Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

Hu, Yanling; Hung, Amos C.; Cui, Hao; Dawkins, Edgar; Bolós, Marta; Foa, Lisa; Young, Karen; Small, David H.

doi:10.1074/jbc.m112.443671

Cited by 32 publications

(36 citation statements)

References 46 publications

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“…Furthermore, inhibition of ␣-secretase was reported to decrease NSPC proliferation, and soluble APP␣ was able to rescue this effect (24). However, our recent study showed that an APP-induced increase in NSPC proliferation was primarily due to the secretion of cystatin C rather than soluble APP␣ (19).…”

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confidence: 90%

“…vious studies from our group (19) showed that NSPCs derived from APPKO mice proliferated less rapidly and differentiated into neurons less readily than NSPCs from WT mice. The effect on proliferation was found to be mediated by the secretion of cystatin C. Therefore, to examine the possibility that cystatin C might also influence NSPC differentiation, we first compared the neural differentiation levels of NSPCs derived from P0 WT and APPKO mice.…”

Section: Cystatin C Is Not Involved In Neuronal Differentiation-pre-mentioning

confidence: 99%

“…APP expression increases as NSPCs mature into neurons (26), and soluble APP has been reported to promote neural differentiation (27,28). We previously found that NSPCs derived from Tg2576 mice, which overexpress APP, possessed a greater potential to differentiate into neurons, whereas cells derived from APP-knock-out (APPKO) mice exhibited decreased neuronal differentiation (19).…”

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confidence: 99%

“…Cells were washed with PBS and then lysed as described previously (19). Cortices, 4 per group, derived from WT and APPKO mice were homogenized in RIPA buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 1% Nonidet P-40, 0.1% SDS, and protease inhibitor mixture from Roche Diagnostics).…”

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confidence: 99%

“…Neurosphere and Isolated NSPC Culture-Primary neurosphere cultures derived from cerebral cortices of postnatal day 0 mice were prepared according to previously described procedures (19). Neurospheres were prepared by growing cells in suspension in 75-cm 2 cell culture flasks at a density of 400,000 cells in proliferation medium (DMEM supplemented with 2% (v/v) B27, 100 units/ml penicillin, 100 units/ml streptomycin, 20 ng/ml human bovine FGF, and 20 ng/ml human EGF).…”

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confidence: 99%

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Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Bolós

Young

et al. 2014

Journal of Biological Chemistry

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Background: Amyloid-␤ precursor protein is implicated in neural stem cell development. Results: Neurogenin 2 expression and neuronal differentiation correlated with amyloid-␤ precursor protein expression in neural stem/progenitor cells. Conclusion: Amyloid-␤ precursor protein regulates neuronal differentiation by altering neurogenin 2 expression. Significance: The study provides a new mechanism to explain the effects of amyloid-␤ precursor protein on neural stem cell differentiation.

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confidence: 90%

Section: Cystatin C Is Not Involved In Neuronal Differentiation-pre-mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Bolós

Young

et al. 2014

Journal of Biological Chemistry

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The N‐terminal fragment of the β‐amyloid precursor protein of Alzheimer's disease (N‐APP) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons

Dawkins

Gasperini

et al. 2014

J of Neuroscience Research

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The function of the β-amyloid precursor protein (APP) of Alzheimer's disease is poorly understood. The secreted ectodomain fragment of APP (sAPPα) can be readily cleaved to produce a small N-terminal fragment (N-APP) that contains heparin-binding and metal-binding domains and that has been found to have biological activity. In the present study, we examined whether N-APP can bind to lipids. We found that N-APP binds selectively to phosphoinositides (PIPs) but poorly to most other lipids. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 )-rich microdomains were identified on the extracellular surface of neurons and glia in primary hippocampal cultures. N-APP bound to neurons and colocalized with PIPs on the cell surface. Furthermore, the binding of N-APP to neurons increased the level of cell-surface PI(4,5)P2 and phosphatidylinositol 3,4,5-trisphosphate. However, PIPs were not the principal cell-surface binding site for N-APP, because N-APP binding to neurons was not inhibited by a short-acyl-chain PIP analogue, and N-APP did not bind to glial cells which also possessed PI(4,5)P2 on the cell surface. The data are explained by a model in which N-APP binds to two distinct components on neurons, one of which is an unidentified receptor and the second of which is a PIP lipid, which binds more weakly to a distinct site within N-APP. Our data provide further support for the idea that N-APP may be an important mediator of APP's biological activity.

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Knockout of Amyloid β Protein Precursor (APP) Expression Alters Synaptogenesis, Neurite Branching and Axonal Morphology of Hippocampal Neurons

et al. 2018

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The function of the β-A4 amyloid protein precursor (APP) of Alzheimer's disease (AD) remains unclear. APP has a number of putative roles in neuronal differentiation, survival, synaptogenesis and cell adhesion. In this study, we examined the development of axons, dendrites and synapses in cultures of hippocampus neutrons derived from APP knockout (KO) mice. We report that loss of APP function reduces the branching of cultured hippocampal neurons, resulting in reduced synapse formation. Using a compartmentalised culture approach, we found reduced axonal outgrowth in cultured hippocampal neurons and we also identified abnormal growth characteristics of isolated hippocampal neuron axons. Although APP has previously been suggested to play an important role in promoting cell adhesion, we surprisingly found that APPKO hippocampal neurons adhered more strongly to a poly-L-lysine substrate and their neurites displayed an increased density of focal adhesion puncta. The findings suggest that the function of APP has an important role in both dendritic and axonal growth and that endogenous APP may regulate substrate adhesion of hippocampal neurons. The results may explain neuronal and synaptic morphological abnormalities in APPKO mice and the presence of abnormal APP expression in dystrophic neurites around amyloid deposits in AD.

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Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

Cited by 32 publications

References 46 publications

Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

The N‐terminal fragment of the β‐amyloid precursor protein of Alzheimer's disease (N‐APP) binds to phosphoinositide‐rich domains on the surface of hippocampal neurons

Knockout of Amyloid β Protein Precursor (APP) Expression Alters Synaptogenesis, Neurite Branching and Axonal Morphology of Hippocampal Neurons

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