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Early Phenotypic Changes in Transgenic Mice That Overexpress Different Mutants of Amyloid Precursor Protein in Brain*
- D. Moechars, I. Dewachter, F. van Leuven
- Biology, PsychologyThe Journal of Biological Chemistry
- 5 March 1999
Cognitive deficits and phenotypic traits early in life that dissociated in time from the formation of amyloid plaques will be good models for both early and late neuropathological and clinical aspects of Alzheimer’s disease.
Intraneuronal Abeta42 accumulation in human brain.
It is suggested that intracellular Abeta42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Abeta 42 aggregation may be an important therapeutic direction for the treatment of AD.
Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.
- A. Herreman, D. Hartmann, B. de Strooper
- BiologyProceedings of the National Academy of Sciences…
- 12 October 1999
It is demonstrated in vivo that PS1 and PS2 have partially overlapping functions and thatPS1 is essential andPS2 is redundant for normal Notch signaling during mammalian embryological development.
Intraneuronal Aβ42 Accumulation in Human Brain
The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein.
O-phenanthroline and BB3103 and TAPI, the inhibitors of metalloenzymes ADAM10 and ADAM17, are identified as the protease candidates responsible for normal cleavage of PrPc, and for the first time, disintegrins could participate in the catabolism of glycosyl phosphoinositide-anchored proteins such asPrPc.
TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity.
It is reported that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma- secretase cleavage without affecting epsilon-secretase activity.
Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and…
Findings suggest that the shedding of BACE may play a role in the amyloidogenic processing of betaAPP, a major factor in the etiology of Alzheimer's disease.
Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides.
These studies demonstrate that Abeta40 (Abeta1-40 plus Abetax-40, where x is an NH2-terminal truncation) is generated exclusively within the trans-Golgi Network (TGN) and packaged into post-TGN secretory vesicles.
Amyloid Precursor Protein, Presenilins, and α-Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Treatments that block the accumulation of Aβ and α-synuclein might benefit a broad spectrum of neurodegenerative disorders, because some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways.
Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation
It is found that neurodegeneration was significantly accelerated in mice older than 13 months (aged mice) with familial Alzheimer disease mutant PS-1, without amyloid plaque formation, but there were significantly more neurons containing intracellularly deposited Aβ42 in aged mutant transgenic mice.