Impaired Adult Neurogenesis Research Articles

PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons

Recent evidence suggests neurogenesis is on-going throughout life but the relevance of these findings for neurodegenerative disorders such as Parkinson’s disease (PD) is poorly understood. Biallelic PINK1 mutations cause early onset, Mendelian inherited PD. We studied the effect of PINK1 deficiency on adult neurogenesis of dopaminergic (DA) neurons in two complementary model systems. Zebrafish are a widely-used model to study neurogenesis in development and through adulthood. Using EdU analyses and lineage-tracing studies, we first demonstrate that a subset of ascending DA neurons and adjacent local-projecting DA neurons are each generated into adulthood in wild type zebrafish at a rate that decreases with age. Pink1-deficiency impedes DA neurogenesis in these populations, most significantly in early adult life. Pink1 already exerts an early effect on Th1+ progenitor cells rather than on differentiated DA neurons only. In addition, we investigate the effect of PINK1 deficiency in a human isogenic organoid model. Global neuronal differentiation in PINK1-deficient organoids and isogenic controls is similar, but PINK1-deficient organoids display impeded DA neurogenesis. The observation of impaired adult dopaminergic neurogenesis in Pink1 deficiency in two complementing model systems may have significant consequences for future therapeutic approaches in human PD patients with biallelic PINK1 mutations.

Rosmarinic acid and ursolic acid alleviate deficits in cognition, synaptic regulation and adult hippocampal neurogenesis in an Aβ1-42-induced mouse model of Alzheimer's disease

BackgroundRosmarinus officinalis, commonly known as rosemary, is a medicinal herb that presents significant biological properties such as antimicrobial, antioxidant, anti-inflammatory, anti-diabetic and anti-depressant activities. Recent findings correlate impaired adult neurogenesis, which is crucial for the maintenance of synaptic plasticity and hippocampal functioning, synaptic regulation with the pathological hallmarks of Alzheimer's disease (AD). These observations call for the need to developing compounds that promote neurogenesis and alleviates deficits in cognition and synaptic regulation. Purpose and study designThe present study was conducted to determine the proneurogenic effects of R. officinalis and its active compounds (ursolic acid and rosmarinic acid) in comparison to Donepezil in an Aβ1-42-induced mouse model of AD. MethodsBALB/c mice were divided into ten groups. Half were injected with Aβ1-42 in the hippocampus through stereotaxic surgery to generate the disease groups. The other half received control injections. Each set of five groups were administered orally with vehicle, an ethanolic extract of R. officinalis, ursolic acid, rosmarinic acid or donepezil. Behavior analysis included the Morris water maze test, the novel object recognition test and the Elevated plus maze. The mice were then sacrificed and the hippocampal tissue was processed for immunohistochemistry and gene expression analysis. ResultsThe results show a protective effect by rosmarinic acid and ursolic acid in reversing the deficits in spatial and recognition memory as well as changes in anxiety induced by Aβ1-42. The neuronal density and the expression levels of neurogenic (Ki67, NeuN and DCX) and synaptic (Syn I, II, III, Synaptophysin and PSD-95) markers were also normalized upon treatment with rosmarinic and ursolic acid. ConclusionOur findings indicate the potential of R. officinalis and its active compounds as therapeutic agents against Aβ1-42-induced neurotoxicity in AD.

NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice

Neuroinflammation has been classified as a trigger of behavioral alterations and cognitive impairments in many neurological conditions, including Alzheimer's disease, major depression, anxiety and others. Regardless of the cause of neuroinflammation, key molecules, which sense neuropathological conditions, are intracellular multiprotein signaling inflammasomes. Increasing evidence shows that the inflammatory response, mediated by activated nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasomes, is associated with the onset and progression of a wide range of diseases of the CNS. However, whether the NLRP3 inflammasome in the CNS is involved in the learning, development of anxiety and adult neurogenesis remains elusive. Therefore, the present study was designed to assess NLRP3 inflammasome contribution in anxiety and reveal its potential involvement in the experimental acquisition of fear responses and hippocampal neurogenesis. Behavioral, immunohistochemical and electrophysiological alterations were measured to evaluate role of neuroinflammation in the limbic system of mice.In this study, we describe interrelated neurophysiological mechanisms, which culminate in absence of NLRP3 inflammasome in young 4 months mice. These include the following: anxious behavior and deterioration in learning and memory of fear conditioning; impairment of adult neurogenesis; reduction and altered morphology of astrocytes in the brain; hyperexcitability in basolateral amygdala (BLA); impaired activation in axons of pyramidal cells of CA1 hippocampal zone in NLRP3 KO mice particularly via the Schaffer collateral pathway; and impaired synaptic transduction in pyramidal cells mediated by an embarrassment of neurotransmitter release from presynaptic site in CA3 hippocampal zone.The present study has demonstrated the novel findings that basal level of NLRP3 inflammasome in the brain of young mice is required for conditioning-induced plasticity in the ventral hippocampus and the basolateral amygdala. The deletion of NLRP3 impair synaptic transduction and caused anxiety-like behavior and labored fear learning, suggesting that low grade inflammation, mediated by NLRP3 expression, play a key role in memory consolidation.

Critical Roles of Embryonic Born Dorsal Dentate Granule Neurons for Activity-Dependent Increases in BDNF, Adult Hippocampal Neurogenesis, and Antianxiety-like Behaviors

BackgroundDentate gyrus (DG), a “gate” that controls information flow into the hippocampus, plays important roles in regulating both cognitive (e.g., spatial learning and memory) and mood behaviors. Deficits in DG neurons contribute to the pathogenesis of not only neurological, but also psychiatric, disorders, such as anxiety disorder. Whereas DG’s function in spatial learning and memory has been extensively investigated, its role in regulating anxiety remains elusive. MethodsUsing c-Fos to mark DG neuron activation, we identified a group of embryonic born dorsal DG (dDG) neurons, which were activated by anxiogenic stimuli and specifically express osteocalcin (Ocn)-Cre. We further investigated their functions in regulating anxiety and the underlying mechanisms by using a combination of chemogenetic, electrophysiological, and RNA-sequencing methods. ResultsThe Ocn-Cre+ dDG neurons were highly active in response to anxiogenic environment but had lower excitability and fewer presynaptic inputs than those of Ocn-Cre− or adult born dDG neurons. Activating Ocn-Cre+ dDG neurons suppressed anxiety-like behaviors and increased adult DG neurogenesis, whereas ablating or chronically inhibiting Ocn-Cre+ dDG neurons exacerbated anxiety-like behaviors, impaired adult DG neurogenesis, and abolished activity (e.g., voluntary wheel running)-induced anxiolytic effect and adult DG neurogenesis. RNA-sequencing screening for factors induced by activation of Ocn-Cre+ dDG neurons identified BDNF, which was required for Ocn-Cre+ dDG neurons mediated antianxiety-like behaviors and adult DG neurogenesis. ConclusionsThese results demonstrate critical functions of Ocn-Cre+ dDG neurons in suppressing anxiety-like behaviors but promoting adult DG neurogenesis, and both functions are likely through activation of BDNF.

The possible role of O‐GlcNAc modification in the pathogenesis of depression disorder

Diabetes mellitus leads to a number of complications involving brain function, including cognitive decline and depression. Depression is linked to impaired adult neurogenesis in the gyrus dentatus of the hippocampus, but the underlying molecular mechanisms are incompletely understood. The process of neurogenesis consists of the proliferation of neural progenitors and differentiation of new neurons, and the chloride conductance IClswell, activated after anisosmotic cell swelling during cell volume regulation, is thought to be essential in cell proliferation and differentiation. Diabetes also leads to increase in the post‐translational O‐GlcNAcylation (O‐GlcNAc) of cellular proteins. Recently, the protein ICln, which is crucial in the activation of the current IClswell, has been found to be O‐GlcNacylated. In the present study, we investigated the characteristic of the current IClswell following O‐GlcNAc elevation in neuronal‐like SH‐SY5Y and HEK 293 Phoenix cells, with focus on the role of ICln. In parallel to cell viability tests, IClswell was measured by patch‐clamp in native cells or cells overexpressing either the wild type or non‐glycosilable forms of ICln (IClnT223A, IClnS193X and IClnS67A). O‐GlcNAc elevation significantly reduced the metabolic activity of SH‐SY5Y and HEK 293 Phoenix cells. In SH‐SY5Y cells, O‐GlcNAc elevation significantly suppressed the basally activated IClswell current. In HEK 293 Phoenix cells, O‐GlcNAc elevation inhibited the ICln‐induced IClswell current, with no effect on the endogenous IClswell current, thus indicating that O‐GlcNAc impairs the ICln function. The IClnT223A‐induced current was similar to IClnWT‐induced current and was similarly suppressed after O‐GlcNAc elevation. IClnS193X lost most of its activity, though the residual current was sensitive to O‐GlcNAc elevation. Finally, the IClnS67A‐induced current is similar to the IClnWT‐induced current, but insensitive to O‐GlcNAc elevation. The present work underscores the essential role of O‐GlcNAcylation in governing the IClswell current through modification of the ICln protein. The results indicate that the O‐GlcNAc modification site responsible for the suppression of the ICln‐induced current should be located upstream the amino acid 193, most likely on Serine 67. We conclude that O‐GlcNAcylation of the IClswell activator ICln in the context of hyperglycaemic conditions may lead to IClswell inhibition in brain, which may result in reduced adult neurogenesis and eventually in the depression disorder. We suggest that the protein ICln may represent a novel target in the prevention or treatment of pathological states characterized by chronically elevated O‐GlcNAcylation of cellular proteins, including mood disorders linked to hyperglycaemia

Neuropathological Mechanisms Associated with Pesticides in Alzheimer's Disease.

Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.

Impact of Targeted Deletion of the Circadian Clock Gene Bmal1 in Excitatory Forebrain Neurons on Adult Neurogenesis and Olfactory Function.

The circadian system is an endogenous timekeeping system that synchronizes physiology and behavior with the 24 h solar day. Mice with total deletion of the core circadian clock gene Bmal1 show circadian arrhythmicity, cognitive deficits, and accelerated age-dependent decline in adult neurogenesis as a consequence of increased oxidative stress. However, it is not yet known if the impaired adult neurogenesis is due to circadian disruption or to loss of the Bmal1 gene function. Therefore, we investigated oxidative stress and adult neurogenesis of the two principle neurogenic niches, the hippocampal subgranular zone and the subventricular zone in mice with a forebrain specific deletion of Bmal1 (Bmal1 fKO), which show regular circadian rhythmicity. Moreover, we analyzed the morphology of the olfactory bulb, as well as olfactory function in Bmal1 fKO mice. In Bmal1 fKO mice, oxidative stress was increased in subregions of the hippocampus and the olfactory bulb but not in the neurogenic niches. Consistently, adult neurogenesis was not affected in Bmal1 fKO mice. Although Reelin expression in the olfactory bulb was higher in Bmal1 fKO mice as compared to wildtype mice (Bmal1 WT), the olfactory function was not affected. Taken together, the targeted deletion of Bmal1 in mouse forebrain neurons is associated with a regional increase in oxidative stress and increased Reelin expression in the olfactory bulb but does not affect adult neurogenesis or olfactory function.

Parkinson's disease, aging and adult neurogenesis: Wnt/β-catenin signalling as the key to unlock the mystery of endogenous brain repair.

A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease

Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce β-amyloid accumulation.Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate.Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits.Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.

Impaired adult neurogenesis is an early event in Alzheimer\u2019s disease neurodegeneration, mediated by intracellular A\u03b2 oligomers

Alterations of adult neurogenesis have been reported in several Alzheimer's disease (AD) animal models and human brains, while defects in this process at presymptomatic/early stages of AD have not been explored yet. To address this, we investigated potential neurogenesis defects in Tg2576 transgenic mice at 1.5 months of age, a prodromal asymptomatic age in terms of Aβ accumulation and neurodegeneration. We observe that Tg2576 resident and SVZ-derived adult neural stem cells (aNSCs) proliferate significantly less. Further, they fail to terminally differentiate into mature neurons due to pathological, tau-mediated, and microtubule hyperstabilization. Olfactory bulb neurogenesis is also strongly reduced, confirming the neurogenic defect in vivo. We find that this phenotype depends on the formation and accumulation of intracellular A-beta oligomers (AβOs) in aNSCs. Indeed, impaired neurogenesis of Tg2576 progenitors is remarkably rescued both in vitro and in vivo by the expression of a conformation-specific anti-AβOs intrabody (scFvA13-KDEL), which selectively interferes with the intracellular generation of AβOs in the endoplasmic reticulum (ER). Altogether, our results demonstrate that SVZ neurogenesis is impaired already at a presymptomatic stage of AD and is caused by endogenously generated intracellular AβOs in the ER of aNSCs. From a translational point of view, impaired SVZ neurogenesis may represent a novel biomarker for AD early diagnosis, in association to other biomarkers. Further, this study validates intracellular Aβ oligomers as a promising therapeutic target and prospects anti-AβOs scFvA13-KDEL intrabody as an effective tool for AD treatment.

Adipocyte cannabinoid CB1 receptor deficiency alleviates high fat diet-induced memory deficit, depressive-like behavior, neuroinflammation and impairment in adult neurogenesis

BackgroundObesity is a low-grade inflammation condition that facilitates the development of numerous comorbidities and the dysregulation of brain homeostasis. Additionally, obesity also causes distinct behavioral alterations both in humans and rodents. Here, we investigated the effect of inducible genetic deletion of the cannabinoid type 1 receptor (CB1) in adipocytes (Ati-CB1-KO mice) on obesity-induced memory deficits, depressive-like behavior, neuroinflammation and adult neurogenesis. MethodsBehavioral, mRNA expression and immunohistochemical studies were performed in Ati-CB1-KO mice and corresponding wild-type controls under standard and high-fat diet. ResultsAdipocyte-specific CB1 deletion reversed metabolic disturbances associated with an obese condition confirming previous studies. As compared to obese mice, the metabolic amelioration in Ati-CB1-KO mice was associated with an improvement of mood-related behavior and recognition memory, concomitantly with an increase in cell proliferation in metabolic relevant neurogenic niches in hippocampus and hypothalamus. In mutant mice, these changes were related to an increased neuronal maturation/survival in the hippocampus. Furthermore, CB1 deletion in adipocytes was sufficient to reduce obesity-induced inflammation, gliosis and apoptosis in a brain region-specific manner. ConclusionsOverall our data provide compelling evidence of the physiological relevance of the adipocyte-brain crosstalk where adipocyte-specific CB1 influences obesity-related cognitive deficits and depression-like behavior, concomitantly with brain remodeling, such as adult neurogenesis and neuroinflammation in the hippocampus and hypothalamus.

Herpes Simplex Virus Type-1 Infection Impairs Adult Hippocampal Neurogenesis via Amyloid-β Protein Accumulation

We previously reported that Herpes simplex virus type-1 (HSV-1) infection of cultured neurons triggered intracellular accumulation of amyloid-β protein (Aβ) markedly impinging on neuronal functions. Here, we demonstrated that HSV-1 affects in vitro and in vivo adult hippocampal neurogenesis by reducing neural stem/progenitor cell (NSC) proliferation and their neuronal differentiation via intracellular Aβ accumulation. Specifically, cultured NSCs were more permissive for HSV-1 replication than mature neurons and, once infected, they exhibited reduced proliferation (assessed by 5'-bromo-deoxyuridine incorporation, Ki67 immunoreactivity, and Sox2 mRNA expression) and impaired neuronal differentiation in favor of glial phenotype (evaluated by immunoreactivity for the neuronal marker MAP2, the glial marker glial fibrillary astrocyte protein, and the expression of the proneuronal genes Mash1 and NeuroD1). Similarly, impaired adult neurogenesis was observed in the subgranular zone of hippocampal dentate gyrus of an in vivo model of recurrent HSV-1 infections, that we recently set up and characterized, with respect to mock-infected mice. The effects of HSV-1 on neurogenesis did not depend on cell death and were due to Aβ accumulation in infected NSCs. Indeed, they were: (a) reverted, in vitro, by the presence of either β/γ-secretase inhibitors preventing Aβ production or the specific 4G8 antibody counteracting the action of intracellular Aβ; (b) not detectable, in vivo, in HSV-1-infected amyloid precursor protein knockout mice, unable to produce and accumulate Aβ. Given the critical role played by adult neurogenesis in hippocampal-dependent memory and learning, our results suggest that multiple virus reactivations in the brain may contribute to Alzheimer's disease phenotype by also targeting NSCs. Stem Cells 2019;37:1467-1480.

OBESITY AND TYPE 3 DIABETES: NUTRITIONAL APPROACHES AND THERAPEUTIC IMPLICATION

Over nutrition induced diseases such as obesity and type 2 diabetes involve neural deregulation of metabolic physiology. Many findings describe the roles of over nutrition-associated hypothalamic inflammation in neurodegeneration and impaired adult neurogenesis as well as defective neural stem cell regeneration and their significance in obesity and related disease. Metabolic disorders include oxidative stress, insulin resistance, obesity and inflammation. Collectively, metabolic syndrome perturbs brain function and increases the incidence of neurodegenerative diseases, reflecting the possible involvement of obesity induced metabolic syndrome in development of Alzheimer's disease (AD) which is the most common form of dementia. Its key symptoms include progressive decline in the memory, impairment in speech, language, spatial orientation and dysfunction in the sensor motor system . Alzheimer's disease (AD) is a chronic neurodegenerative disease that usually start slowly and worsens over time. It is the cause of 60-70% of cases of dementia . Several mechanisms have been described to understand pathology of AD including damaging groups of cholinergic neurons with down regulation of cholinergic markers accumulation of amyloid beta peptide (Aβ) forming extracellular senile plaques, aggregation of hyperphosphorylated tau to form intracellular neurofibrillary tangles and oxidative stress .

Genetic ablation of tau in postnatal neurons rescues decreased adult hippocampal neurogenesis in a tauopathy model.

Impaired adult hippocampal neurogenesis has been reported as a feature of Alzheimer's disease and other tauopathies and might contribute to defects in learning and memory in these diseases. To assess the interference of tau pathology, a common key-lesion in these diseases, with adult hippocampal neurogenesis we analyzed adult neurogenesis in the hippocampal dentate gyrus in wild-type mice, Tg30 mice expressing a FTDP-17 mutant tau and the same Tg30 mice deficient for mouse tau (Tg30/tauKO). The volume of the granular layer, the number of granule cells and of neuronal precursors expressing the immature markers DCX or 3R-tau were analyzed in the dentate gyrus (DG) using unbiased stereological methods. The co-localization of neurogenic markers with the human mutant tau was also analyzed. We observed a significant reduction of the volume of the granular layer and of granule cells number in mutant tau Tg30 mice, but not in Tg30/tauKO mice. The number of neuronal precursors expressing the immature markers DCX or 3R-tau (the latter only expressed in wild-type and Tg30 mice) and the number of cells expressing the proliferation marker Ki-67 in the neurogenic subgranular zone of the DG was reduced in Tg30 but not in Tg30/tauKO mice. The density of phosphotau positive cells in the DG and the level of soluble human phosphotau was lower in Tg30/tauKO compared to Tg30 mice. The human mutant tau was expressed in mature granule cells in Tg30 and Tg30/tauKO mice but was not expressed in Sox2 positive neural stem cells and in DCX positive neuronal precursors/immature newborn neurons. These results demonstrate an impairment of adult hippocampal neurogenesis in a FTDP-17 mutant tau mice resulting from a decrease of proliferation affecting the pool of neuronal precursors. The mutant tau was not expressed in precursors cells in these mutant tau mice, suggesting that this neurogenic defect is cell non-autonomous. Interestingly, expression of endogenous wild-type tau in mature granule cells was necessary to observe this toxic effect of human mutant tau, since this impaired adult neurogenesis was rescued by lowering tau expression in Tg30/tauKO mice. These observations suggest that development of tau pathology in granule cells of the dentate gyrus is responsible for reduction of adult hippocampal neurogenesis also in human tauopathies by impairing proliferation of neuronal precursors, and that reduction of tau expression might be an approach to rescue this impairment.

Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function.

Impairment of adult neurogenesis in the hippocampus causes cognitive deficits; however, the underlying molecular mechanisms have not been fully elucidated. microRNAs (miRNAs) regulate neural stem cell (NSC) function. With the use of a transgenic mouse line with conditional ablation of the miR-17-92 cluster in nestin lineage NSCs, we tested the hypothesis that the miR-17-92 cluster regulates adult neurogenesis and cognitive function in vivo. Compared with wild-type mice, ablation of the miR-17-92 cluster significantly reduced the number of proliferating NSCs and neuroblasts and neuronal differentiation in the dentate gyrus (DG) of the hippocampus and significantly impaired hippocampal-dependent learning and memory, as assayed by social recognition memory, novel object recognition, and Morris water-maze tests. Statistical analysis showed a highly significant correlation between newly generated neuroblasts in the DG and cognition deficits in miR-17-92 knockout (KO) mice. Western blot analysis showed that conditional KO of the miR-17-92 cluster significantly increased and reduced a cytoskeleton-associated protein, Enigma homolog 1 (ENH1), and its downstream transcription factor, inhibitor of differentiation 1 (ID1), respectively, as well as increased phosphatase and tensin homolog gene. These proteins are related to neuronal differentiation. Our study demonstrates that the miR-17-92 cluster in NSCs is critical for cognitive and behavioral function and regulates neurogenesis and that the miR-17-92 cluster may target ENH1/ID1 signaling.-Pan, W. L., Chopp, M., Fan, B., Zhang, R., Wang, X., Hu, J., Zhang, X. M., Zhang, Z. G., Liu, X. S. Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function.

Jowiseungchungtang Inhibits Amyloid-β Aggregation and Amyloid-β-Mediated Pathology in 5XFAD Mice.

Alzheimer’s disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-β (Aβ) peptides in the brain is considered to be the major pathology of AD, inhibition of Aβ aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aβ aggregation. Thus, we investigated whether JWS could protect against both Aβ aggregates and Aβ-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer’s disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aβ aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aβ aggregation, Aβ-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aβ aggregation, Aβ-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.

Early Impairments of Hippocampal Neurogenesis in 5xFAD Mouse Model of Alzheimer's Disease Are Associated with Altered Expression of SOXB Transcription Factors.

Dysregulation of neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus has been related to cognitive deficits and memory loss in neurodegenerative diseases, such as Alzheimer's disease (AD). Members of the B group of SOX transcription factors play critical roles in regulating neurogenesis in the embryonic and adult nervous system, including maintaining the multipotency, renewal, and cell fate decision of neural stem/progenitor cells. The aim of the present study was to evaluate the expression patterns of selected SOXB proteins in the SGZ, of 8-week-old male and female 5xFAD mice, which represent a transgenic model of AD with a severe and very early development of amyloid pathology. Immunohistochemical analysis showed a significant decrease in the number of cells expressing SOX1, SOX2, and SOX21 transcription factors within the SGZ of 5xFAD mice in comparison to their non-transgenic counterparts which coincidences with reduced number of doublecortin immunoreactive immature neurons found in Tg males. Despite observed changes in expressional pattern of examined SOXB proteins, the proliferative capacity evaluated by the number of Ki-67 immunoreactive cells remained unaffected in transgenic mice of both genders. Based on our results, we suggest that SOXB proteins might be considered as new biomarkers for the detection of early impairments in adult neurogenesis in different animal models or/and new targets in human regenerative medicine.

Abnormal hippocampal neurogenesis in Parkinson's disease: relevance to a new therapeutic target for depression with Parkinson's disease.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized by motor dysfunction, including bradykinesia, tremor, rigidity, and postural instability. Recent clinical findings recognize PD as a complex disease with diverse neuropsychiatric complications. Depression is the most frequent non-motor psychiatric symptom experienced in PD, and it is associated with poor quality of life. While the pathophysiology of PD-associated depression is not directly related to neurodegenerative processes in the substantia nigra, underlying mechanisms remain unclear and there are few symptomatic treatments. Altered adult hippocampal neurogenesis is considered crucial for the development and treatment of depression. In genetic animal models and human postmortem studies of PD, severely impaired adult neurogenesis has been observed, with patients showing hippocampal atrophy and disrupted hippocampal neurogenesis. Because adult newborn neurons appear to exert various functions, which relate to non-motor symptoms observed in PD, there might be a close correlation between malformation of newborn neurons in the adult hippocampus and depressive symptoms. Here, we discuss current concepts regarding impaired hippocampal neurogenesis and non-motor symptoms of PD, and review PD-associated pathophysiological factors regulating neurogenesis, including inflammatory signaling and autophagy. We present a novel framework for targeting adult hippocampal neurogenesis, which could provide a promising treatment for PD-associated depression.

Regulation of Adult Neurogenesis by the Fragile X Family of RNA Binding Proteins.

The fragile X mental retardation protein (FMRP) has an important role in neural development. Functional loss of FMRP in humans leads to fragile X syndrome, and it is the most common monogenetic contributor to intellectual disability and autism. FMRP is part of a larger family of RNA-binding proteins known as FXRs, which also includes fragile X related protein 1 (FXR1P) and fragile X related protein 2 (FXR2P). Despite the similarities of the family members, the functions of FXR1P and FXR2P in human diseases remain unclear. Although most studies focus on FMRP’s role in mature neurons, all three FXRs regulate adult neurogenesis. Extensive studies have demonstrated important roles of adult neurogenesis in neuroplasticity, learning, and cognition. Impaired adult neurogenesis is implicated in neuropsychiatric disorders, neurodegenerative diseases, and neurodevelopmental disorders. Interventions aimed at regulating adult neurogenesis are thus being evaluated as potential therapeutic strategies. Here, we review and discuss the functions of FXRs in adult neurogenesis and their known similarities and differences. Understanding the overlapping regulatory functions of FXRs in adult neurogenesis can give us insights into the adult brain and fragile X syndrome.

T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice

T-type calcium channels are involved in the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel spiroimidazopyridine compound, SAK3 (ethyl 8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate), which enhances T-type calcium channel currents and improves memory deficits in olfactory bulbectomized (OBX) mice. Here, we demonstrated the anti-depressant effects of SAK3 in OBX mice. Chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.) improved depressive-like behaviors in OBX mice. The impaired adult neurogenesis in the hippocampal dentate gyrus (DG) that occurred 4 weeks after OBX administration was significantly restored by chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.). Additionally, SAK3 (0.5 mg/kg, p.o.) promoted the proliferation and survival of newborn cells in the naïve DG. Moreover, SAK3 administration (0.5 mg/kg, p.o.) antagonized the reduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV phosphorylation levels, thereby rescuing the decreased levels of cAMP response element-binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling in the OBX DG. The effects of SAK3 were completely blocked by the T-type calcium channel selective blocker NNC 55-0396 (12.5 mg/kg, i.p.). Altogether, these results suggest that SAK3 improves depressive-like behaviors by promoting adult neurogenesis via T-type calcium channel stimulation in the hippocampus.