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Specialty: Chemistry
Condition: Alzheimer's
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Total 11 results found since Jan 2013.
Phosphorylation of the amyloid precursor protein (APP) at Ser-675 promotes APP processing involving meprin {beta} Molecular Bases of Disease
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of β-amyloid (Aβ) peptides. Aβ is a cleavage product of the amyloid precursor protein (APP), and aberrant posttranslational modifications of APP can alter APP processing and increase Aβ generation. In the AD brain, seven different residues, including Ser-675 (APP695 numbering) in the APP cytoplasmic domain has been found to be phosphorylated. Here, we show that expression of a phosphomimetic variant of Ser-675 in APP (APP-S675E), in human neuroblastoma SK-N-AS cells, reduces secretion of the soluble APP ectodomain (sAPPα), ev...
Source: Journal of Biological Chemistry - November 21, 2019 Category: Chemistry Authors: Preeti Kumaran Menon, Niina Anneli Koistinen, Kerstin Iverfeldt, Anna–Lena Strom Tags: Neurobiology Source Type: research
Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-{beta} oligomers Cell Biology
The cellular prion protein (PrPC) is a key neuronal receptor for β-amyloid oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AβO to the c...
Source: Journal of Biological Chemistry - April 25, 2019 Category: Chemistry Authors: Heledd H. Jarosz-Griffiths, Nicola J. Corbett, Helen A. Rowland, Kate Fisher, Alys C. Jones, Jennifer Baron, Gareth J. Howell, Sally A. Cowley, Satyan Chintawar, M. Zameel Cader, Katherine A. B. Kellett, Nigel M. Hooper Tags: Neurobiology Source Type: research
The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels Molecular Bases of Disease
In this study, we performed an siRNA-based screen of the kinome to identify genetic regulators of PGRN levels in a rodent cell-based model system. We found that knocking down receptor-interacting serine/threonine protein kinase 1 (Ripk1) increased both intracellular and extracellular PGRN protein levels by increasing the translation rate of PGRN without affecting mRNA levels. We observed this effect in Neuro2a cells, wild-type primary mouse neurons, and Grn-haploinsufficient primary neurons from an FTD mouse model. We found that the effect of RIPK1 on PGRN is independent of the kinase activity of RIPK1 and occurs through a...
Source: Journal of Biological Chemistry - February 23, 2017 Category: Chemistry Authors: Amanda R. Mason, Lisa P. Elia, Steven Finkbeiner Tags: Neurobiology Source Type: research
VDAC1 Mediates A{beta} Cytotoxicity Cell Biology
In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in Aβ cell penetration and cell death induction. Aβ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated Aβ interacted with bilayer-reconstituted VDAC1 and increased its conductance ∼2-fold. Incubation of cells with Aβ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented Aβ cellular entry and Aβ-induced mitochondria-mediated apoptosi...
Source: Journal of Biological Chemistry - December 25, 2015 Category: Chemistry Authors: Smilansky, A., Dangoor, L., Nakdimon, I., Ben-Hail, D., Mizrachi, D., Shoshan-Barmatz, V. Tags: Molecular Bases of Disease Source Type: research
GAPDH Aggregates Promote A{beta} Amyloidogenesis Molecular Bases of Disease
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-β peptide (Aβ). Numerous studies have established Aβ amyloidogenesis as a hallmark of AD pathogenesis, particularly with respect to mitochondrial dysfunction. We have previously shown that glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms amyloid-like aggregates upon exposure to oxidative stress and that these aggregates contribute to neuronal cell death. Here, we report that GAPDH aggregates accelerate Aβ amyloidogenesis and subseque...
Source: Journal of Biological Chemistry - October 23, 2015 Category: Chemistry Authors: Itakura, M., Nakajima, H., Kubo, T., Semi, Y., Kume, S., Higashida, S., Kaneshige, A., Kuwamura, M., Harada, N., Kita, A., Azuma, Y.-T., Yamaji, R., Inui, T., Takeuchi, T. Tags: Neurobiology Source Type: research
APP, Neurogenin 2, and Neurogenesis Developmental Biology
In this study we examined the role of APP in NSPC differentiation. To identify proteins that may mediate the effect of APP on NSPC differentiation, we used a gene array approach to find genes whose expression correlated with APP-induced neurogenesis. We found that the expression of neurogenin 2 (Ngn2), a basic helix-loop-helix transcription factor, was significantly down-regulated in NSPCs from APP knock-out mice (APPKO) and increased in APP transgenic (Tg2576) mice. Ngn2 overexpression in APPKO NSPCs promoted neuronal differentiation, whereas siRNA knockdown of Ngn2 expression in wild-type NSPCs decreased neuronal differe...
Source: Journal of Biological Chemistry - November 6, 2014 Category: Chemistry Authors: Bolos, M., Hu, Y., Young, K. M., Foa, L., Small, D. H. Tags: Neurobiology Source Type: research
Role and Regulation of Puma in {beta}-Amyloid-induced Neuron Death Neurobiology
Neurodegeneration underlies the pathology of Alzheimer disease (AD). The molecules responsible for such neurodegeneration in AD brain are mostly unknown. Recent findings indicate that the BH3-only proteins of the Bcl-2 family play an essential role in various cell death paradigms, including neurodegeneration. Here we report that Puma (p53-up-regulated modulator of apoptosis), an important member of the BH3-only protein family, is up-regulated in neurons upon toxic β-amyloid 1–42 (Aβ(1–42)) exposure both in vitro and in vivo. Down-regulation of Puma by specific siRNA provides significant protection against neuron deat...
Source: Journal of Biological Chemistry - April 11, 2014 Category: Chemistry Authors: Akhter, R., Sanphui, P., Biswas, S. C. Tags: Molecular Bases of Disease Source Type: research
Mortalin Inhibition and Mitochondrial Dysfunction Cell Biology
Mitochondrial dynamics greatly influence the biogenesis and morphology of mitochondria. Mitochondria are particularly important in neurons, which have a high demand for energy. Therefore, mitochondrial dysfunction is strongly associated with neurodegenerative diseases. Until now various post-translational modifications for mitochondrial dynamic proteins and several regulatory proteins have explained complex mitochondrial dynamics. However, the precise mechanism that coordinates these complex processes remains unclear. To further understand the regulatory machinery of mitochondrial dynamics, we screened a mitochondrial siRN...
Source: Journal of Biological Chemistry - January 24, 2014 Category: Chemistry Authors: Park, S. J., Shin, J. H., Jeong, J. I., Song, J. H., Jo, Y. K., Kim, E. S., Lee, E. H., Hwang, J. J., Lee, E. K., Chung, S. J., Koh, J.-Y., Jo, D.-G., Cho, D.-H. Tags: Neurobiology Source Type: research
Regulation of Acetylcholinesterase by APP Cell Biology
In conclusion, AChE is regulated in two neuronal cell lines by APP in a manner independent of the generation of sAPPα, sAPPβ, and AICD.
Source: Journal of Biological Chemistry - September 6, 2013 Category: Chemistry Authors: Hicks, D. A., Makova, N. Z., Gough, M., Parkin, E. T., Nalivaeva, N. N., Turner, A. J. Tags: Molecular Bases of Disease Source Type: research
SH3BP5 Mediates Humanin Activity via JNK Molecular Bases of Disease
Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined. In the ...
Source: Journal of Biological Chemistry - August 23, 2013 Category: Chemistry Authors: Takeshita, Y., Hashimoto, Y., Nawa, M., Uchino, H., Matsuoka, M. Tags: Signal Transduction Source Type: research
Activated Legumain in Alzheimer Disease Neurobiology
Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2PP2A. In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2PP2A is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subun...
Source: Journal of Biological Chemistry - June 14, 2013 Category: Chemistry Authors: Basurto-Islas, G., Grundke-Iqbal, I., Tung, Y. C., Liu, F., Iqbal, K. Tags: Molecular Bases of Disease Source Type: research
