scholarly journals Galectin 3–binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein

2020 ◽  
Vol 295 (11) ◽  
pp. 3678-3691 ◽  
Author(s):  
Tsuneyoshi Seki ◽  
Motoi Kanagawa ◽  
Kazuhiro Kobayashi ◽  
Hisatomo Kowa ◽  
Naoki Yahata ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Binding Protein ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Precursor Protein ◽  
Hek293 Cells ◽  
Endogenous Factors ◽  
App Processing ◽  
Galectin 3 ◽  
Aβ Production

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aβ production, we performed a gene microarray–based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aβ production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aβ production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3–binding protein (GAL3BP), which suppressed Aβ production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aβ production by directly interacting with APP and thereby inhibiting APP processing by β-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

scholarly journals Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

2020 ◽  
Vol 31 (1) ◽  
pp. 27-44 ◽  
Author(s):  
Jing Zhi A. Tan ◽  
Lou Fourriere ◽  
Jingqi Wang ◽  
Franck Perez ◽  
Gaelle Boncompain ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Primary Neurons ◽  
App Processing

The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.

scholarly journals Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

2019 ◽  
Author(s):  
Tatiana Burrinha ◽  
Ricardo Gomes ◽  
Ana Paula Terrasso ◽  
Cláudia Guimas Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Early Endosomes ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein

2021 ◽  
Vol 18 ◽  
Author(s):  
Chika Seiwa ◽  
Ichiro Sugiyama ◽  
Makoto Sugawa ◽  
Hiroaki Murase ◽  
Chiaki Kudoh ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
Novel Therapy ◽  
App Processing ◽  
App Metabolism

Background: The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer’s disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism / processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. Methods: We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon II. Results: A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. Conclusion: Together, these findings suggest that in the absence of MBP, there is a marked reduction of non-amyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

scholarly journals A novel mechanism for the regulation of amyloid precursor protein metabolism

2002 ◽  
Vol 158 (1) ◽  
pp. 79-89 ◽  
Author(s):  
Qi Chen ◽  
Hideo Kimura ◽  
David Schubert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Amyloid Precursor Protein ◽  
Proteasome Inhibitors ◽  
Amyloid Β ◽  
Cellular Adhesion ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
App Processing

Modifier of cell adhesion protein (MOCA; previously called presenilin [PS] binding protein) is a DOCK180-related molecule, which interacts with PS1 and PS2, is localized to brain areas involved in Alzheimer's disease (AD) pathology, and is lost from the soluble fraction of sporadic Alzheimer's disease (AD) brains. Because PS1 has been associated with γ-secretase activity, MOCA may be involved in the regulation of β-amyloid precursor protein (APP) processing. Here we show that the expression of MOCA decreases both APP and amyloid β-peptide secretion and lowers the rate of cell-substratum adhesion. In contrast, MOCA does not lower the secretion of amyloid precursor-like protein (APLP) or several additional type 1 membrane proteins. The phenotypic changes caused by MOCA are due to an acceleration in the rate of intracellular APP degradation. The effect of MOCA expression on the secretion of APP and cellular adhesion is reversed by proteasome inhibitors, suggesting that MOCA directs nascent APP to proteasomes for destruction. It is concluded that MOCA plays a major role in APP metabolism and that the effect of MOCA on APP secretion and cell adhesion is a downstream consequence of MOCA-directed APP catabolism. This is a new mechanism by which the expression of APP is regulated.

scholarly journals The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
David A. Hicks ◽  
Alys C. Jones ◽  
Stuart M. Pickering-Brown ◽  
Nigel M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
App Processing ◽  
Cellular Expression ◽  
Aβ Generation ◽  
Human Neuronal Cells ◽  
Inducible Cell Line

Abstract Alzheimer’s disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid β (Aβ) peptides. These peptides are generated via proteolysis of the amyloid precursor protein (APP), in a manner dependent on the β-secretase, BACE1 and the multicomponent γ-secretase complex. Recent data also suggest a contributory role in AD of transactive response DNA binding protein 43 (TDP-43). There is little insight into a possible mechanism linking TDP-43 and APP processing. To this end, we used cultured human neuronal cells to investigate the ability of TDP-43 to interact with APP and modulate its proteolytic processing. Immunocytochemistry showed TDP-43 to be spatially segregated from both the extranuclear APP holoprotein and its nuclear C-terminal fragment. The latter (APP intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither overexpression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated overexpression of TDP-43 was explored in an inducible cell line. Overexpression of TDP-43 had no effect on expression of the APP holoprotein, nor any of the key proteins involved in its proteolysis. Furthermore, increased TDP-43 expression had no effect on BACE1 enzymatic activity or immunoreactivity of Aβ1-40, Aβ1-42 or the Aβ1-40:Aβ1-42 ratio. Also, siRNA-mediated knockdown of TDP-43 had no effect on BACE1 immunoreactivity. Taken together, these data indicate that TDP-43 function and/or dysfunction in AD is likely independent from dysregulation of APP expression and proteolytic processing and Aβ generation.

scholarly journals The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2

2016 ◽  
Vol 397 (8) ◽  
pp. 777-790 ◽  
Author(s):  
Anna-Madeleine Beckmann ◽  
Konstantin Glebov ◽  
Jochen Walter ◽  
Olaf Merkel ◽  
Martin Mangold ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Iron Homeostasis ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
App Processing ◽  
Kunitz Domain ◽  
Membrane Bound ◽  
Aβ Generation ◽  
Slow Binding Inhibitor

Abstract Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-β (Aβ) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aβ generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aβ region, thus preventing the generation of N-terminally truncated Aβ.

scholarly journals BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production

2005 ◽  
Vol 280 (35) ◽  
pp. 30768-30772 ◽  
Author(s):  
Angeliki Fotinopoulou ◽  
Maria Tsachaki ◽  
Maria Vlavaki ◽  
Alexandros Poulopoulos ◽  
Agueda Rostagno ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Aβ Production

scholarly journals Caffeine Stimulates Amyloid β-Peptide Release from β-Amyloid Precursor Protein-Transfected HEK293 Cells

1997 ◽  
Vol 69 (4) ◽  
pp. 1580-1591 ◽  
Author(s):  
Henry W. Querfurth ◽  
Jinwei Jiang ◽  
Jonathan D. Geiger ◽  
Dennis J. Selkoe
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Hek293 Cells ◽  
Amyloid Β Peptide ◽  
Peptide Release ◽  
Β Amyloid

scholarly journals Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1807
Author(s):  
Filomena Iannuzzi ◽  
Rossana Sirabella ◽  
Nadia Canu ◽  
Thorsten J. Maier ◽  
Lucio Annunziato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tyrosine Kinase ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Adaptor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Fyn Tyrosine Kinase

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI.

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