GGA1 overexpression attenuates amyloidogenic processing of the amyloid precursor protein in Niemann-Pick type C cells

2014 ◽  
Vol 450 (1) ◽  
pp. 160-165 ◽  
Author(s):  
Marko Kosicek ◽  
Patrick Wunderlich ◽  
Jochen Walter ◽  
Silva Hecimovic
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
C Cells ◽  
Amyloidogenic Processing ◽  
Type C ◽  
Niemann Pick

Loss of amyloid precursor protein in a mouse model of Niemann–Pick type C disease exacerbates its phenotype and disrupts tau homeostasis

2011 ◽  
Vol 42 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Ana Nunes ◽  
Sarah N.R. Pressey ◽  
Jonathan D. Cooper ◽  
Salvador Soriano
Keyword(s):  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Type C ◽  
Niemann Pick

scholarly journals The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0255715
Author(s):  
Edward T. Parkin ◽  
Jessica E. Hammond ◽  
Lauren Owens ◽  
Matthew D. Hodges
Keyword(s):  
Amyloid Precursor Protein ◽  
Orphan Drug ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Amyloid Beta Peptides ◽  
Over Expression ◽  
Beta Peptides ◽  
Amyloidogenic Processing ◽  
Beta Peptide

The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ’amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ’non-amyloidogenic’ pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β–secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer’s disease.

Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein

2020 ◽  
Vol 34 (9) ◽  
pp. 12127-12146
Author(s):  
Po‐Fan Wu ◽  
Noopur Bhore ◽  
Yen‐Lurk Lee ◽  
Ju‐Yun Chou ◽  
Yun‐Wen Chen ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloidogenic Processing ◽  
Phosphatidylinositol 4 ◽  
Aβ Production

scholarly journals Amyloidogenic Processing but Not Amyloid Precursor Protein (APP) Intracellular C-terminal Domain Production Requires a Precisely Oriented APP Dimer Assembled by Transmembrane GXXXG Motifs

2008 ◽  
Vol 283 (12) ◽  
pp. 7733-7744 ◽  
Author(s):  
Pascal Kienlen-Campard ◽  
Bernadette Tasiaux ◽  
Joanne Van Hees ◽  
Mingli Li ◽  
Sandra Huysseune ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Terminal Domain ◽  
Amyloidogenic Processing

scholarly journals Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice

2017 ◽  
Vol 39 (6) ◽  
pp. 1085-1098
Author(s):  
Tongrong He ◽  
Ruohan Sun ◽  
Anantha VR Santhanam ◽  
Livius V d'Uscio ◽  
Tong Lu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Local Concentration ◽  
Microvascular Endothelium ◽  
Cerebral Microvessels ◽  
Protein Levels ◽  
Enhanced Production ◽  
Amyloidogenic Processing

The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2). In vitro studies in human brain microvascular endothelial cells (BMECs) revealed that knockdown of AC3 significantly suppressed ADAM10 protein levels, and that activation of TXA2 receptor decreased APP expression. Furthermore, levels of soluble APPα (sAPPα, a product of α-processing of APP) were significantly reduced in hippocampus of T1D mice. In contrast, amyloidogenic processing of APP was not affected by T1D in both cerebral microvessels and hippocampus. Most notably, studies in endothelial specific APP knockout mice established that genetic inactivation of APP in endothelium was sufficient to significantly reduce sAPPα levels in the hippocampus. In aggregate, our findings suggest that T1D impairs non-amyloidogenic processing of APP in cerebral microvessels. This may exert detrimental effect on local concentration of neuroprotective molecule, sAPPα, in the hippocampus.

P4-211: AMPA receptor activation promotes non-amyloidogenic processing of the amyloid precursor protein in neurones

2009 ◽  
Vol 5 (4S_Part_16) ◽  
pp. P492-P492
Author(s):  
Sarah E. Hoey ◽  
Michael S. Perkinton ◽  
Robert J. Williams
Keyword(s):  
Amyloid Precursor Protein ◽  
Ampa Receptor ◽  
Receptor Activation ◽  
Precursor Protein ◽  
Amyloidogenic Processing

scholarly journals Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains

Glia ◽  
2010 ◽  
Vol 58 (11) ◽  
pp. 1267-1281 ◽  
Author(s):  
A. Kodam ◽  
M. Maulik ◽  
K. Peake ◽  
A. Amritraj ◽  
K. S. Vetrivel ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Deficient Mouse ◽  
Processing Enzymes ◽  
Niemann Pick

Guinea-pig primary cell cultures provide a model to study expression and amyloidogenic processing of endogenous amyloid precursor protein

Neuroscience ◽  
1999 ◽  
Vol 95 (1) ◽  
pp. 243-254 ◽  
Author(s):  
M. Beck ◽  
M.K. Brückner ◽  
M. Holzer ◽  
S. Kaap ◽  
T. Pannicke ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Amyloid Precursor Protein ◽  
Cell Cultures ◽  
Precursor Protein ◽  
Primary Cell ◽  
Primary Cell Cultures ◽  
Amyloidogenic Processing
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