The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice

Ultrastructural reconstruction of 27 fibrillar plaques in different stages of formation and maturation was undertaken to characterize the development of fibrillar plaques in the brains of human APP(SW) transgenic mice (Tg2576 ). The study suggests that microglial cells are not engaged in A beta remov al and plaque degradation, but in contrast, are a driving force in plaque f ormation and development. Fibrillar A beta deposition at the amyloid pole o f microglial cells appears to initiate three types of neuropil response: de generation of neurons, protective activation of astrocytes, and attraction and activation or microglial cells sustaining plaque growth. Enlargement of neuronal processes and synapses with accumulation of degenerated mitochond ria, dense bodies, and Hirano-type bodies is the marker of toxic injury of neurons by fibrillar A beta. Separation of amyloid cores from neurons and d egradation of amyloid cores by cytoplasmic processes of hypertrophic astroc ytes suggest the protective and defensive character of astrocytic response to fibrillar A beta. The growth of cored plaque from a small plaque with on e microglial cell with an amyloid star. and a few dystrophic neurites to a large plaque formed by several dozen microglial cells seen in old mice is t he effect of attraction and activation of microglial cells residing outside of the plaque perimeter. This mechanism of growth of plaques appears to be characteristic of cored plaques in transgenic mice. Other features in mous e microglial cells that are absent in human brain are clusters of vacuoles, probably of lysosomal origin. They evolve into circular cisternac and fina lly into large vacuoles filled with osmiophilic, amorphous material and bun dles of fibrils that are poorly labeled with antibody to A beta. Microglial cells appear to release large amounts of fibrillar A beta acid accumulate traces of fibrillar A beta in a lysosomal pathway. (C) 2001 Elsevier Scienc e Inc. All rights reserved.