Ultrastructural Studies of the Cells Forming Amyloid Fibers in Classical Plaques

Abstract

ABSTRACT:Three-dimensional reconstruction and ultrastructural studies of classical plaques from the cortex of patients with Alzheimer's disease showed that microglial cells of the plaques are the amyloid-forming cells. The amyloid star of the single plaque represents the product of five or six microglial cells covering about 80% of the amyloid star surface. The amyloid fibers appear to be formed within altered cisterns of the endoplasmic reticulum. Distended cisterns form channels filled with amyloid fibers. Numerous vesicles derived from the Golgi apparatus appear to be attached to or fused with the amyloid-filled channels. Reconstruction of the amyloid star and the microglia cell pole that forms the amyloid star reveals three different zones of distribution of cytoplasmic organelles and amyloid deposits. The peripheral zone comprises channels filled with loosely packed amyloid fibers arranged in a parallel manner. The transient zone consists of a mixture of fusing amyloid channels and products of disintegration of cytoplasmic pockets, dense bodies and fragments of cellular membranes. The core of the amyloid star is composed of condensed, densely packed amyloid fibers that are free of cellular debris. Formation of the three zones supports the idea that the microglia/macrophages are not phagocytes but instead are the cells manufacturing the amyloid fibers.

Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures

“…These results are consistent with either negative translational regulation of APP gene expression or enhanced turnover of APP in microglial cells and meninges, whereas increased translational efficiency or lower turnover of APPs may explain the relatively abundant APPs in astrocytes. A high turnover rate of APPs would support the postulate that microglia are producers as well as processors of,BA P peptide [25]. Further studies, such as pulse chase experiments, will determine which of these mechanisms regulates the steady-state levels of APP proteins in these cells.…”

“…The close association of micro. glial cells with senile plaques has led to the hypothesis that microglia are the producers and processors offlAP [25,26] although it has also been suggested that amyloid deposition precedes microglial involvement [27][28][29]. Astrocytes, which appear in high numbers and in close proximity to senile plaques [30,31] and have been shown to have elevated levels of APP expression in lesioned brains [32] could also play a role in flAP deposition.…”

Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease

“…Numerous light and electron microscopic studies showing fibrillar A␤ internalization in phagosomes in cultured microglia are in striking contrast with all in vivo ultrastructural studies of microglia in human and tg mouse amyloid plaques carried out thus far. In the latter, these cells lack any evidence of A␤ internalization and degradation [39,50,51,53,55]. In fact, to date, there is no ultrastructural documentation of A␤ internalization/phagocytosis by microglia within plaques or capillaries in humans, non-treated APP tg mice and vaccinated mice.…”

“…However, in spite of numerous studies, mechanisms of fibrillar amyloid plaque formation and fibrillar A␤ deposition and degradation are still not clear. One of the most controversial elements of plaques is its associated microglia, which are a key component of brain inflammation in AD and are closely associated with fibrillar amyloid cores in human [47,50,55] and tg mouse plaques [15,51,53], starting from the earliest stages of plaque formation to the latest stages of their disintegration (Fig. 1D).…”

“…This hypothesis is supported by ultrastructural studies of cells migrating from microvessels into the brain parenchyma (Figs. 1D and 2), their relationships with A␤ deposits in the wall of capillaries and amyloid plaques, and morphometric models of amyloid plaque formation, growth, and degradation [49][50][51]53,55,57].…”