In addition to participating in γ-secretase activity, presenilin 1 (PS1) regulates trafficking and subcellular localization of β-amyloid precursor protein (APP). We previously showed that gamma-secretase activating protein (GSAP) selectively modulates γ-secretase activity by inducing conformational change in PS1. However, little is known whether and how GSAP might influence APP trafficking and consequent generation of β-amyloid (Aβ) peptides. Here, to explore whether GSAP has any role in regulating APP trafficking, and to systematically investigate the intracellular trafficking routes of APP, we paired total internal reflection fluorescence microscopy, high-speed line scanning microscopy, and 4D microscopy with comprehensive imaging analysis methodologies to depict the elusive modes of APP trafficking at a single-vesicle level. Mobility and diffusivity changes reveal the existence of two kinetically distinct pathways, classified into mobile and immobile pools, for vesicular APP trafficking, suggesting high association between immobile vesicle pool and amyloidogenic processing. GSAP knockdown significantly lowers immobile pool without overturning APP vesicle diffusivity, suggesting that GSAP affects vesicular APP trafficking by retaining APP in membrane microdomains known to favor amyloidogenic processing. Our study reveals a novel role of GSAP in the regulation of Aβ-peptide formation that modulates switching of APP vesicles between immobile and mobile pools, which may help identifying new therapeutic strategies to treat Alzheimer’s disease.

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A new finger-type epicardial echocardiographic probe was evaluated in 26 children with complex cardiac anomalies during open heart surgery. The probe is a small 3.75 MHz phased array transducer for 2-dimensional echo and color Doppler imaging. The tip is slightly angled to facilitate the apical approach through a median sternotomy. The patients included 4 neonates and 8 infants, and the major cardiac lesions were complete atrioventricular (AV) canal, transposition of the great arteries, double outlet right ventricle, and others. The intraoperative study was possible in most of the patients facilitating various approaches for the assessment of left-sided AV valve function, left ventricular outflow obstruction, residual shunt and intraatrial anatomy. Four patients received subsequent operative procedures after the assessment. This transducer appears to be useful in the intraoperative study during surgery for complex cardiac anomalies in neonates and small infants.

Biochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

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