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

Abstract

Background: β-Amyloid (Aβ) is the product of concerted cleavage of the amyloid precursor protein (APP) by β- 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 Aβ 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 Aβ 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 Aβ, 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.

GSAP modulates γ-secretase specificity by inducing conformational change in PS1

“…Our findings provide a route to the investigation of γ-secretase modulation and, ultimately, to the development of therapeutic agents for AD. In addition, abnormal activation of γ-secretase by GSAP that is associated with aging, AD, and Down syndrome (14–16) may lead to AD.…”

“…Nevertheless, GSAP RNAi mice crossed with double transgenic APPsweXPS1ΔE9 Alzheimer’s disease (AD) model mice have reduced Aβ burden (12), indicating that GSAP is a novel therapeutic target for the treatment of AD. Furthermore, genetic studies have shown that GSAP is linked with aging, AD, and Down syndrome (14–16). Therefore, investigating the function of GSAP in Aβ production and in γ-secretase activity and specificity is critical for developing an in-depth understanding of γ-secretase modulation and effective AD therapeutics.…”

γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors

“…Cells possess a different type of γ-secretase complexes with variable levels of activities (PDB structure: 6IDF), which under certain cellular circumstances GSMP can bind and modify its activity and selectivity (clockwise): endoplasmic reticulum (ER) stress upregulate stress-associated ER protein 1 (SERP1) expression which binds and localize the γ-secretase complex to lipid rafts where amyloid precursor protein (APP) resides thus increasing APP cleavage but not Notch processing (Jung et al, 2020), hypoxic conditions stabilize Hif-1α which in turn binds to γ-secretase and increase its activity for Notch substrates (Villa et al, 2014), innate immune response and aging triggers the binding of interferon-induced transmembrane protein 3 (IFITM3) thus enhancing γ-secretase for APP but reducing Notch processing (Hur et al, 2020) and under unknown conditions GSAP attenuates γ-secretase activity solely towards APP but not Notch (Wong et al, 2019; Magenta-Nicastrin, Green-Presenilin, Blue-Aph-1 and Red-Pen-2). GSAP that is associated with AD, which might associate GSAP as a disease-related risk factor (Zhu et al, 2014;Perez et al, 2017). This was the first study that demonstrated the extent to which GSMPs attenuate γ-secretase activity by interacting with the enzyme in the allosteric site and changing its active site conformation.…”

“…A later study revealed that GSAP modulates γ-secretase activity by altering the active site and subsequently enhancing APP processing while not affecting Notch processing (Wong et al, 2019 ). In the case of GSAP, the precise cellular cue that is responsible for its interaction with γ-secretase is unclear, but there is an SNP in GSAP that is associated with AD, which might associate GSAP as a disease-related risk factor (Zhu et al, 2014 ; Perez et al, 2017 ). This was the first study that demonstrated the extent to which GSMPs attenuate γ-secretase activity by interacting with the enzyme in the allosteric site and changing its active site conformation.…”

GSAP modulates γ-secretase specificity by inducing conformational change in PS1

“…Nevertheless, GSAP RNAi mice crossed with double transgenic APPsweXPS1ΔE9 AD model mice have reduced Aβ burden 12 , indicating that GSAP is a novel therapeutic target for the treatment of AD. Furthermore, genetic studies have shown that GSAP is linked with aging, AD and Down syndrome [14][15][16] . Therefore, investigating the function of GSAP in Aβ production and γ-secretase activity and specificity is critical for developing an in-depth understanding of γ-secretase modulation and effective AD therapeutics.…”