Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
TLDR
Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.Abstract:
Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...read more
Citations
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Journal ArticleDOI
The Cell Adhesion Protein P-selectin Glycoprotein Ligand-1 Is a Substrate for the Aspartyl Protease BACE1
Stefan F. Lichtenthaler,Diana Ines Dominguez,Gil G. Westmeyer,Karina Reiss,Christian Haass,Paul Saftig,Bart De Strooper,Brian Seed +7 more
TL;DR: It is shown that BACE1 acts on the P-selectin glycoprotein ligand 1 (PSGL-1), which mediates leukocyte adhesion in inflammatory reactions, and concludes that PS GL-1 is an additional substrate for Bace1.
Journal ArticleDOI
Age-dependent cognitive decline in the APP23 model precedes amyloid deposition.
Debby Van Dam,Rudi D'Hooge,Matthias Staufenbiel,Chris Van Ginneken,Frans Van Meir,Peter Paul De Deyn +5 more
TL;DR: Determination of plaque‐associated human amyloid‐β1–42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics, which coincided with the first appearance of plaques in hippocampus and neocortex.
Journal ArticleDOI
Presenilin-dependent γ-Secretase-like Intramembrane Cleavage of ErbB4
Hahn Jun Lee,Kwang-Mook Jung,Yang Z. Huang,Lori B. Bennett,Joanne S. Lee,Lin Mei,Tae-Wan Kim +6 more
TL;DR: The study indicates that ErbB4 represents a first receptor tyrosine kinase that undergoes intramembrane proteolysis and may mediate a novel signaling function independent of its canonical role as a receptor tyrose kinase.
Journal ArticleDOI
Age- and region-dependent alterations in Aβ-degrading enzymes: implications for Aβ-induced disorders
TL;DR: It is suggested that age- and region-specific changes in the proteolytic clearance of Aβ represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM.
Journal ArticleDOI
Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration.
TL;DR: Current findings on the genetics of AMD are discussed to highlight areas of rapid progress and new challenges and it is attempted to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.
References
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Journal ArticleDOI
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Journal ArticleDOI
Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
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