Medizinische Universität Graz - Research portal
Selected Publication:
Kumar-Singh, S; De Jonghe, C; Cruts, M; Kleinert, R; Wang, R; Mercken, M; De Strooper, B; Vanderstichele, H; Löfgren, A; Vanderhoeven, I; Backhovens, H; Vanmechelen, E; Kroisel, PM; Van Broeckhoven, C.
Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease.
Hum Mol Genet. 2000; 9(18):2589-2598
Doi: 10.1093/hmg/9.18.2589
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Kleinert Reinhold
- Kroisel Peter
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid beta-peptide (A beta(42)) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid A beta(42) deposits have to mature in the presence of A beta(40) into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving gamma-secretase cleavages of APP. The mutation had the most drastic effect on A beta(42)/A beta(40) ratio in vitro of approximately 11-fold, simultaneously increasing A beta(42) and decreasing A beta(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta(42) in complete absence of A beta(40). These data indicate that N-truncated A beta(42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length A beta(42 )by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta(42).
- Find related publications in this database (using NLM MeSH Indexing)
- Alzheimer Disease - enzymology
- Amino Acid Substitution - genetics
- Amyloid Precursor Protein Secretases - genetics
- Amyloid beta-Protein - chemistry
- Aspartic Endopeptidases - chemistry
- Cell Line - chemistry
- Endopeptidases - genetics
- Enzyme-Linked Immunosorbent Assay - genetics
- Female - genetics
- Humans - genetics
- Immunohistochemistry - genetics
- Male - genetics
- Mutation, Missense - genetics
- Pedigree - genetics
- Peptide Fragments - chemistry
- Protein Processing, Post-Translational - chemistry
- Senile Plaques - chemistry
- Solubility - chemistry
- Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization - chemistry
- Transfection - chemistry