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

Aims: A recent study showed that gamma-secretase activating protein (GSAP), derived from a C-terminal fragment of pigeon homolog (PION), increases amyloid-beta (A beta) production by interacting with presenilin-1 (PS1) and the beta-secretase-cleaved C-terminal fragment of amyloid precursor protein (APP-CTF). In the study, knockdown of GSAP reduces production of A beta and plaque formation in the brain of APPswe and PS1 Delta E9 double transgenic mice without affecting the Notch-dependent pathway. Therefore, GSAP is an ideal target for designing gamma-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 A beta deposition, indicated the most distinguishing features of AD pathology. Conclusions: Aberrant regulation of GSAP expression plays a key role in acceleration of gamma-cleavage of APP-CTF and accumulation of A beta in AD brains.