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

  title={Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate A$\beta$1–42/1–40 Ratio In Vitro and In Vivo},
  author={David R. Borchelt and Gopal Thinakaran and Christopher B. Eckman and Michael K. Lee and Frances Davenport and Tamara Ratovitsky and C. -M. Prada and Grace Kim and Sophia Seekins and Debra Yager and Hilda H. Slunt and Rong Wang and Mary Seeger and Allan I. Levey and Samuel E. Gandy and NealG . Copeland and Nancy A. Jenkins and Donald L. Price and Steven G. Younkin and Sangram S. Sisodia},

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Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes
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Support for the hypothesis that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles is provided.
Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein
It is proposed that the conformational change observed may provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations, and treatment of M146L PS1-overexpressing neurons with high-dose NSAIDs somewhat offsets the conformular change associated with the mutation.
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These findings establish a protective role of the wild-type PS1 against the FAD mutation-induced amyloid pathology through a partial loss-of-function mechanism.
Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase.
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Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease
The findings indicate that the FAD–linked mutations may all cause Alzheimer's disease by increasing the extracellular concentration of Aβ42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.
The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology
The results in brain tissue are consistent with recent biochemical evidence of increased Aβ42 levels in PS1–FAD patients and strongly suggest that mutant PS1 proteins alter the proteolytic processing of the β–amyloid precursor protein at the C–terminus of Aβ to favor deposition of A β42.
A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid
A double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co–segregates with the disease in two large (probably related) early–onset Alzheimer's disease families from Sweden is identified.
Genetic dissection of Alzheimer disease, a heterogeneous disorder.
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  • Biology
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Analysis of the nucleotide sequence of the open reading frame of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50–70 years versus 30–60 years for AD3).
Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3.
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Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene
The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.
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Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system
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