Author:

Keywords:

Alzheimer Disease, Amino Acid Substitution, Amyloid beta-Protein, Cell Line, Endopeptidases, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Male, Mutation, Missense, Pedigree, Peptide Fragments, Protein Processing, Post-Translational, Research Support, Non-U.S. Gov't, Senile Plaques, Solubility, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Transfection, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Genetics & Heredity, HEREDITARY CEREBRAL-HEMORRHAGE, BETA-PROTEIN FIBRILLOGENESIS, PRECURSOR PROTEIN, SPASTIC PARAPARESIS, MASS-SPECTROMETRY, APOLIPOPROTEIN-E, SENILE PLAQUES, CELL BIOLOGY, PRESENILIN-1, GENE, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Plaque, Amyloid, 06 Biological Sciences, 11 Medical and Health Sciences, 3105 Genetics

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).