Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex.
The deposition of the amyloid beta-protein (Abeta) is a pathological hallmark of Alzheimer's disease (AD). Abeta is a peptide consisting of 39-43 amino acids and is derived by beta- and gamma-secretase cleavage from the Abeta protein precursor (AbetaPP). An N-terminal-truncated form of Abeta can occur following alpha- and gamma-secretase cleavage of AbetaPP. Fleecy amyloid is a recently identified distinct type of Abeta deposits occurring in the internal layers (pri-alpha, pri-beta and pri-gamma) of the human entorhinal cortex. Fleecy amyloid consists exclusively of N-terminal-truncated Abeta and is a transient form of Abeta deposits, which disappears in late-stage beta-amyloidosis. In this study, the entorhinal cortex of 15 cases with AD-related pathology was used to examine astrocytes in the vicinity of N-terminal-truncated Abeta in fleecy amyloid of the layers pri-alpha, pri-beta, and pri-gamma in comparison to astrocytes in the vicinity of full-length Abeta in layers pre-beta and pre-gamma. Immunohistochemistry was performed with antibodies directed against AbetaPP, Abeta40, Abeta42, APbeta17-24, Abeta1-17 and Abeta8-17 as well as by double-labeling with antibodies directed against Abeta17-24, Abeta42, and glial fibrillary acid protein (GFAP). A large number of GFAP-positive astrocytes containing N-terminal-truncated Abeta fragments appeared in the vicinity of N-terminal-truncated Abeta, whereas Abeta-containing astrocytes were rarely seen in the vicinity of full-length Abeta. These results suggest that N-terminal-truncated Abeta peptide may be cleared preferentially from the extracellular space by astrocytic uptake and processing. Such an astroglial uptake of N-terminal-truncated Abeta may account for the transient nature of fleecy amyloid and point to the use of N-terminal truncation of Abeta in potential therapeutic strategies aimed at preventing the brain from amassing full-length Abeta deposits.
Thal
D R
DR
Department of Anatomy, J.W. Goethe University, Frankfurt, Germany. Thal@em.uni-frankfurt.de
Schultz
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C
Dehghani
F
F
Yamaguchi
H
H
Braak
H
H
Braak
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E
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments