Occurrence of the diffuse amyloid β-protein (Aβ) deposits with numerous Aβ-containing glial cells in the cerebral cortex of patients with Alzheimer's disease

Abstract

Diffuse amyloid β-protein (Aβ) deposits with numerous glial cells containing C-terminal Aβ fragments occur in the cerebral cortex of patients with Alzheimer's disease. By using a panel of antibodies specific for various epitopes in the Aβ peptide, we have investigated the immunohistochemical nature of the diffuse Aβ deposits. The extracellular material contains Aβ with a C-terminus at residue valine40 (Aβ40) as well as residues alanine42/threonine43 (Aβ42). The N-termini include aspartare1, pyroglutamate3, and pyroglutamate11, with pyroglutamate3 being dominant. Microglia and astrocytes in and around these deposits contain intensely staining granules. Most of these granules are negative for antibodies to the N-terminally located sequences of Aβ. These include 6E10 (Aβ1-17), 6F/3D (Aβ8-17), and the N-terminal antibodies specific to aspartate1, pyroglutamate3, and pyroglutamate11. The C-termini of intraglial Aβ are comparable with those of the extracellular deposits. The microglia and astrocytes have quiescent morphology compared with those associated with senile plaques and other lesions such as ischemia. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Although factors which may cause this type of deposit remain unclear, lack of strong tissue responses suggests that these deposits are a very early stage of Aβ deposition. They were found only inconsistently and were absent in a number of cases examined in this study. Further analysis of these deposits might provide important clues regarding the accumulation and clearance of Aβ in Alzheimer's disease brain.