Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease.

Background: beta-Amyloid (A beta) is the product of concerted cleavage of the amyloid precursor protein (APP) by beta-and gamma-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that gamma-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in A beta metabolism through a mechanism involving its interaction with both.-secretase and APP. However, a detailed evaluation of GSAP protein levels and their association with clinical and neuropathological variables are lacking during the clinical progression of Alzheimer disease (AD). Methods: We quantified levels of the GSAP precursor (98 kDa) and its active form (16 kDa) in the frontal cortex and hippocampus, areas displaying extensive A beta and neurofibrillary tangle (NFT) pathology, in subjects who came to autopsy with a premortem clinical diagnosis of noncognitive impairment, mild cognitive impairment, mild to moder ate AD, and severe AD using Western blotting. Results: Analysis found that 98-kDa GSAP levels were increased, while those of 16 kDa were reduced in the frontal cortex of severe-AD subjects. By contrast, GSAP levels remained stable in the hippocampus. Frontal cortex and hippocampal GSAP 98- and 16-kDa levels were not associated with A beta, NFT, and neuropathological criteria across clinical groups. Interestingly, only neocortical 98-kDa GSAP values showed a significant correlation with the Mini-Mental State Examination and episodic memory scores. Conclusions: These data demonstrate that GSAP proteins are differentially dysregulated in severe AD, but only the full-length form was associated with cognitive test scores in AD. (C) 2017 S. Karger AG, Basel