Decline In Neurogenesis Research Articles

Longitudinal Study of Irradiation-Induced Brain Microstructural Alterations With S-Index, a Diffusion MRI Biomarker, and MR Spectroscopy

Radiation therapy is widely used for the treatment of brain tumors, but it may lead to severe cognitive impairments. Previous studies have shown that ionizing irradiation induces demyelination, blood-brain barrier alterations, and impaired neurogenesis in animal models. Hence, noninvasive and sensitive biomarkers of irradiation injury are needed to investigate these effects in patients and improve radiation therapy protocols. The heads of 3-month-old male C57BL/6RJ mice (15 control mice and 15 irradiated mice) were exposed to radiation doses of 3 fractions of 5Gy from a 60Co source with a medical irradiator.A longitudinal study was performed to investigate cranial irradiation-induced (3 fractions of 5Gy) microstructural tissue alterations using water diffusion magnetic resonance imaging and magnetic resonance spectroscopy in different areas of the mouse brain (cortex, thalamus, striatum, olfactory bulbs [OBs], hippocampus, and subventricular zone [SVZ]). In addition to the quantification of standard non-Gaussian diffusion parameters, apparent diffusion coefficient (ADC0) and kurtosis (K), we evaluated a new composite diffusion metric, designated the S-index (ie, "signature index"). We observed a significant decrease in the S-index in the SVZ from 1month to 8months after brain irradiation (P<.05). An interesting finding was that, along with a decrease in taurine levels (up to -15% at 2months, P<.01), a delayed S-index drop was observed in the OBs from 4months after irradiation and maintained until the end of our experiment (P<.0001). These observations suggest that S-index variations revealed the irradiation-induced decline of neurogenesis that was further confirmed by a decrease in neural stem cells in the SVZ and in newborn neurons in the OBs of irradiated animals. This study demonstrates that diffusion magnetic resonance imaging, especially through the S-index approach, is a relevant imaging modality to monitor brain irradiation injury and probe microstructural changes underlying irradiation-induced cognitive deficits.

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain

SUMMARYRestoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.

Effects of fractionated whole-brain irradiation on cellular composition and cognitive function in the rat brain

Purpose: The aim of this study was investigate whether histopathological changes in the neurogenic region correlate with appropriate cognitive impairment in the experimental model of radiation-induced brain injury.Materials and methods: Adult male Wistar rats randomized into sham (0 Gy) and two experimental groups (survived 30 and 100 days after treatment) received fractionated whole-brain irradiation (one 5 Gy fraction/week for four weeks) with a total dose of 20 Gy of gamma rays. Morris water maze cognitive testing, histochemistry, immunohistochemistry and confocal microscopy were used to determine whether the cognitive changes are associated with the alteration of neurogenesis, astrocytic response and activation of microglia along and/or adjacent to well-defined pathway, subventricular zone-olfactory bulb axis (SVZ-OB axis).Results: Irradiation revealed altered cognitive functions usually at 100 days after treatment. Neurodegenerative changes were characterized by a significant increase of Fluoro-Jade-positive cells 30 days after irradiation accompanied by a steep decline of neurogenesis 100 days after treatment. A strong astrocytic response and upregulation of the activated microglia were seen in both of experimental groups.Conclusions: Results shows that fractionated irradiation led to cognitive impairment closely associated with accerelation of neuronal cell death, inhibition of neurogenesis, activation of astrocytes and microglia indicate early delayed radiation-induced changes.

Abstract TMP29: Type II Diabetes Induces an Early Decline of Neurogenesis With Increased Morphological Alteration in Neuroblasts

Introduction: Diabetes increases the severity of stroke outcome and impairs the capacity for neuroplasticity. Evidence suggests that neurogenesis, a mechanism of neuroplasticity, is induced after experimental stroke, although how it is confounded by type 2 diabetes mellitus (T2DM) or aging remains to be clarified. Hypothesis: We hypothesize that T2DM exacerbates age-associated reduction in neurogenesis. Methods: Experimental stroke was induced by distal middle cerebral artery occlusion (dMCAO) in young (11-13 weeks-old, n=12) and middle-aged (53-75 weeks-old, n=50) db/+ or db/db mice, as well as in db/+ mice of old age (99-124 weeks-old, n=30). Thymidine analog 5-bromo-2′-deoxyuridine-5′(BrdU) was administered i.p. at 50 mg/kg twice daily from days 4-7 after dMCAO to label proliferating cells. Mice were euthanized 28 days after dMCAO and their brain tissue was processed for immunohistochemistry for BrdU and markers of neuronal or glial lineages. Results: A significant reduction in the number of DG neuroblasts was found in the db/db compared to db/+ mice in both young and middle-aged groups at baseline and after dMCAO. There was a further decline of neurogenesis in the old db/+ mice compared to the middle-aged db/+ mice by 6.2 and 3 folds at baseline and after dMCAO, respectively. dMCAO induces an increase of DCX(+) neuroblasts in all age groups of db/+ mice but not in db/db mice, suggesting that T2DM elicited an early decline of neurogenesis, leading to a failed regeneration after stroke. Large DCX(+) cells without processes were found in the DG of old db/+ and middle-aged db/db mice. Neuroblasts with aberrant morphology do not express markers of astrocytes or oligodendrocytes, although their identity and nature remains unclear. Conclusions: Our data suggest that T2DM accelerates the decline of neurogenesis induced by aging, which may potentially affect the functional outcome of regeneration and post stroke neuroplasticity impacted by this comorbidity. Ongoing investigation will further characterize the functional change of the neuroblasts with altered morphology and determine the effect on differentiation and survival of newborn neurons in the DG of db/db mice.

Intracerebroventricular streptozotocin impairs adult neurogenesis and cognitive functions via regulating neuroinflammation and insulin signaling in adult rats

Neurogenesis is a complex process involved in memory formation and is known to be altered in Alzheimer's disease (AD). Neuroinflammation and insulin signaling dysfunction, key players during intracerebroventricular Streptozotocin (ICV-STZ) induced dementia variedly affects neurogenesis. The aim of this work was to study the variation in neurogenic process associated with AD in ICV STZ induced dementia. Adult male Sprague Dawley rats weighing 180–200 g were given two different doses of ICV STZ (3 mg/kg on Day 1 and 3, & 1 mg/kg on Day 1) in two different experimental setup. Memory functions were assessed by Morris Water Maze. Immunofluorescence and western blotting was done to study the variation in neurogenesis, amyloid and tau pathology, neuroinflammation and insulin signaling. ICV STZ 6 mg/kg (3 mg/kg twice on Day 1 and 3 of 21 days study) caused impairment in learning and memory and severe atrophy of the neurogenic areas. Modified dose of ICV STZ (1 mg/kg once on Day 1) caused a significant decline in neurogenesis in subventricular zone (SVZ) and dentate gyrus (DG) as indicated by decrease in the number of (5-Bromo-2′-deoxyuridine) BrdU+ Nestin+ cells, Doublecortin (DCX+) cells and BrdU+ NeuN+ cells after day 11 and 18 of ICV STZ injection. However, impairment in learning and memory was observed only during 18 days study post ICV STZ injection (1 mg/kg on Day 1). Up regulation of proteins of amyloid and tau pathology (Amyloid precursor protein (APP), β site amyloid precursor protein cleaving enzyme 1 (BACE1) & p-Tau Ser 396) was observed at this time point with no significant change in amyloid β42 (Aβ42) expression. Enhanced neuroinflammation (increased Glial fibrillary acidic protein (GFAP) & nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)) and diminished insulin signaling was also observed in our study in both neurogenic areas, however the extent to which they may have negative impact on neurogenes is yet to be explored.

Aging impairs dendrite morphogenesis of newborn neurons and is rescued by 7, 8-dihydroxyflavone.

SummaryAll aging individuals will develop some degree of decline in cognitive capacity as time progresses. The molecular and cellular mechanisms leading to age‐related cognitive decline are still not fully understood. Through our previous research, we discovered that active neural progenitor cells selectively become more quiescent in response to aging, thus leading to the decline of neurogenesis in the aged hippocampus. Here, we further find that aging impaired dendrite development of newborn neurons. Currently, no effective approach is available to increase neurogenesis or promote dendrite development of newborn neurons in the aging brain. We found that systemically administration of 7, 8‐dihydroxyflavone (DHF), a small molecule imitating brain‐derived neurotrophic factor (BDNF), significantly enhanced dendrite length in the newborn neurons, while it did not promote survival of immature neurons, in the hippocampus of 12‐month‐old mice. DHF‐promoted dendrite development of newborn neurons in the hippocampus may enhance their function in the aging animal leading to a possible improvement in cognition.

Human adult neurogenesis across the ages: An immunohistochemical study.

Neurogenesis in the postnatal human brain occurs in two neurogenic niches; the subventricular zone (SVZ) in the wall of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. The extent to which this physiological process continues into adulthood is an area of ongoing research. This study aimed to characterize markers of cell proliferation and assess the efficacy of antibodies used to identify neurogenesis in both neurogenic niches of the human brain. Cell proliferation and neurogenesis were simultaneously examined in the SVZ and SGZ of 23 individuals aged 0.2-59 years, using immunohistochemistry and immunofluorescence in combination with unbiased stereology. There was a marked decline in proliferating cells in both neurogenic niches in early infancy with levels reaching those seen in the adjacent parenchyma by 4 and 1 year of age, in the SVZ and SGZ, respectively. Furthermore, the phenotype of these proliferating cells in both niches changed with age. In infants, proliferating cells co-expressed neural progenitor (epidermal growth factor receptor), immature neuronal (doublecortin and beta III tubulin) and oligodendrocytic (Olig2) markers. However, after 3 years of age, microglia were the only proliferating cells found in either niche or in the adjacent parenchyma. This study demonstrates a marked decline in neurogenesis in both neurogenic niches in early childhood, and that the sparse proliferating cells in the adult brain are largely microglia.

Editorial: 50th Anniversary of Adult Neurogenesis: Olfaction, Hippocampus, and Beyond.

Editorial: 50th Anniversary of Adult Neurogenesis: Olfaction, Hippocampus, and Beyond.

Blunted response of hippocampal AMPK associated with reduced neurogenesis in older versus younger mice

The rate of hippocampal neurogenesis declines with aging. This is partly explained by decreased neural responsiveness to various cues stimulating metabolism. AMP-activated protein kinase (AMPK), a pivotal enzyme regulating energy homeostasis in response to metabolic demands, showed the diminished sensitivity in peripheral tissues during aging. AMPK is also known to be involved in neurogenesis. We aimed to see whether AMPK reactivity is also blunted in the aged hippocampus, and thus is associated with aging-related change in neurogenesis. Following subchronic (7days) intraperitoneal and acute intracerebroventricular (i.c.v.) administration of either 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR; AMPK activator) or saline (sham) to young (16-week-old) and old (72-week-old) mice, we measured changes in AMPK activity, brain-derived neurotrophic factor (BDNF) expression or neurogenesis in the hippocampus. AICAR-induced changes in AMPK activity were observed in the hippocampus of young mice after acute i.c.v. injection. However, neither subchronic nor acute treatment induced significant changes in AMPK activity in old mice. Intriguingly, directions of AICAR-induced changes in AMPK activity were opposite between the hippocampus (decrease) and skeletal muscle (increase). ATP levels were inversely correlated with hippocampal AMPK activity, suggesting that the higher energy levels achieved by AICAR treatment might deactivate neuronal AMPK in young mice. The blunted response of AMPK to AICAR in old age was also indicated by the observations that the levels of neurogenesis and BDNF expression were significantly changed only in young mice upon AICAR treatment. Our findings suggest that the blunted response of neuronal AMPK in old age might be responsible for aging-associated decline in neurogenesis. Therefore, in addition to activation of AMPK, recovering its sensitivity may be necessary to enhance hippocampal neurogenesis in old age.

Age-related neurogenesis decline in the subventricular zone is associated with specific cell cycle regulation changes in activated neural stem cells.

Although neural stem cells (NSCs) sustain continuous neurogenesis throughout the adult lifespan of mammals, they progressively exhibit proliferation defects that contribute to a sharp reduction in subventricular neurogenesis during aging. However, little is known regarding the early age-related events in neurogenic niches. Using a fluorescence-activated cell sorting technique that allows for the prospective purification of the main neurogenic populations from the subventricular zone (SVZ), we demonstrated an early decline in adult neurogenesis with a dramatic loss of progenitor cells in 4 month-old young adult mice. Whereas the activated and quiescent NSC pools remained stable up to 12 months, the proliferative status of activated NSCs was already altered by 6 months, with an overall extension of the cell cycle resulting from a specific lengthening of G1. Whole genome analysis of activated NSCs from 2- and 6-month-old mice further revealed distinct transcriptomic and molecular signatures, as well as a modulation of the TGFβ signalling pathway. Our microarray study constitutes a cogent identification of new molecular players and signalling pathways regulating adult neurogenesis and its early modifications.

FGF Signaling Is Necessary for Neurogenesis in Young Mice and Sufficient to Reverse Its Decline in Old Mice.

Hippocampal deficits can result from trauma, neurodegeneration, or aging and can lead to loss of memory and mood control. The addition of new neurons to the hippocampus facilitates memory formation, but how this process is regulated and how we might manipulate it to reverse hippocampal dysfunction remains unclear. The FGF signaling pathway has been hypothesized to be important, but its role in generating new neurons had been poorly defined. Our study indicates that FGF signaling maintains and expands subsets of neural precursor cells. Moreover, in older mice, increasing FGF signaling is sufficient to reverse the decline in neuron production to levels found in young adults, providing a potential means of reversing age-related hippocampal deficits.

Stem- and progenitor cell proliferation in the dentate gyrus of the reeler mouse.

Adult hippocampal neurogenesis has been implicated in hippocampus-dependent learning and memory. Furthermore, the decline of neurogenesis accompanying aging could be involved in age-related cognitive deficits. It is believed that the neural stem cell niche comprises a specialized microenvironment regulating stem cell activation and maintenance. However, little is known about the significance of the extracellular matrix in controlling adult stem cells. Reelin is a large glycoprotein of the extracelluar matrix known to be of crucial importance for neuronal migration. Here, we examined the local interrelation between Reelin expressing interneurons and putative hippocampal stem cells and investigated the effects of Reelin deficiency on stem cell and progenitor cell proliferation. Reelin-positive cells are found in close vicinity to putative stem cell processes, which would allow for stem cell regulation by Reelin. We investigated the proliferation of stem cells in the Reelin-deficient reeler hippocampus by Ki67 labeling and found a strong reduction of mitotic cells. A detailed analysis of dividing Type 1, type 2 and type 3 cells indicated that once a stem cell is recruited for proliferation, the progression to the next progenitor stage as well as the number of mitotic cycles is not altered in reeler. Our data point to a role for Reelin in either regulating stem cell quiescence or maintenance.

The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation

A decrease in neurogenesis in the aged brain has been correlated with cognitive decline. The molecular signaling that regulates age-related decline in neurogenesis is still not fully understood. We found that different subtypes of neural stem cells (NSCs) in the hippocampus were differentially impaired by aging. The quiescent NSCs decreased slowly, although the active NSCs exhibited a sharp and dramatic decline from the ages of 6–9 months and became more quiescent at an early stage during the aging process. The activity of the mammalian target of rapamycin (mTOR) signal pathway is compromised in the NSCs of the aged brain. Activating the mTOR signaling pathway increased NSC proliferation and promoted neurogenesis in aged mice. In contrast, inhibiting the mTOR signaling pathway decreased NSCs proliferation. These results indicate that an age-associated decline in neurogenesis is mainly because of the reduction in proliferation of active NSCs, at least partially because of the compromise in the mTOR signaling activity. Stimulating the mTOR signaling revitalizes the NSCs, restores their proliferation, and enhances neurogenesis in the hippocampus of the aged brain.

CHD7 maintains neural stem cell quiescence and prevents premature stem cell depletion in the adult hippocampus.

Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain–helicase‐DNA‐binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle‐aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin‐remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo‐insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits. Stem Cells 2015;33:196–210

Persistent Loss of Hippocampal Neurogenesis and Increased Cell Death following Adolescent, but Not Adult, Chronic Ethanol Exposure

Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, probably due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after chronic ethanol exposure in adolescence.

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.

The number of newly formed neurons declines rapidly during aging, and this decrease in neurogenesis is associated with decreased function of neural stem/progenitor cells (NPCs). Here, we determined that a WIP1-dependent pathway regulates NPC differentiation and contributes to the age-associated decline of neurogenesis. Specifically, we found that WIP1 is expressed in NPCs of the mouse subventricular zone (SVZ) and aged animals with genetically enhanced WIP1 expression exhibited higher NPC numbers and neuronal differentiation compared with aged WT animals. Additionally, augmenting WIP1 expression in aged animals markedly improved neuron formation and rescued a functional defect in fine odor discrimination in aged mice. We identified the WNT signaling pathway inhibitor DKK3 as a key downstream target of WIP1 and found that expression of DKK3 in the SVZ is restricted to NPCs. Using murine reporter strains, we determined that DKK3 inhibits neuroblast formation by suppressing WNT signaling and Dkk3 deletion or pharmacological activation of the WNT pathway improved neuron formation and olfactory function in aged mice. We propose that WIP1 controls DKK3-dependent inhibition of neuronal differentiation during aging and suggest that regulating WIP1 levels could prevent certain aspects of functional decline of the aging brain.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.

Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation

Neurogenesis is thought to play a role in cognitive function and hippocampal plasticity. Previous studies suggest that neurogenesis declines with aging. However, the onset and mechanism of declined neurogenesis are not fully elucidated. Here we show that the major decline in neurogenesis takes place during adulthood, before aging. Decline in neurogenesis takes place in the subgranular layer of the dentate gyrus and in the subventricular zone, and is primarily due to a reduced number of fast-proliferating neural progenitor cells. Importantly, this decline can be rescued by intraventricular injection of recombinant soluble amyloid precursor protein (sAPPα), which regulates neural progenitor cell proliferation in the adult brain. The counterpart, sAPPβ, a product of the amyloidogenic cleavage pathway of amyloid precursor protein, fails to exhibit a proliferative effect in vitro and in vivo, in equimolar concentrations to sAPPα. These observations suggest that adulthood is an appropriate time window for an intervention that upregulates neurogenesis, such as enhancement of sAPPα levels, for the prevention of declining brain plasticity and cognitive function.

Vascular‐derived TGF‐β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain

Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging.

Intrahippocampal injection of Aβ1-42 inhibits neurogenesis and down-regulates IFN-γ and NF-κB expression in hippocampus of adult mouse brain

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) is widely recognized as a key factor in the pathogenesis of AD. Aβ1-42, a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. Alteration of neurogenesis in AD patients has been reported, while little is known about how Aβ1-42 affects hippocampal neurogenesis in the adult brain. In this study, we injected human Aβ1-42 peptide into hippocampal CA1 area of adult mouse brain bilaterally and evaluated histological change and neurogenesis in the hippocampus. Hematoxylin and eosin (HE) stain showed that Aβ1-42-injection resulted in an extensive neurodegeneration in the Aβ-accumulated area and CA3 in hippocampus. Immunostaining showed that intrahippocampal Aβ1-42-injection dramatically decreased the number of bromodeoxyuridine (BrdU)-positive cells in the dentate gyrus (DG) compared to the vehicle injection. Moreover, a significant decrease in the number of BrdU/double-cortin double-positive cells in Aβ1-42-injected hippocampus was observed, suggesting that Aβ1-42-injection inhibited progenitor cell proliferation and neurogenesis in subgranular zone of the DG in the adult brain. We also found that the Aβ1-42-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon-γ (IFN-γ) and transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus. These results suggest that Aβ1-42 inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF-γ and NF-κB signaling pathway. This study provides a new insight into Aβ1-42-mediated decrease in hippocampal neurogenesis in the adult central nervous system.Abbreviations: Aβ, Amyloid-β; AD, Alzheimer’s disease; AβPP (APP), Amyloid β precursor protein; BrdU, Bromodeoxyuridine; CNS, central nervous system; DCX, doublecortin; DG, dentate gyrus; IFN-γ, interferon-γ; NF-κB, nuclear factor-kappa B; NS, normal saline; RT, room temperature; SGZ, subgranular zone; SVZ, subventricular zone.