Neuropathol Appl Neurobiol. 2012 Apr;38(2):132-41. doi: 10.1111/j.1365-2990.2011.01206.x.

Immunohistochemical characterization of γ-secretase activating protein expression in Alzheimer's disease brains.


AIMS: A recent study showed that γ-secretase activating protein (GSAP), derived from a C-terminal fragment of pigeon homolog (PION), increases amyloid-β (Aβ) production by interacting with presenilin-1 (PS1) and the β-secretase-cleaved C-terminal fragment of amyloid precursor protein (APP-CTF). In the study, knockdown of GSAP reduces production of Aβ and plaque formation in the brain of APPswe and PS1ΔE9 double transgenic mice without affecting the Notch-dependent pathway. Therefore, GSAP is an ideal target for designing γ-secretase modulators with least side effects in Alzheimer's disease (AD). However, at present, the precise distribution of GSAP in AD brains remains to be characterized.
METHODS: By immunohistochemistry, we studied GSAP expression in the frontal cortex and the hippocampus of 11 aged AD and 17 age-matched control cases.
RESULTS: GSAP immunoreactivity exhibited distinct morphological features, such as fine granular cytoplasmic deposits, dense nodular and patchy deposits, beads and string-like deposits, and diffuse dot-like deposits. In both AD and control brains, a fairly small subset of cerebral cortical and hippocampal neurones expressed fine granular cytoplasmic deposits, while diffuse dot-like deposits were more frequently found in the neuropil and neuronal processes, particularly enriched in the hippocampal CA2 and CA3 regions. Among GSAP-immunoreactive deposits, dense nodular and patchy deposits, located in the neuropil and closely associated with PS1 expression and Aβ deposition, indicated the most distinguishing features of AD pathology.
CONCLUSIONS: Aberrant regulation of GSAP expression plays a key role in acceleration of γ-cleavage of APP-CTF and accumulation of Aβ in AD brains.


アルツハイマー病脳(11例)の前頭葉皮質と海馬のγ-secretase activating protein (GSAP)発現を免疫組織化学的に検索し、顆粒状、結節状、斑状の陽性構造を見出した。陽性構造は、neuropil と神経突起(特に海馬 CA2 とCA3領域)に認められた。

PMID:  21718343