Amyloid precursor protein (APP) derived amyloid beta (Aβ) peptides have already been extensively investigated in Alzheimer’s disease pathology of the brain. key points will be re-emphasized. It appears that APP promotes cell adhesion to several components of the extracellular matrix GS-9137 based upon its interactions with perlecan laminin collagen type IV and entactin. Studies using wild APP and type?/? mice demonstrate that APP could also work as a membrane receptor and regulate behavior from the axonal transportation proteins kinesin-I which mediates motion of membrane-bound compartments such as for example melanosomes along microtubules. Oddly enough APP also seems to regulate copper homeostasis as recommended by its capability to decrease Cu(II) to Cu(I) resulting in oxidative tension and apoptosis in the basal epidermis in human being keratinocytes. Furthermore to these features attributed to complete length proteins the APP fragment sAPPα promotes human being keratinocyte proliferation and migration and regulates melanocyte function in human being psoriasis individual keratinocytes raises transcription of kynureninase that may induce an inflammatory pores and skin response (Romanowska et al. 2009 Improved APP manifestation also correlates with advanced melanoma development in human cells and downregulation by RNA interference in human melanoma cell lines results in terminal and irreversible differentiation (Botelho et al. Rabbit Polyclonal to MYBPC1. 2010 APP processing and Aβ release has also been shown to be regulated by protein kinase C (PKC) activity in cultured skin fibroblasts from familial Alzheimer’s disease (FAD) patients in which phorbol ester stimulation of PKC-α activity increases sAPP-α and decreases Aβ secretion (Gasparini et al. 1998 Aβ secretion is basally elevated in cultured skin fibroblasts from FAD patients suggesting that FAD has a deficit in PKC activity. FAD cultured fibroblasts also have increased total membrane bound calcium with attenuated calcium uptake as well as increased lactate production and altered glucose utilization compared to non-AD controls. This suggests that APP may be involved in regulating a disease phenotype in FAD GS-9137 epidermis (Gasparini et al. 1998 GS-9137 Collectively these findings from the skin indicate that APP and its metabolites have a role in regulating epidermal cell phenotypes with a significant ability to modulate proliferative and migratory behavior. Disease-associated changes in expression or processing of APP correlate with perturbations of these behaviors in a variety of diseases. 4 APP function and Aβ pathology in adipose tissue APP and its Aβ fragments are also expressed in human adipose tissue adipocytes and macrophages (Lee et al. 2008 Obesity upregulates APP levels in human adipose tissue which correlates with insulin resistance hyperinsulinemia and an increase in the expression profile of the GS-9137 proinflammatory genes monocyte chemotactic protein -1 (MCP-1) macrophage inflammatory protein-1α (MIP-1α) and interleukin-6 (IL-6) in human adipocytes (Lee et al. 2008 Elevated human adipocyte APP gene expression also correlates with increased plasma Aβ40 levels (Lee et al. 2009 Tumor necrosis factor α (TNFα) stimulation increases APP protein levels in 3T3-L1 adipocytes in a dose-dependent manner (Sommer et al. 2009 This correlates with an observed increase in levels of adipose tissue TNFα and APP in a murine model of diet-induced obesity although agonist antibody stimulation of APP does not alter murine adipocyte viability proinflammatory TNFα secretion or differentiation state (Puig et al. 2012 These data from both rodent and human studies indicate that APP expression in adipose tissue appears to be correlatively up-regulated during proinflammatory conditions such as obesity and is positively regulated by direct proinflammatory stimulation of adipocytes. However the function of APP or its metabolites basally or during proinflammatory upregulation in adipose tissue remains unclear. 5 APP function and Aβ pathology in intestine APP is expressed in the intestine and is localized to enterocytes neurons and smooth muscle of the muscualaris externa in mice (Puig et al. 2011 APP and Aβ levels are increased in absorptive columnar epithelial cells in mice fed a high fat diet that is enriched in saturated fat and cholesterol. However Aβ levels are attenuated by fasting for 65hr recommending that APP or its metabolites may control chylomicron biosynthesis (Galloway et al. 2007 Aβ immunoreactivity colocalizes with apo B in little intestine enterocytes along.