Deregulation of the Phosphatidylinositol-3 Kinase Signaling Cascade Is Associated with Neurodegeneration in Npc1−/− Mouse Brain

Bi, Xiaoning; Liu, Jihua; Yao, Yueqin; Baudry, Michel; Lynch, Gary

doi:10.1016/s0002-9440(10)61197-2

Cited by 29 publications

(26 citation statements)

References 75 publications

(73 reference statements)

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“…For example, increased Akt activation and hyperphosphorylation of critical Akt substrates has been demonstrated in AD brain [17]. Moreover, it has been suggested that excessive activation of the PI3K/Akt pathway contributes to neuronal degeneration in a mouse model of Niemann-Pick type C [6], a neurodegenerative disease also characterized by the presence of neurofibrillary tangles. Furthermore, transient PI3K inhibition has been shown to protect neurons from oxidative stress via suppression of ERK activation, suggesting that the PI3K pathway may serve opposing roles, acting at distinct kinetic phases to either promote or limit a slowly developing program of cell death [35].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Felice

Lambert

et al. 2008

Neurobiology of Aging

391

317

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Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar Aβ in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble Aβ oligomers (ADDLs). A major question is how these disparate facets of AD pathology are mechanistically related. Here we show that, independent of the presence of fibrils, ADDLs stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells at epitopes characteristically hyperphosphorylated in AD. A monoclonal antibody that targets ADDLs blocked their attachment to synaptic binding sites and prevented tau hyperphosphorylation. Tau phosphorylation was blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP1), and by the phosphatidylinositol-3-kinase inhibitor LY294002. Significantly, tau hyperphosphorylation was also induced by a soluble aqueous extract containing Aβ oligomers from AD brains, but not by an extract from non-AD brains. Aβ oligomers have been increasingly implicated as the main neurotoxins in AD, and the current results provide a unifying mechanism in which oligomer activity is directly linked to tau hyperphosphorylation in AD pathology.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Felice

Lambert

et al. 2008

Neurobiology of Aging

391

317

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“…Some recent studies have indicated that deregulation of the phosphatidylinositol 3-kinase pathway (93), A␤-mediated signaling cascades (20,21), or increased levels/activity of cathepsins (24,30) may contribute to the loss of neurons in NPC1 knock-out mouse brains. It has been shown that cathepsin D level/expression is increased not only in neurons but also in activated microglia located in close proximity to neurons in vulnerable regions of NPC1 knock-out mouse brains (21, 24 -26, 30).…”

Section: Discussionmentioning

confidence: 99%

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj

Wang

Revett

et al. 2013

Journal of Biological Chemistry

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Background: Cathepsin D has been implicated in Niemann-Pick type C (NPC) disease, which is associated with intracellular cholesterol accumulation. Results: Increased cytosolic and extracellular levels of cathepsin D enhanced neuronal death via different mechanisms. Conclusion: Leakage of cathepsin D within and outside the cell can cause cell death. Significance: Cathepsin D may be involved in the degeneration of neurons in NPC pathology.

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“…[13][14][15]18 However, neither the intracellular mechanisms nor the underlying cause of preferential vulnerability of these neurons has been established. Some recent studies have indicated that deregulation of the phosphatidylinositol-3 kinase pathway 75 and/or ␤-amyloid peptide-mediated signaling cascades 21,66,76 may contribute to the degeneration of neurons in Npc1 Ϫ/Ϫ mouse brains. However, the significance of these pathways in defining the underlying cause of preferential neuronal vulnerability in Npc1 Ϫ/Ϫ mouse brains remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

Amritraj

Peake

Kodam

et al. 2009

The American Journal of Pathology

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Niemann-Pick disease type C (NPC), caused by mutations in the Npc1 or Npc2 genes, is a progressive neurodegenerative disorder characterized by intracellular accumulation/redistribution of cholesterol in a number of tissues including the brain. This is accompanied by a severe loss of neurons in selected brain regions. In this study, we evaluated the role of lysosomal enzymes, cathepsins B and D, in determining neuronal vulnerability in NPC1-deficient (Npc1 ؊/؊ ) mouse brains. Our results showed that Npc1 ؊/؊ mice exhibit an age-dependent degeneration of neurons in the cerebellum but not in the hippocampus. The cellular level/expression and activity of cathepsins B and D are increased more predominantly in the cerebellum than in the hippocampus of Npc1 ؊/؊ mice. In addition, the cytosolic levels of cathepsins, cytochrome c, and Bax2 are higher in the cerebellum than in the hippocampus of Npc1 ؊/؊ mice, suggesting a role for these enzymes in the degeneration of neurons. This suggestion is supported by our observation that degeneration of cultured cortical neurons treated with U18666A, which induces an NPC1-like phenotype at the cellular level, can be attenuated by inhibition of cathepsin B or D enzyme activity. These results suggest that the increased level/activity and altered subcellular distribution of cathepsins may be associated with the underlying cause of neuronal vulnerability in Npc1 ؊/؊ brains. Therefore , their inhibitors may have therapeutic potential in attenuating NPC

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Deregulation of the Phosphatidylinositol-3 Kinase Signaling Cascade Is Associated with Neurodegeneration in Npc1−/− Mouse Brain

Cited by 29 publications

References 75 publications

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Increased Activity and Altered Subcellular Distribution of Lysosomal Enzymes Determine Neuronal Vulnerability in Niemann-Pick Type C1-Deficient Mice

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