Function and Dysfunction of Adult Hippocampal Neurogenesis in Regeneration and Disease

Lei, Peng; Bonaguidi, Michael A.

doi:10.1016/j.ajpath.2017.09.004

Cited by 64 publications

(50 citation statements)

References 60 publications

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“…However, almost all existing antidepressants are not particularly effective against cognitive dysfunction [18][19][20][21]. In addition to mood dysregulation, the role of HI neurogenesis in cognitive impairment has been widely studied in general [22,23]. Current evidence suggests that inhibition of HI neurogenesis may also be responsible specifically for the cognitive impairment in depressed patients [24,25].…”

Section: Introductionmentioning

confidence: 99%

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

et al. 2019

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NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference −1.8, p = 0.22, 80 mg pooled mean difference −1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference −8.2; Cohen's d for Stages 1 and 2 = −0.11 and −0.64, p = 0.04), and CPFQ scores (pooled mean difference −1.9; Cohen's d for Stages 1 and 2 = −0.28 and −0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (−2.5; Cohen's d Stages 1 and 2 = −0.03 and −0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.

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Section: Introductionmentioning

confidence: 99%

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

et al. 2019

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“…One study demonstrated that high levels of typical BMP signaling were detected in hippocampal niches. In addition, ligands of the BMP family are involved in the regulation of resting adult hippocampal stem cells and in the control of progenitor cell maturation at multiple stages of the neurogenic lineage [16]. Changes in neurogenesis in the subgranular area of the hippocampal dentate gyrus (DG) have been demonstrated in various animal models of AD and in patients with AD.…”

Section: Introductionmentioning

confidence: 99%

BMP4 overexpression induces upregulation of APP/TAU and memory deficits in Alzheimer’s disease

Zhang

et al. 2020

Preprint

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Background: Alzheimer's disease (AD) is a chronic progressive degenerative disease of the nervous system. Its pathogenesis is complex, which is related to abnormal expression of the amyloid b-protein (Ab), APP, and TAU protein. Evidence has demonstrated that bone morphogenetic protein 4 (BMP4) is highly expressed in transgenic mouse models of AD, and endogenous level of BMP4 mainly affects hippocampal function.Methods: To determine whether BMP4 participates in AD development, transgenic mice were constructed with overexpression of BMP4 under control of the neuron-specific enolase (NSE) promoter. We also performed MTT, FACS, Transfection, TUNEL and Western blotting assay to define the role of BMP4 in cells.Results: We found that middle-aged BMP4 transgenic mice exhibited memory disorder via Morris water maze experiment. Moreover, the hippocampal tissues have high expression of AD related proteins including APP, Ab, PSEN-1, TAU, P-TAU (Thr181), and P-TAU (Thr231) proteins. Furthermore, in multiple cell lines, overexpression of BMP4 increased the expression of AD related proteins, whereas downregulation of BMP4 demonstrated opposed effects. Consistently, BMP4 modulation participated in cell apoptosis via regulation of BAX and Bcl-2 expression in cells. Conclusion: Our findings indicate that BMP4 overexpression might be a potential factor to induce AD.

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“…In the adult hippocampus, neural stem cells (NSCs) give rise to new dentate granule neurons and astrocytes through a sequential process of cell cycle entry and generation of intermediate progenitor cells (Bonaguidi et al, 2011;Bond et al, 2015). New neurons play critical roles in regulating neural plasticity as well as cognitive and affective behaviors, whereas deficits in adult hippocampal neurogenesis have been implicated in age-related brain disorders (Anacker and Hen, 2017;Choi et al, 2018;Peng and Bonaguidi, 2018). While hippocampal neurogenesis persists throughout adulthood, this process is highly compromised during chronological aging.…”

Section: Introductionmentioning

confidence: 99%

Early Stem Cell Aging in the Mature Brain

Ibrayeva

Bay

et al. 2019

Preprint

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Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initiate stem cell dysfunction represent early targets to enhance tissue resiliency throughout life. Here, we pinpoint multiple factors that compromise neural stem cell (NSC) behavior in the adult hippocampus. We find that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and intermediate-term NSCs (IT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent IT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of cellular aging in the mature brain, including changes in tyrosine-protein kinases Abl1 and Abl2. Treatment with the Abl-inhibitor Imatinib was sufficient to overcome deep quiescence and restore NSC proliferation in the middle-aged brain. Further examination of mature NSC with old epidermal, hematopoietic and muscle stem cell transcriptomes identified consensus changes in stem cell aging. Our study elucidates multiple origins of adult neurogenesis decline and reveals that hippocampal NSCs are particularly vulnerable to a shared stem cell aging signature.

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Function and Dysfunction of Adult Hippocampal Neurogenesis in Regeneration and Disease

Cited by 64 publications

References 60 publications

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

BMP4 overexpression induces upregulation of APP/TAU and memory deficits in Alzheimer’s disease

Early Stem Cell Aging in the Mature Brain

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