Amyloid β-protein (Aβ)-containing astrocytes are located preferentially near N-terminal-truncated αβ deposits in the human entorhinal cortex

The deposition of the amyloid beta -protein (A beta) is a pathological hallmark of Alzheimer's disease (AD). A beta is a peptide consisting of 39-43 amino acids and is derived by beta- and gamma -secretase cleavage from the AP protein precursor (A beta PP). An N-terminal-truncated form of A beta can occur following alpha- and gamma -secretase cleavage of A beta PP. Fleecy amyloid is a recently identified distinct type of A beta 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 A beta and is a transient form of A beta 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 A beta in fleecy amyloid of the layers pri-alpha, pri-beta, and pri-gamma in comparison to astrocytes in the vicinity of full-length A beta in layers pre-beta and pre-gamma. Immunohistochemistry was performed with antibodies directed against A beta PP, A beta (40), A beta (42), A beta (17-24) A beta (1-17) and A beta (8-17) as well as by double-labeling with antibodies directed against A beta (17-24) A beta (42), and glial fibrillary acid protein (GFAP). A large number of GFAP-positive astrocytes containing N-terminal-truncated A beta fragments appeared in the vicinity of N-terminal-truncated A beta, whereas A beta -containing astrocytes were rarely seen in the vicinity of full-length A beta. These results suggest that N-terminal-truncated A beta peptide may be cleared preferentially from the extracellular space by astrocytic uptake and processing. Such an astroglial uptake of N-terminal-truncated A beta may account for the transient nature of fleecy amyloid and point to the use of N-terminal truncation of A beta in potential therapeutic strategies aimed at preventing the brain from amassing full-length A beta deposits.