Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice

@article{Citron1997MutantPO,
  title={Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid $\beta$-protein in both transfected cells and transgenic mice},
  author={Martin O. Citron and David Westaway and Weiming Xia and George Carlson and Thekla S. Diehl and Georges Lévesque and Kelly Johnson-wood and Michael K. Lee and Peter Seubert and Angela K. Davis and Dora Kholodenko and Ruth N Motter and Robin Sherrington and Billie J. Perry and H Yao and Robert R Strome and Ivan Lieberburg and Johanna M. Rommens and Soyeon Kim and Dale B. Schenk and Paul D. Fraser and Peter St. George Hyslop and Dennis J. Selkoe},
  journal={Nature Medicine},
  year={1997},
  volume={3},
  pages={67-72}
}
The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic Aβ42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid β-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models… 
Human wild presenilin-1 mimics the effect of the mutant presenilin-1 on the processing of Alzheimer's amyloid precursor protein in PC12D cells
TLDR
The results suggest that APP metabolism is physiologically regulated by the PS1 and that loss of normal PS1 affects gamma-secretase activity.
Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein
TLDR
It is demonstrated that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule, consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by gamma-secretases.
Enhancement of amyloid β 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease
TLDR
The results suggest that increased Aβ42 secretion is important for the development of Alzheimer's disease (AD), but may not be the only factor contributing to the onset of AD.
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.
Decreased Aβ secretion by cells expressing familial Alzheimer's disease-linked mutant presenilin 1
TLDR
Familial Alzheimer's disease (FAD) results from PS mutations, which may alter gamma-secretase activity to enhance the production of highly aggregable Abeta42, and the amount of Abeta secreted by FAD mutant PS1-expressing cells was significantly reduced.
Presenilin transgenic mice as models of Alzheimer’s disease
TLDR
Mice in which PS1 has been conditionally knocked out in adult forebrain on a PS2 null background develop a striking neurodegeneration that mimics AD neuropathology in being associated with neuronal and synaptic loss, astrogliosis and hyperphosphorylation of tau, although it is not accompanied by plaque deposits.
Enhanced generation of intracellular Aβ42 amyloid peptide by mutation of presenilins PS1 and PS2
TLDR
The data collectively indicate that PS mutations promote the accumulation of intracellular Aβ42, which appears to be localized in multiple subcellular compartments.
Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes
TLDR
The development of AD-like pathology is substantially enhanced when a P51 mutation, which causes a modest increase in Aβ42(43), is introduced into Tg2576-derived mice, and both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a “Y” maze before substantial Aβ deposition was apparent.
Molecular dissection of domains in mutant presenilin 2 that mediate overproduction of amyloidogenic forms of amyloid beta peptides. Inability of truncated forms of PS2 with familial Alzheimer's disease mutation to increase secretion of Abeta42.
TLDR
Data indicate that the Abeta42-promoting effects of mutant PS2 proteins reach the maximum level with a given single amino acid substitution, and cooperative interactions of NH2- and COOH-terminal fragments generated from full-length Mutant PS2 may be important for the overproduction of Abeta 42 that may underlie familial Alzheimer's disease.
Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease.
TLDR
It is demonstrated that wt and mutant PS1 and PS2 proteins form complexes with APP in living cells, strongly supporting the hypothesis that mutant PS interacts withAPP in a way that enhances the intramembranous proteolysis of the latter by a gamma-secretase cleaving at Abeta42.
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