|Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1996: ¥1,400,000 (Direct Cost: ¥1,400,000)
Microglia and astrocytes sometimes contain granules immunopositive for amyloid beta-protein (Abeta) in brains of patients with Alzheimer's disease (AD). Although the significance of Abeta-containing glial cells has yet to be fully understood, overproduction of Abeta or failure in the degradative pathway of Abeta may induce such granular accumulation of Abeta in glial cells. Abeta removal from brain tissues is seen most typically in Alzheimer brain mwhich mis complicated with recent ischemia. In such lisions, Abeta deposits, together with necrotic tissue debris, are removed by infiltrating macrophages and reactive microglia. Abeta forms granules in the phagocytic cells. Abeta in these cells is N-terminally truncated around the alpha-secretase cleavage site.
In the present study, we describe an uncommon form of diffuse Abeta deposits which is associated with many Abeta-containing glial cells. In these deposits, Abeta with the C-terminus of a residue valine^<40> (Abeta40) and Abeta with th
e C-termini of alanine^<42>/threonine^<43> (Abeta42) coexist both extracellularly and intracellularly. The N-termini of Abeta in the extracellular diffuse deposits include aspartate^1, pyroglutamate^3, and pyroglutamate^<11>, among which pyroglutamate^3 staining is the most intense. Abeta in glial granules is N-terminally truncated around the alpha-secretase cleavage site. The diffuse Abeta deposits of this type are found only inconsistently and are absent in a number of cases examined in this study. It has to be noted, however, the neuropathological observation is always limited to a very small area of the entire brain. Complement activation in these deposits is not prominent and often below the sensitivity of immunohistochemical detection. Microglia and astrocytes in these Abeta deposit areas look quiescent compared with those associated with senile plaques and other lesions such as ischemia.
Abeta secreted from neurons may be taken up by glial cells in its early, non-fibrous form. Within the glial cells proteolytic processing of Abeta takes place, with the C-terminal fragment being more slowly broken down than the N-terminal fragment. Such ready uptake would account for the lack of an inflammatory response to the Abeta. Despite their infrequency, the diffuse deposits described here may represent a very early stage of Abeta deposition. Abeta40, which is generally considered to deposit in the later stages of Abeta deposition, predominates in these deposits and may actually precede Abeta42 deposition. Association of Abeta containing glial cells with a presumably early stage of Abeta deposition infers the overproduction of Abeta or the impaired intraglial processing of Abeta in these areas. The results of this study also suggests that Abeta accumulates by continuous addition of newly produced Abeta. It suggests as well that significant removal of previously deposited Abeta can occur. Thus, there may be turnover of Abeta in every diffuse Abeta deposit. Less