The Presence of Isoaspartic Acid in β-Amyloid Plaques Indicates Plaque Age

Abstract

Extracellular deposits of fibrillar β-amyloid are a characteristic neuropathology of Alzheimer's disease (AD). We have developed a novel antibody to a hypothesized “older isomer” of the amyloid protein. This antibody, raised against a synthetic β-amyloid peptide containing isoaspartic acid at position 7 (isoaspartic-7-Aβ), reacts with isoaspartic-7-Aβ, a nonenzymatic modification found in long-lived proteins. Plaques stained with this antibody are thioflavine positive and are found throughout the frontal and entorhinal cortices of AD cases. In frontal cortex, isoaspartic-7-Aβ plaques are clustered but have a widespread distribution in all cortical layers. Isoaspartic-7-Aβ is found primarily in the core of individual plaques surrounded by nonisomerized amyloid. Activated microglia are associated with plaques containing isomerized and nonisomerized amyloid. In contrast to AD, isoaspartic-7-Aβ plaques in Down's syndrome (DS) cases are found primarily in the superficial layers of frontal cortex. Using image analysis isoaspartic-7-Aβ deposition was correlated with dementia severity in AD and with age in DS. The results indicate that this antibody against altered aspartyl amyloid could be a useful indicator of the age of amyloid plaques.