Yamaguchi (Abstract 1245) presented his theory that very diffuse plaques within nondemented individuals are cleared by astrocytic phagocytosis. He showed many examples of very diffuse Aβ-positive staining within the brains of 40-50 year olds. Within the boundaries of these plaques were dense Aβ immunopositive granules which were colocalized with GFAP. The punctate granules were positive with antibodies to several C-terminal and midregions of Aβ, but were usually not labelled with N-terminal antibodies. Preadsorption with Aβ peptides completely abolished the staining of these granules. At the EM level, these appeared to be polycystic electron dense structures; probably secondary lysosomes.

The occurrence of these intra-astrocytic accumulations of Aβ were inversely age-dependent. While the apparent phagocytosis of Aβ was observed in nearly half of 40-50 year olds, the older the individual, the less frequently these structures were observed. Interestingly, the presence of phagocytosis was not observed in AD brains. Yamaguchi proposed that there is a dynamic balance between diffuse plaque formation and resolution in normal aging, and suggested that in AD, the clearance mechanism is overloaded and neuritic plaques form.

H. Wiswiewski, who was chairing the session, agreed that diffuse plaques can be removed, but also thinks that neuritic plaques can also be resolved and that astrocytes are involved in the process. On the contrarian side, I see no evidence that the phagocytosis of Aβ is actually "successful" at clearing an entire plaque. I only saw one or two Aβ-positive astrocytes per plaque; it doesn't look like they could possibly eat all that amyloid. Yamaguchi's presentation raises the novel possibility that AD is due to the failure of astrocytes to clear Aβ. News flash: Is AD caused by astrocyte aging?-Brian Cummings.

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