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Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease.

Crews L, Patrick C, Adame A, Rockenstein E, Masliah E - Cell Death Dis (2011)

Bottom Line: Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown.These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5.Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA.

ABSTRACT
Recent studies show that in Alzheimer's disease (AD), alterations in neurogenesis contribute to the neurodegenerative process. Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown. First, to study AD-like abnormal activation of CDK5 signaling in an in vitro model of neurogenesis, neuronal progenitor cells (NPCs) were infected with a viral vector expressing p35, and exposed to amyloid-β protein (Aβ(1-42)). These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5. Similarly, neurogenesis was impaired in a transgenic mouse model of AD that expresses high levels of amyloid precursor protein (APP), and this effect was reversed in transgenic mice crossed with a CDK5 heterozygous-deficient mouse line. A similar rescue effect was observed in APP transgenic mice treated with Roscovitine, a pharmacological inhibitor of CDK5. Taken together, these data suggest that the CDK5 signaling pathway has a critical role in maintaining the integrity of NPCs and neuronal maturation in the adult hippocampus. Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD.

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Characterization of expression patterns of the CDK5 signaling pathway in the neurogenic niche of the adult hippocampus in APP tg mice. Brain sections from APP tg mice (9 months old) were double-labeled with antibodies against APP and CDK5 or p35, and CDK5 and the mature neuron marker microtubule-associated protein-2 (MAP2) or the immature neuron marker doublecortin (DCX). All images are from the dentate gyrus (DG) of the hippocampus. (a–c) Double-labeling analysis of APP and CDK5, showing coexpression in cells of the DG (arrows), particularly in the granular cell layer (GCL). (d–f) Double-labeling analysis of APP and p35, showing coexpression of these markers throughout the neuropil of the DG. (g–i) Double-labeling analysis of MAP2 and CDK5, showing CDK5 expression localized primarily to the GCL and subgranular zone (SGZ). MAP2 was detected more predominantly in the molecular layer (ML). (j–l) Double-labeling analysis of CDK5 and DCX in the SGZ and GCL regions, showing expression in and around cells in the SGZ. A subset of cells were co-immunolabeled with both CDK5 and DCX (arrows). Scale bar=20 μm
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fig4: Characterization of expression patterns of the CDK5 signaling pathway in the neurogenic niche of the adult hippocampus in APP tg mice. Brain sections from APP tg mice (9 months old) were double-labeled with antibodies against APP and CDK5 or p35, and CDK5 and the mature neuron marker microtubule-associated protein-2 (MAP2) or the immature neuron marker doublecortin (DCX). All images are from the dentate gyrus (DG) of the hippocampus. (a–c) Double-labeling analysis of APP and CDK5, showing coexpression in cells of the DG (arrows), particularly in the granular cell layer (GCL). (d–f) Double-labeling analysis of APP and p35, showing coexpression of these markers throughout the neuropil of the DG. (g–i) Double-labeling analysis of MAP2 and CDK5, showing CDK5 expression localized primarily to the GCL and subgranular zone (SGZ). MAP2 was detected more predominantly in the molecular layer (ML). (j–l) Double-labeling analysis of CDK5 and DCX in the SGZ and GCL regions, showing expression in and around cells in the SGZ. A subset of cells were co-immunolabeled with both CDK5 and DCX (arrows). Scale bar=20 μm

Mentions: To further elucidate the role of AD-related aberrant CDK5 activation in adult neurogenesis in vivo, we first characterized the expression patterns of members of the CDK5 signaling pathway in the DG of a transgenic (tg) mouse line expressing high levels of neuronal amyloid precursor protein (APP). We have previously shown that hippocampal neurogenesis is impaired in the brains of these animals.19, 24 In support of a role for CDK5 in the adult hippocampus, double-labeling immunocytochemical analyses demonstrated that APP, CDK5, and p35 were expressed in the DG of APP tg mice (Figures 4a–i). Moreover, CDK5 was detected in cells surrounding and within a subset of SGZ cells that are immunopositive for the developing neuronal marker DCX (Figures 4j–l).


Modulation of aberrant CDK5 signaling rescues impaired neurogenesis in models of Alzheimer's disease.

Crews L, Patrick C, Adame A, Rockenstein E, Masliah E - Cell Death Dis (2011)

Characterization of expression patterns of the CDK5 signaling pathway in the neurogenic niche of the adult hippocampus in APP tg mice. Brain sections from APP tg mice (9 months old) were double-labeled with antibodies against APP and CDK5 or p35, and CDK5 and the mature neuron marker microtubule-associated protein-2 (MAP2) or the immature neuron marker doublecortin (DCX). All images are from the dentate gyrus (DG) of the hippocampus. (a–c) Double-labeling analysis of APP and CDK5, showing coexpression in cells of the DG (arrows), particularly in the granular cell layer (GCL). (d–f) Double-labeling analysis of APP and p35, showing coexpression of these markers throughout the neuropil of the DG. (g–i) Double-labeling analysis of MAP2 and CDK5, showing CDK5 expression localized primarily to the GCL and subgranular zone (SGZ). MAP2 was detected more predominantly in the molecular layer (ML). (j–l) Double-labeling analysis of CDK5 and DCX in the SGZ and GCL regions, showing expression in and around cells in the SGZ. A subset of cells were co-immunolabeled with both CDK5 and DCX (arrows). Scale bar=20 μm
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101702&req=5

fig4: Characterization of expression patterns of the CDK5 signaling pathway in the neurogenic niche of the adult hippocampus in APP tg mice. Brain sections from APP tg mice (9 months old) were double-labeled with antibodies against APP and CDK5 or p35, and CDK5 and the mature neuron marker microtubule-associated protein-2 (MAP2) or the immature neuron marker doublecortin (DCX). All images are from the dentate gyrus (DG) of the hippocampus. (a–c) Double-labeling analysis of APP and CDK5, showing coexpression in cells of the DG (arrows), particularly in the granular cell layer (GCL). (d–f) Double-labeling analysis of APP and p35, showing coexpression of these markers throughout the neuropil of the DG. (g–i) Double-labeling analysis of MAP2 and CDK5, showing CDK5 expression localized primarily to the GCL and subgranular zone (SGZ). MAP2 was detected more predominantly in the molecular layer (ML). (j–l) Double-labeling analysis of CDK5 and DCX in the SGZ and GCL regions, showing expression in and around cells in the SGZ. A subset of cells were co-immunolabeled with both CDK5 and DCX (arrows). Scale bar=20 μm
Mentions: To further elucidate the role of AD-related aberrant CDK5 activation in adult neurogenesis in vivo, we first characterized the expression patterns of members of the CDK5 signaling pathway in the DG of a transgenic (tg) mouse line expressing high levels of neuronal amyloid precursor protein (APP). We have previously shown that hippocampal neurogenesis is impaired in the brains of these animals.19, 24 In support of a role for CDK5 in the adult hippocampus, double-labeling immunocytochemical analyses demonstrated that APP, CDK5, and p35 were expressed in the DG of APP tg mice (Figures 4a–i). Moreover, CDK5 was detected in cells surrounding and within a subset of SGZ cells that are immunopositive for the developing neuronal marker DCX (Figures 4j–l).

Bottom Line: Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown.These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5.Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA.

ABSTRACT
Recent studies show that in Alzheimer's disease (AD), alterations in neurogenesis contribute to the neurodegenerative process. Neurodegeneration in AD has been associated with aberrant signaling through the cyclin-dependent kinase-5 (CDK5) pathway via its activators p35/p25; however, the role of CDK5 in the mechanisms of defective adult neurogenesis in AD is unknown. First, to study AD-like abnormal activation of CDK5 signaling in an in vitro model of neurogenesis, neuronal progenitor cells (NPCs) were infected with a viral vector expressing p35, and exposed to amyloid-β protein (Aβ(1-42)). These conditions resulted in impaired maturation and neurite outgrowth in vitro, and these effects were reversed by pharmacological or genetic inhibition of CDK5. Similarly, neurogenesis was impaired in a transgenic mouse model of AD that expresses high levels of amyloid precursor protein (APP), and this effect was reversed in transgenic mice crossed with a CDK5 heterozygous-deficient mouse line. A similar rescue effect was observed in APP transgenic mice treated with Roscovitine, a pharmacological inhibitor of CDK5. Taken together, these data suggest that the CDK5 signaling pathway has a critical role in maintaining the integrity of NPCs and neuronal maturation in the adult hippocampus. Moreover, potential therapeutic approaches could focus on modulating the aberrant activity of CDK5 to target the neurogenic and neurodegenerative alterations in AD.

Show MeSH
Related in: MedlinePlus