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

ABSTRACT

BACKGROUND: ß-Amyloid (Aß) is the product of concerted cleavage of the amyloid precursor protein (APP) by ß- and γ-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that γ-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in Aß metabolism through a mechanism involving its interaction with both γ-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 Aß and neurofibrillary tangle (NFT) pathology, in subjects who came to autopsy with a premortem clinical diagnosis of noncognitive impairment, mild cognitive impairment, mild to moderate 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 Aß, 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.