Frontal Cortex And Hippocampal Î³-Secretase Activating Protein Levels In Prodromal Alzheimer Disease
Background: Î²-Amyloid (AÎ²) is the product of concerted cleavage of the amyloid precursor protein (APP) by Î²-and Î³-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that Î³-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in AÎ² metabolism through a mechanism involving its interaction with both Î³-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 AÎ² 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 AÎ², 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.
Digital Object Identifier (DOI)
Perez, Sylvia E.; Nadeem, Muhammad; Malek-Ahmadi, Michael H.; He, Bin; and Mufson, Elliott J., "Frontal Cortex And Hippocampal Î³-Secretase Activating Protein Levels In Prodromal Alzheimer Disease" (2017). Neurobiology. 319.