RAGE regulates BACE1 and Aβ generationviaNFAT1 activation in Alzheimer's disease animal model

Abstract

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid beta peptide (Abeta) is one of the ligands for RAGE. Because RAGE is a transporter of Abeta from the blood to the brain, RAGE is believed to play an important role in Alzheimer's disease (AD) pathogenesis. In the present study, the role of RAGE in Abeta production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because beta-site APP-cleaving enzyme 1 (BACE1), an essential protease for Abeta production, is up-regulated in cells overexpressing RAGE and in RAGE-injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Abeta production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T-cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE-induced BACE1 expression followed by Abeta generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full-length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, Abeta, BACE1, and the active form of NFAT1 compared with fRAGE-injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Abeta production and deposition in the brain.

A 1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling

“…Notably, RAGE expression upregulates severalfold in cerebral vessels, microglia, and neurons that are affected in human AD brains and rodent AD model brains (Zlokovic, 2008). Several studies, including our previous report, have shown that RAGE levels rise with age in rodents and humans (Simm et al, 2004;Cho et al, 2009). In addition, RAGE expression in neurons and human brain microvascular endothelial cells is increased on treatment with A␤ (Cho et al, 2009;Li et al, 2009).…”

“…Several studies, including our previous report, have shown that RAGE levels rise with age in rodents and humans (Simm et al, 2004;Cho et al, 2009). In addition, RAGE expression in neurons and human brain microvascular endothelial cells is increased on treatment with A␤ (Cho et al, 2009;Li et al, 2009). Figure 4 shows that RAGEoverexpressing bEnd.3 cells experience greater reductions in ZO-1 levels during treatment with A␤.…”

“…Further, increasing intracellular calcium levels interferes with the formation of TJ (Stuart et al, 1996). We have observed that RAGE affects A␤-induced calcium influx (Cho et al, 2009) and that the influx is sustained during A␤ treatment (Fig. 2 A).…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…Multiple mechanisms are recently proposed to mediate the upregulation of BACE1 associated with AD. Those include the increased phosphorylation of the translation initiation factor eIF2a Devi and Ohno, 2010b;O'Connor et al, 2008), caspase-3-dependent inactivation of GGA3 leading to decreased lysosomal degradation of BACE1 (Sarajarvi et al, 2009;Tesco et al, 2007), changes in microRNA expression profiles (Hebert et al, 2008;Wang et al, 2008), p25/cyclin-dependent kinase 5 pathways (Cruz et al, 2006;Wen et al, 2008), calpain activation (Liang et al, 2010), the receptor for advanced glycation end products (RAGE) (Cho et al, 2009;Guglielmotto et al, 2010), and oxidative stress or related signals such as nuclear factor-kB, c-Jun N-terminal kinase, and p38 MAPK (Chen et al, 2011;Chen et al, 2008;Coma et al, 2008;Xiong et al, 2007). Further study will be needed to determine the molecular pathways by which activation of BDNF-TrkB signaling may counteract the BACE1 elevation in 5XFAD mice.…”

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

“…Chronic accumulation of AGEs is accelerated with aging and with aging‐related diseases such as diabetes, hyperlipidemia, and renal disease (Cho et al ., 2009). Advanced glycation end products AGEs may accumulate in vascular tissues, thickening and stiffening vascular walls, and increasing the risk of hypertension (Singh et al ., 2001; Goh & Cooper, 2008).…”