BrdU-positive cells in the aged dentate gyrus, suggesting that the age-related decline in neurogenesis may be attributable primarily to reduced proliferation. Additionally, we also found that NPCs in the subventricular zone of young-adult and aged rat brain were increased after focal cerebral ischemia, suggesting that the increase in neurogenesis induced by ischemia may result from an increase in the rate of NPC proliferation, but not from a decrease in NPC death. Thus, our results suggest that age-related and injury-induced changes in the rate of neurogenesis are controlled at the level of NPC proliferation. Furthermore, our results may imply that the mechanisms that maintain a stable population of NPCs in the normal adult and in the ischemic brain, which account for the observed age-dependent reduction or injury-induced increases in neurogenesis, impinge on the regulation of cell division at the NPC level.     

身体活动对海马体可塑性和认知功能的影响

背景:身体活动作为一种实用模型,可以从各个方面来研究运动与大脑健康之间的关联,从而更清楚地认识运动对大脑的促进作用,特别是身体活动对海马体结构和功能的改变。目的:综述身体活动与海马体和认知方面的研究,并提出目前研究和实际应用方面许多亟待解决的问题。方法:以"Physical activity,Exercise,Hippocampal,Cognition,Neuroplasticity,Adaptive,Mechanisms"为检索词,检索PubMed数据库1995至2019年发表的相关文章,文献检索语种限制为英文。纳入身体活动和海马、认知调节机制和应用方面的相关内容。结果与结论:计算机初检得到142篇文献,排除无关和重复的文献,保留89篇进行综述。海马体齿状回具有神经再生的能力。规律性身体活动对身体和大脑健康产生深远的影响,运动可促进海马体齿状回的神经再生,可增加两三倍,此类神经主要发生在齿状回背侧。此外,运动对神经元的成熟、形态和连接性等特性的改变也十分重要,并能改变新神经元的整合通路,增加传入新生神经元和传入细胞突触的数量。海马体齿状回的神经再生与运动诱导的多种因素有关,新生神经元的发育和整合需要多个神经递质的参与,而运动可通过调节兴奋性和抑制性神经递质,促进海马体突触可塑性的变化;运动诱导的血清脑源性神经营养因子水平升高则可减缓海马体体积的变化;运动的持续时间和强度可差异性地调节脑血流量,进而影响神经元活动,而长期运动后血管内皮生长因子的过表达,则可促进海马体的血管增殖,增加海马体的神经发生。此外,运动也可改变成人新生神经元的突触可塑性和连接网络,增强成人新生神经元与现有海马-内嗅通路的整合。     

Chronic non-invasive glucocorticoid administration decreases polysialylated neural cell adhesion molecule expression in the adult rat dentate gyrus

The expression of the polysialylated neural cell adhesion molecule (PSA-NCAM) is increased in the hippocampus after chronic restraint stress (CRS) and may play a permissive role in structural changes that include dendrite reorganization in dentate gyrus (DG) and CA3 pyramidal neurons and suppression of neurogenesis in DG. We report that chronic oral corticosterone (CORT) administration decreases the number of PSA-NCAM immunoreactive granule neurons in the adult rat dentate gyrus, and the available evidence suggests that this is an indirect effect of CORT, possibly involving excitatory amino acids, that may not be directly related to neurogenesis. Because CORT treatment reduces but does not eliminate PSA-NCAM expression, the present results do not exclude a permissive role for PSA-NCAM in CORT or CRS-induced structural plasticity in hippocampus.     

Morphological basis of nitric oxide production and its correlation with the polysialylated precursor cells in the dentate gyrus of the adult guinea pig hippocampus

Neurogenesis in the hippocampus persist throughout life and precursors of neurons reside in the granule cell layer of the dentate gyrus. Until now, the role of nitric oxide (NO) in the phenomenon has been unclear. By using specific antibodies and a confocal laser scanning microscope, the localization of NO synthase (NOS) was examined in the dentate gyrus of the adult guinea pig in relation with the neuronal precursor marker highly polysialylated neural cell adhesion molecule (PSA-N-CAM). Observation of single immunolabeled sections has revealed that both the PSA-N-CAM- and most NOS-positive cells were localized in the granule cell layer of the dentate gyrus. The former were small in size and showed a punctate, clustered immunoreaction with an irregular cellular margin, whereas the latter showed somewhat diverse cellular profiles. Some NOS-positive neurons had elliptical-like morphology with elongated dendrites, whereas others were small, irregularly shaped and mostly lacking dendritic spines. Double immunolabeling has revealed that NOS-immunoreactivity intermingled, as well as colocalized, with that of PSA-N-CAM, particulary in the granule cell layer. The doubly stained cells were morphologically indistinguishable from PSA-N-CAM single positive cells. These results not only suggest the role of NO production in adult hippocampal neurogenesis, but also indicate that some PSA-N-CAM-expressing neuronal precursors produce NO.     

Age-related effects on hippocampal precursor cell subpopulations and neurogenesis

Hippocampal neurogenesis continuously declines in the aging brain but only little is known about age-related alterations in the subgranular zone (SGZ) of the dentate gyrus which accommodates different subpopulations of precursor cells. Here, we examined the age-related effects on total number and proliferation rate of distinct precursor cell populations in the dentate gyrus of 3 and 16 months old transgenic pNestin-GFP mice. Following a single injection of bromodeoxyuridine (BrdU) we observed a significant reduction of all proliferating precursor subtypes in aged mice compared to young controls. Stereological analysis further revealed that this decreased proliferation was not only caused by a general reduction in total number of precursor subtypes but also by a subtype-specific alteration of the proliferation rate. Whereas radial glia-like and early neuronal precursor cells demonstrate decreased proliferation rates, no difference was found for doublecortin-positive precursors. Additional long-term experiments further revealed that these age-related alterations in the proliferative zone were accompanied by a strongly decreased neurogenesis while hippocampal function was not impaired.     

Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb

Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions.     

NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus

The production of new neurons declines during adulthood and persists, although at very low levels, in the aged hippocampus. Since neurogenesis in young adults has been related to learning and memory, its reduction may contribute to the age-related impairments in these abilities. Adrenalectomy (ADX) enhances neurogenesis in the aged hippocampus, although it also induces neuronal cell death. Since the administration of an NMDA receptor antagonist enhances neurogenesis in young adult rats without deleterious morphological effects, we have tested whether neurogenesis could be reactivated in aged rats. Our study shows that cell proliferation, cell death, neurogenesis and the number of radial glia-like nestin immunoreactive cells decrease in middle-age (10 months) and remain very low in the aged hippocampus. Injection of the NMDA receptor antagonist to aged rats increases significantly the number of proliferating cells, new neurons and radial glia-like cells in the hippocampus.     

Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats

During adulthood, neuronal precursor cells persist in two discrete regions, the subventricular zone[19]and the hippocampal subgranular zone,[11]as recently demonstrated in primates.[10]To date, a few factors such as adrenal steroids[9]and trophic factors[13]are known to regulate adult neurogenesis. Since neuronal activity may also influence cellular development and plasticity in brain, we investigated the effects of serotonin depletion on cell proliferation occurring in these regions. Indeed, in addition to its role as a neurotransmitter, 5-hydroxytryptamine (serotonin) is considered as a developmental regulatory signal.14, 22Prenatal depletion in 5-hydroxytryptamine delays the onset of neurogenesis in 5-hydroxytryptamine target regions[14]and 5-hydroxytryptamine promotes the differentiation of cortical and hippocampal neurons.15, 23Although in the adult brain, a few studies have suggested that 5-hydroxytryptamine may play a role in neuronal plasticity by maintaining the synaptic connections in the cortex and hippocampus,3, 6, 16no information is actually available concerning the influence of 5-hydroxytryptamine on adult neurogenesis. If further work confirms that new neurons can be produced in the adult human brain as is the case for a variety of species, it is particularly relevant to determine the influence of 5-hydroxytryptamine on neurogenesis in the hippocampal formation, a part of the brain largely implicated in learning and memory processes. Indeed, lack of 5-hydroxytryptamine in the hippocampus has been associated with cognitive disorders, such as depression,[1]schizophrenia and Alzheimer's disease.[7]In the present study, we demonstrated that both inhibition of 5-hydroxytryptamine synthesis and selective lesions of 5-hydroxytryptamine neurons are associated with decreases in the number of newly generated cells in the dentate gyrus, as well as in the subventricular zone.