GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease

Abstract

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’s syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the 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 that lowering GSAP expression reduces pathological effects associated with AD.

The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer’s disease and the potential countermeasure

“…γ-secretase activating protein (GSAP) fluorescence staining showed high colocalization with a MAM marker Facl4. Knockdown of GSAP significantly increased mitochondrial basal respiration and total ATP levels, which suggests that GSAP impairs mitochondria function ( Xu et al, 2021 ). In an AD cell model, increased concentration of unprocessed C99 in the MAM region increased sphingolipid turnover and altered the lipid composition of mitochondrial membranes, which can interfere with the normal activity of the respiratory supercomplexes and thus may contribute to the bioenergetic defects in AD ( Pera et al, 2017 ).…”

“…The concentration of unprocessed C99 at the MAMs is increased in models of AD and cells from AD patients, subsequently associated with the increase in ceramide levels ( Pera et al, 2017 ). GSAP enriched in MAMs regulates lipid homeostasis through the processing of APP ( Xu et al, 2021 ). In a cortical impact mice model of AD, the injured cortex and hippocampus exhibited significant increases in MAM activity, phospholipid synthesis, sphingomyelinase (SMases) activity, and cholesterol turnover ( Agrawal et al, 2022 ).…”

Astrocyte, Lipid Metabolism in Alzheimer’s Disease and Glioblastoma

“…Single-nucleotide polymorphisms (SNPs) at the GSAP locus have been shown association with AD diagnosis [308,309], of which one SNP was found to correlate with GSAP expression and AD risk [310]. Genetic knockdown and pharmacological inhibition of GSAP suppress Aβ generation and deposition and tau phosphorylation in AD mouse models [304,305,311]. Apart from the promotion of APP-CTF partitioning into Aβ production-favoring lipid rafts, GSAP has also been shown to be enriched in mitochondria-associated membranes (MAMs), an intracellular domain where amyloidogenic APP processing responsible for dysregulated lipid metabolism is performed [312,313].…”

Diagnosis of Alzheimer’s Disease and In Situ Biological Imaging via an Activatable Near-Infrared Fluorescence Probe

“…In the middle stage, the cerebrocortical metabolism is decreased with reduced memory recall. The related pathophysiological feature of AD is excessive accumulation of amyloid-β ( Aβ ) aggregates. − After neural system atrophy, the mechanisms of Aβ aggregation and clearance are destroyed with disrupted metabolism. , The clinical symptom of AD can only be accurately observed in the later stage, which is undoubtedly the biggest problem in the clinical diagnosis and treatment of the disease. , The diagnostic strategy should therefore concentrate on urgently tracking and detecting disease biomarkers. Butyrylcholinesterase ( BChE ) is widespread in the liver and cerebral cortex and overexpressed at the specific populations of neurons of hippocampal in AD mice models .…”