Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism

Abstract

The amyloid precursor protein (APP) is a transmembrane protein that can be cleaved by proteases through two different pathways to yield a number of small peptides, each with distinct physiological properties and functions. It has been extensively studied in the context of Alzheimer`s disease, with the APP-derived amyloid β (Aβ) peptide being a major constituent of the amyloid plaques observed in this disease. It has been known for some time that APP can regulate neuronal metabolism; however, the present review examines the evidence indicating that APP and its peptides can also regulate key metabolic processes such as insulin action, lipid synthesis and storage and mitochondrial function in peripheral tissues. This review presents the hypothesis that amyloidogenic processing of APP in peripheral tissues plays a key role in the response to nutrient excess and that this could contribute to the pathogenesis of metabolic diseases such as obesity and type 2 diabetes (T2D). K E Y W O R D Samyloid β, APP, insulin resistance, mitochondria | INTRODUCTIONThe amyloid precursor protein (APP) has been extensively studied, primarily because it gives rise to the amyloid β (Aβ) peptide, which has been implicated in the pathogenesis of Alzheimer's disease (AD). It is clear that APP, as well as other peptides generated by its cleavage, have biological functions beyond those attributed to Aβ alone. Indeed, loss of function models have established that APP is involved in neuronal development and progenitor cell proliferation and differentiation, synaptic plasticity and specific cellular signalling processes.1 A growing body of evidence suggests that APP and its cleaved peptides also regulate a variety of metabolic processes. | APP STRUCTURE, EXPRESSION AND APP PROCESSINGBased on homology, APP belongs to a family of proteins that in mammals also includes the APP like proteins (APLP) 1 and 2. 4 The present review primarily focuses on APP; however, there is considerable functional overlap between these proteins. 4 These transmembrane proteins all have a large extracellular region and a smaller cytoplasmic region, which are linked by a single pass transmembrane domain. 5These domains can be cleaved by a number of different proteases to yield a number of distinct peptides. Interestingly, APP is the only APP family member to contain the domain that encodes the Aβ peptide. 6Although all APP family members are highly expressed in neurones,

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

“…Consequently, the bloodstream becomes one of the major chronic supplies of Aβ peptides to the brain [31]. Both APP and its Aβ production pathway are involved in several cerebral physiological processes, such as neurotrophic activity, modulation of synaptic plasticity, neurogenesis, metal ion sequestration, antioxidant activity, and calcium homeostasis [32].…”

“…Aβ protein has an important physiological role, which can be dysregulated with aging or in AD [5,32]. Impairment of the balance between Aβ production and clearance leads to an accumulation of Aβ within the brain parenchyma or in the vessel walls, which can generate neurodegenerative processes leading to dementia [45].…”

Nicotinamide Reduces Amyloid Precursor Protein and Presenilin 1 in Brain Tissues of Amyloid Beta-Tail Vein Injected Mice

“…Therefore, Aβ peptide and tau protein are often considered as potential pharmacological targets. Amyloid precursor protein (APP) is cleaved by β-secretase 1, a beta-site APP cleaving enzyme 1, to produce Aβ peptide [ 2 ]. Presenilin 1 (PS1) is a part of γ-secretase complex which cleaves APP [ 3 ].…”

APP deficiency results in resistance to obesity but impairs glucose tolerance upon high fat feeding

“…Data obtained from Drosophila melanogaster suggest that fragmentation of behavioural rhythmicity is attributable to both α-and β-processing of APP (Blake et al 2015), which may further highlight the differences observed in energy balance and activity between the previously published BACE1-deficient mice vs APP KO mice from this study. These studies highlight the complexity in APP-mediated regulation of whole body energy homeostasis and as we have recently hypothesised, could indicate that peptides derived from the amyloidogenic and non-amyloidogenic processing of APP could have different effects on aspects of systemic metabolism (Czeczor & McGee 2017).…”