Article

Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability.

Laboratory of Neurogenetics, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
Human Molecular Genetics (Impact Factor: 7.69). 09/2001; 10(16):1665-71. DOI: 10.1093/hmg/10.16.1665
Source: PubMed

ABSTRACT Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.

0 Bookmarks
 · 
42 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative foldopathies are characterized by aberrant folding of diseased modified proteins, which are major constituents of the intracellular and extracellular lesions. These lesions correlate with the cognitive and/or motor impairment seen in these diseases. The majority of the disease modified proteins in neurodegenerative foldopathies belongs to the group of proteins termed as intrinsically disordered proteins (IDPs). Several independent studies have showed that abnormal protein processing constitutes the key pathological feature of these disorders. The current review focuses on protein truncation as a common denominator of neurodegenerative foldopathies, which is considered to be the major driving force behind the pathological metamorphosis of brain IDPs. The aim of the review is to emphasize the key role of the protein truncation in the pathogenic pathways of neurodegenerative diseases. A deeper understanding of the complex downstream processing of the IDPs, resulting in the generation of pathologically modified proteins might be a prerequisite for the successful therapeutic strategies of several fatal neurodegenerative diseases.
    Molecular Neurobiology 03/2013; · 5.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Accumulation, aggregation and deposition of Aβ peptides are pathological hallmarks in the brains of individuals affected by Alzheimer's disease (AD) or by cerebral β-amyloid angiopathy (Aβ-CAA). While Aβ is a peptide of yet largely unknown function, it is constantly produced in the human brain where it normally remains in a soluble state. However, Aβ peptides are aggregation prone by their intrinsic ability to adopt alternative conformations rich in β-sheet structure that aggregate into oligomeric as well as fibrillar formations. This transition from soluble to aggregated state has been hypothesized to initiate the pathological cascade and is therefore subject to intensive research. Mounting evidence suggests prion-like templated misfolding as the biochemical phenomenon responsible for promoting progressive Aβ aggregation. Here, we review studies in vitro and in vivo that suggest that cerebral Aβ aggregation may indeed progress via prion-like templated misfolding. The implications of these findings are discussed with respect to understanding initiation and progression of the disease and to developing therapeutics.
    Brain Pathology 05/2013; 23(3):333-41. · 4.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, senile plapue. The Aβ peptide is cleaved from amyloid precursor protein (APP) by β-secretase and γ-secretase. Until now, many literatures have documented that the high concentration of copper is present in Aβ plaques and enhances aggregation of. The APP copper binding domain (CuBD) is located in the N-terminal next to the growth factor-like domain that gets involved in APP homodimerization. Importantly, dimerization of APP has profound effect on Aβ production. We investigated whether copper alters the state of APP dimerization and how it affects APP metabolism. Here, we demonstrate that copper enhanced APP dimerization and increased extracellular release of Aβ. Moreover, copper chelator, D-penicillamine, suppressed APP dimerization and decreased extracellular release of Aβ. These results suggest that the action of copper may be profoundly associated with the pathway of Aβ production in AD pathogenesis.
    Neuroscience Letters 05/2013; · 2.03 Impact Factor