Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus

Li, Bin; Yamamori, Hidenaga; Tatebayashi, Yoshitaka; Shafit‐Zagardo, Bridget; Tanimukai, Hitoshi; Chen, She; Iqbal, Khalid; Grundke‐Iqbal, Inge

doi:10.1097/nen.0b013e318160c5db

Cited by 213 publications

(158 citation statements)

References 32 publications

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“…A few brain areas have the potential to grow or shrink according to cognitive demands of the environment (1), and acute insults stimulate adult neurogenesis (2). However, resident neuron factories, sustained by neural stem cell niches, usually fail to compensate for the deleterious consequences of severe trauma or neurodegenerative diseases (3,4). Therefore, exogenous cell therapy has been proposed as an attractive alternative for treating a variety of neurological diseases (5).…”

Section: Introductionmentioning

confidence: 99%

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Nivet¹,

Vignes²,

Girard³

et al. 2011

J. Clin. Invest.

115

107

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Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/ fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) -adult stem cells from human nasal olfactory lamina propria -migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.

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Section: Introductionmentioning

confidence: 99%

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Nivet¹,

Vignes²,

Girard³

et al. 2011

J. Clin. Invest.

115

107

View full text Add to dashboard Cite

show abstract

“…Enriched environment, exercise, pharmacological compounds, as well as stroke, epilepsy, and neurodegeneration, affect adult neurogenesis and enhanced neurogenesis may restore functions in neurodegenerative diseases including AD (Bengzon et al, 1997;Kempermann et al, 1997;Parent et al, 1997;van Praag et al, 1999;Arvidsson et al, 2002;Curtis et al, 2003;Santarelli et al, 2003;Lie et al, 2004;Kuhn et al, 2007;Abdipranoto et al, 2008). Initial signs for increased neurogenesis in postmortem brains obtained from patients with AD were not confirmed by subsequent studies suggesting impaired maturation of new neurons (Jin et al, 2004;Li et al, 2008). Because aggregated oligomeric forms of A␤ are neurotoxic in vivo (Lesne et al, 2006;Shankar et al, 2008), we explored whether reducing brain A␤ by A␤ immunotherapy has a protective role in adult neurogenesis in doubly transgenic amyloid precursor protein/presenilin-1 (APP/PS1) mice.…”

Section: Introductionmentioning

confidence: 99%

Aβ Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

Biscaro

Lindvall²,

Höck

et al. 2009

J. Neurosci.

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The hippocampus is heavily affected by progressive neurodegeneration and ␤-amyloid pathology in Alzheimer's disease (AD). The hippocampus is also one of the few brain regions that generate new neurons throughout adulthood. Because hippocampal neurogenesis is regulated by both endogenous and environmental factors, we determined whether it benefits from therapeutic reduction of ␤-amyloid peptide (A␤)-related toxicity induced by passive A␤ immunotherapy. A␤ immunotherapy of 8 -9-month-old mice expressing familial AD-causing mutations in the amyloid precursor protein and presenilin-1 genes with an antibody against A␤ decreased compact ␤-amyloid plaque burden and promoted survival of newly born neurons in the hippocampal dentate gyrus. As these neurons matured, they exhibited longer dendrites with more complex arborization compared with newly born neurons in control-treated transgenic littermates. The newly born neurons showed signs of functional integration indicated by expression of the immediate-early gene Zif268 in response to exposure to a novel object. A␤ immunotherapy was associated with higher numbers of synaptophysin-positive synaptic boutons. Labeling dividing progenitor cells with a retroviral vector encoding green fluorescent protein (GFP) showed that A␤ immunotherapy restored the impaired dendritic branching, as well as the density of dendritic spines in new mature neurons. The presence of cellular prion protein (PrP c ) on the dendrites of the GFP ϩ newly born neurons is compatible with a putative role of PrP c in mediating A␤-related toxicity in these cells. In addition, passive A␤ immunotherapy was accompanied by increased angiogenesis. Our data establish that passive A␤ immunotherapy can restore the morphological maturation of the newly formed neurons in the adult hippocampus and promote angiogenesis. These findings provide evidence for a role of A␤ immunotherapy in stimulating neurogenesis and angiogenesis in transgenic mouse models of AD, and they suggest the possibility that A␤ immunotherapy can recover neuronal and vascular functions in brains with ␤-amyloidosis.

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“…Lines of evidence suggest that some neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis and PD, are related to neural differentiation disorders [32][33][34] . The characteristics of PD are progressive degeneration of dopaminergic neurons in the substantia nigra of the midbrain and other brain regions, and visible intracellular inclusions, known as Lewy bodies [35] .…”

Section: Discussionmentioning

confidence: 99%

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

et al. 2015

Acta Pharmacol Sin

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Aim:Omi is an ATP-independent serine protease that is necessary for neuronal function and survival. The aim of this study was to investigate the role of protease Omi in regulating differentiation of mouse neuroblastoma cells and to identify the substrate of Omi involved in this process. Methods: Mouse neuroblastoma N2a cells and Omi protease-deficient mnd2 mice were used in this study. To modulate Omi and E2F1 expression, N2a cells were transfected with expression plasmids, shRNA plasmids or siRNA. Protein levels were detected using immunoblot assays. The interaction between Omi and E2F1 was studied using immunoprecipitation, GST pulldown and in vitro cleavage assays. N2a cells were treated with 20 μmol/L retinoic acid (RA) and 1% fetal bovine serum to induce neurite outgrowth, which was measured using Image J software. Results: E2F1 was significantly increased in Omi knockdown cells and in brain lysates of mnd2 mice, and was decreased in cells overexpressing wild-type Omi, but not inactive Omi S276C. In brain lysates of mnd2 mice, endogenous E2F1 was co-immunoprecipitated with endogenous Omi. In vitro cleavage assay demonstrated that Omi directly cleaved E2F1. Treatment of N2a cells with RA induced marked differentiation and neurite outgrowth accompanied by significantly increased Omi and decreased E2F1 levels, which were suppressed by pretreatment with the specific Omi inhibitor UCF-101. Knockdown of Omi in N2a cells suppressed RA-induced neurite outgrowth, which was partially restored by knockdown of E2F1. Conclusion: Protease Omi facilitates neurite outgrowth by cleaving the transcription factor E2F1 in differentiated neuroblastoma cells; E2F1 is a substrate of Omi.

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Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus

Cited by 213 publications

References 32 publications

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions

Aβ Immunotherapy Protects Morphology and Survival of Adult-Born Neurons in Doubly Transgenic APP/PS1 Mice

Protease Omi facilitates neurite outgrowth in mouse neuroblastoma N2a cells by cleaving transcription factor E2F1

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