Amyloid precursor protein α‐ and β‐cleaved ectodomains exert opposing control of cholesterol homeostasisviaSREBP2

Abstract

Amyloid precursor protein (APP) is ubiquitously expressed. Studies in neuronal cells have implicated APP or its fragments as negative regulators of cholesterol metabolism. In the current study, APP acted, via its α-cleavage, as a positive regulator of sterol regulatory element-binding protein-2 (SREBP2) signaling in human astrocytic cells (U251MG), hepatic cells (HepG2), and primary fibroblasts, leading to an approximate 30% increase in SRE-dependent gene expression and, consequently, enhanced cholesterol biosynthesis and LDL receptor levels. This effect was mediated via the secretory ectodomain APPsα. The β-cleaved ectodomain, in turn, repressed SRE-dependent gene expression by up to ∼ 30%. This resulted in decreased cholesterol synthesis and LDL receptor content, establishing a physiological feedback loop in cholesterol-loaded cells, where APP undergoes preferential β-cleavage. Patients with familial Alzheimer's disease had decreased circulating lathosterol, reflecting hepatic cholesterol synthesis, and their fibroblasts had reduced LDL receptor content, which was alleviated by decreasing β-cleavage. These results show that APP regulates cholesterol metabolism in cells relevant for whole-body cholesterol balance and reveal that APP α- and β-cleavages produce opposing paracrine regulators of SREBP2 signaling.

Shared polygenic risk and causal inferences in amyotrophic lateral sclerosis

“…Dysregulation of cholesterol homeostasis in the brain has been linked to many neurodegenerative diseases such as Huntington's disease, Parkinson's disease, Niemann‐Pick disease type C, and, most notably, Alzheimer's disease . The generation and clearance of β‐amyloid protein is regulated by cholesterol, and drugs that inhibit cholesterol synthesis lower this protein within neurons, as is the more recent finding that the two secretory forms (APPɑ and APP β) of amyloid precursor protein (APP) have opposing associations with β‐amyloid generation, cholesterol biosynthesis, and LDL receptor levels . The identification of the cholesterol transport protein, apolipoprotein E, as a major genetic risk factor for Alzheimer's disease is also consistent with a role for cholesterol in the pathogenesis of neurodegenerative disease .…”

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

“…Many of the LRPs are also g-secretase substrates (Haapasalo and Kovacs, 2011), and LRPs themselves could regulate APP trafficking and processing (Marzolo and Bu, 2009), indicating that APP might couple synaptic activity with lipid flux. An exciting new finding is that APP can also bind cholesterol directly (Barrett et al, 2012;Beel et al, 2008) such that APP fragments might be able to regulate genes in the cholesterol pathway directly (Grimm et al, 2005;Pierrot et al, 2013;Wang et al, 2014). Since the generation of these APP fragments is regulated by neuronal activity (Kamenetz et al, 2003), APP and APP fragments might thus regulate lipid intake and distribution to support membrane reorganization during synaptic activity.…”

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

“…SREBP‐2 overexpression in APP/PS1 mice exhibited exacerbated amyloid pathology and neuronal death with cognitive decline along with hyperphosphorylated tau and NFT formation while SREBP‐2 inhibition reduces amyloid burden in APP/PS1 mice . APP expression/processing and Aβ could also impact cholesterol homeostasis : APP interacts with SREBP‐1 and inhibits its cleavage/activation and the α‐ and β‐cleaved ectodomains of APP may have opposing effects on SREBP‐2 . Oligomeric Aβ impairs the cleavage SREBP‐2 and inhibits cholesterol biosynthesis in vitro .…”