scholarly journals Optimization of in vitro gene delivery to neurons containing an APP gene with a mutation responsible for familial Alzheimer’s disease for the development of a base editing therapy

2020 ◽  
Vol 16 (S9) ◽  
Author(s):  
Jacques P. Tremblay ◽  
Antoine Guyon ◽  
Rousseau P. Joël
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Delivery ◽  
Familial Alzheimer’S Disease ◽  
Base Editing ◽  
Familial Alzheimer's Disease ◽  
App Gene

scholarly journals APP Osaka Mutation in Familial Alzheimer’s Disease—Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance

2020 ◽  
Vol 21 (4) ◽  
pp. 1413 ◽  
Author(s):  
Takami Tomiyama ◽  
Hiroyuki Shimada
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Synaptic Function ◽  
Recessive Inheritance ◽  
Familial Alzheimer’S Disease ◽  
Aβ Oligomers ◽  
Unique Character ◽  
Familial Alzheimer's Disease

Alzheimer’s disease is believed to begin with synaptic dysfunction caused by soluble Aβ oligomers. When this oligomer hypothesis was proposed in 2002, there was no direct evidence that Aβ oligomers actually disrupt synaptic function to cause cognitive impairment in humans. In patient brains, both soluble and insoluble Aβ species always coexist, and therefore it is difficult to determine which pathologies are caused by Aβ oligomers and which are caused by amyloid fibrils. Thus, no validity of the oligomer hypothesis was available until the Osaka mutation was discovered. This mutation, which was found in a Japanese pedigree of familial Alzheimer’s disease, is the deletion of codon 693 of APP gene, resulting in mutant Aβ lacking the 22nd glutamate. Only homozygous carriers suffer from dementia. In vitro studies revealed that this mutation has a very unique character that accelerates Aβ oligomerization but does not form amyloid fibrils. Model mice expressing this mutation demonstrated that all pathologies of Alzheimer’s disease can be induced by Aβ oligomers alone. In this review, we describe the story behind the discovery of the Osaka mutation, summarize the mutant’s phenotypes, and propose a mechanism of its recessive inheritance.

P4-108 First indentified case of familial Alzheimer's disease in Europe associated with mutation (VAL717PHE) in the APP gene

2004 ◽  
Vol 25 ◽  
pp. S505
Author(s):  
Gabriela Rolkova ◽  
Eva Hanusovska ◽  
Norbert Zilka ◽  
Stanislav Sutovsky ◽  
Robert Garay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease ◽  
App Gene

scholarly journals Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo

Neuron ◽  
1996 ◽  
Vol 17 (5) ◽  
pp. 1005-1013 ◽  
Author(s):  
David R. Borchelt ◽  
Gopal Thinakaran ◽  
Christopher B. Eckman ◽  
Michael K. Lee ◽  
Frances Davenport ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease

scholarly journals Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nobuto Kakuda ◽  
Mako Takami ◽  
Masayasu Okochi ◽  
Kensaku Kasuga ◽  
Yasuo Ihara ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Middle Ages ◽  
Senile Plaques ◽  
Genetic Mutation ◽  
Familial Alzheimer’S Disease ◽  
Cerebral Parenchyma ◽  
Familial Alzheimer's Disease ◽  
Aβ Generation

AbstractPresenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.

Familial Alzheimer's disease presenilin 1 mutation M146V increases gamma secretase cutting of p75NTR in vitro

2007 ◽  
Vol 1147 ◽  
pp. 248-255 ◽  
Author(s):  
Caroline Sara Hatchett ◽  
Sue Tyler ◽  
Dawn Armstrong ◽  
David Dawbarn ◽  
Shelley Jane Allen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Gamma Secretase ◽  
Familial Alzheimer’S Disease ◽  
Presenilin 1 Mutation ◽  
Familial Alzheimer's Disease

Alzheimer's Disease and Chromosome 14

1993 ◽  
Vol 163 (1) ◽  
pp. 2-5 ◽  
Author(s):  
Paul Harrison
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chromosome 14 ◽  
Familial Alzheimer’S Disease ◽  
The Past ◽  
Β Amyloid ◽  
Familial Alzheimer's Disease ◽  
Additional Locus ◽  
App Gene ◽  
Combined Data

Over the past three years, progress in the molecular genetics of familial Alzheimer's disease has been fast and fundamental. The seminal finding that some cases are due to a mutation in the β-amyloid precursor protein (APP) gene has been followed by the discovery of a major additional locus for the disease on chromosome 14. The combined data suggest that the genetic sites accounting for most early-onset familial Alzheimer's disease cases have now been located. In addition, research is revealing the mechanisms by which the genes exert their pathogenicity. This promises to provide the explanatory link between the genes and the clinicopathological syndrome. The ultimate goal, an understanding in similar terms of the much commoner senile, sporadic form of Alzheimer's disease, is now a realistic target.

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