High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation

Abstract

Obesity and type 2 diabetes are risk factors of Alzheimer’s disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP β (sAPPβ). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPβ. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of β-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage.

Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, β-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease

“…Our data are in agreement with the majority of studies, which point to a clear ability of HFD to increase plaque deposition in mouse models of AD e.g. (Ettcheto, et al, 2016, Levin-Allerhand, et al, 2002, Maesako, et al, 2015). There is less consensus as to the specific cause of this accumulation with evidence for and against enzymatic activity, amyloid transport across the blood brain barrier, and glial cell response as driving forces behind the pathogenesis.…”

“…HFD can promote cleavage of APP by altered regulation of BACE1 trafficking, and thus ultimately resulting in greater production of Aβ (Dall'Armellina, et al, 2013, Maesako, et al, 2015). Studies that have used long-term HFD interventions, or earlier starting points tend to find greater changes in amyloid accumulation (Maesako, et al, 2012a, Maesako, et al, 2012b, Shie, et al, 2002).…”

Retracted: Palmitate‐induced C/EBP homologous protein activation leads to NF‐κB‐mediated increase in BACE1 activity and amyloid beta genesis

“…Palmitate has been shown to increase de novo ceramide synthesis and expression of pro-inflammatory cytokines in primary astrocytes in culture that led to an increase in BACE1 expression in primary cortical neurons that were challenged with the conditioned medium from the palmitate-treated primary astrocytes (Patil et al 2006(Patil et al , 2007Liu et al 2013a,b;Liu and Chan 2014). A wide spectrum of laboratory studies have demonstrated the effects of a high-fat diet on BACE1 activity and Ab burden in a multitude of rodent models of AD (Refolo et al 2000;Levin-Allerhand et al 2002;Ho et al 2004;Cao et al 2007;Thirumangalakudi et al 2008;Fitz et al 2010;Julien et al 2010;Maesako et al 2012Maesako et al , 2015Wang et al 2013;Vandal et al Fig. 7 Constitutive activation of nuclear factor of kappa-light-polypeptide gene enhancer of activated B cells (NF-jB) induces b-site APP cleaving enzyme 1 (BACE1) expression despite the knock-down of C/ EBP homologous protein (CHOP) expression.…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…Animal studies have shown diets high in saturated fats or cholesterol increase levels of Ab and decrease brain insulin levels. [81][82][83] Also, increased consumption of hydrogenated and saturated fats is associated with insulin resistance. Indeed, AD and obesity share pathophysiological mechanisms, including insulin resistance.…”