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

@article{Scheuner1996SecretedA,
  title={Secreted amyloid $\beta$–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},
  author={Donalyn L Scheuner and Christopher B. Eckman and Malene Duedal Jensen and X. Song and Martin O. Citron and N. Suzuki and Thomas D. Bird and John Hardy and Michael L. Hutton and Walter A Kukull and E. B. Larson and L. Levy-Lahad and Matti H Viitanen and Elaine Peskind and Parvoneh Poorkaj and G D Schellenberg and Rudolph E. Tanzi and Wilma Wasco and Lars Lannfelt and Dennis J. Selkoe and Steven G. Younkin},
  journal={Nature Medicine},
  year={1996},
  volume={2},
  pages={864-870}
}
To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid β-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid β–protein (Aβ) ending at Aβ42(43) in vivo, we performed a blinded comparison of plasma Aβ levels in carriers of these mutations and controls. Aβ1 –42(43) was elevated in plasma from subjects with FAD–linked PS1 (P < 0.0001), PS2N141I (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV717I… 
Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1
TLDR
Results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.
Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes
TLDR
The data support the view that PS1 mutations lead to a strong γ-secretase loss-of-function phenotype and an increased Aβ1–42/Aβ1-40 ratio, two mechanisms that are potentially involved in the pathogenesis of Alzheimer's disease.
Relative Ratio and Level of Amyloid-β 42 Surrogate in Cerebrospinal Fluid of Familial Alzheimer Disease Patients with Presenilin 1 Mutations
TLDR
A higher relative ratio of the CSF A β42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive Aβ42 accumulation in the PS1 -FAD brain occurs without an apparent increase in Aβ40 secretion.
The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.
TLDR
It is shown that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation, which suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.
Aberrant Amyloid Precursor Protein (APP) Processing in Hereditary Forms of Alzheimer Disease Caused by APP Familial Alzheimer Disease Mutations Can Be Rescued by Mutations in the APP GxxxG Motif*
TLDR
It is shown that aberrant Aβ42 levels of FAD mutations can be rescued by GxxxG mutations, contributing to a general understanding of the mechanism how APP is processed by the γ-secretase module and strongly emphasize the potential of the GxxG motif in the prevention of sporadic AD as well as FAD.
Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase
TLDR
A direct correlation between the concentration of Aβ42 and the rate of amyloid deposition is demonstrated and suggests that PS1 variants do not simply alter the preferred cleavage site for γ-secretase, but rather that they have more complex effects on the regulation of ιsecretase and its access to substrates.
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TLDR
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