scholarly journals The protective mutation A673T in amyloid precursor protein gene decreases Aβ peptides production for 14 forms of Familial Alzheimer’s Disease in SH-SY5Y cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0237122
Author(s):  
Antoine Guyon ◽  
Joël Rousseau ◽  
Gabriel Lamothe ◽  
Jacques P. Tremblay

The deposition of Aβ plaques in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is cleaved by α-secretase (non-amyloidogenic processing of APP), however increased cleavage by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms plaques. APP mutations mapping to exons 16 and 17 favor plaque accumulation and cause Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) originally found in an Icelandic population reduces BACE1 cleavage by 40%. A series of plasmids containing the APP gene, each with one of 29 different FAD mutations mapping to exon 16 and exon 17 was created. These plasmids were then replicated with the addition of the A673T mutation. Combined these formed the library of plasmids that was used in this study. The plasmids were transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. The production of Aβ peptides was decreased for some FAD mutations due to the presence of the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as for A673T control in SH-SY5Y cells. These preliminary results suggest that the insertion of A673T in APP genes containing FAD mutations might confer a clinical benefit in preventing or delaying the onset of some FADs.

2016 ◽  
Vol 12 (5) ◽  
pp. 1468-1477 ◽  
Author(s):  
Jan Harold M. Alcantara ◽  
Angelyn R. Lao ◽  
Leonor A. Ruivivar

The proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in the formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer's disease (AD).


Nature ◽  
1991 ◽  
Vol 349 (6311) ◽  
pp. 704-706 ◽  
Author(s):  
Alison Goate ◽  
Marie-Christine Chartier-Harlin ◽  
Mike Mullan ◽  
Jeremy Brown ◽  
Fiona Crawford ◽  
...  

Nature ◽  
1991 ◽  
Vol 353 (6347) ◽  
pp. 844-846 ◽  
Author(s):  
Marie-Christine Chartier-Harlin ◽  
Fiona Crawford ◽  
Henry Houlden ◽  
Andrew Warren ◽  
David Hughes ◽  
...  

1995 ◽  
Vol 199 (3) ◽  
pp. 183-186 ◽  
Author(s):  
William S. Brooks ◽  
Ralph N. Martins ◽  
Joke De Voecht ◽  
Garth A. Nicholson ◽  
Peter R. Schofield ◽  
...  

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