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Iron deposition in the brain is an early issue in Alzheimer's disease (AD). However, the pathogenesis of iron-induced pathological changes in AD remains elusive. Insulin resistance in brains is an essential feature of AD. Previous studies determined that insulin resistance is involved in the development of pathologies in AD. Tau pathology is one of most important hallmarks in AD and is associated with the impairment of cognition and clinical grades of the disease. In the present study, we observed that ferrous (Fe2+) chloride led to aberrant phosphorylation of tau, and decreased tyrosine phosphorylation levels of insulin receptor β (IRβ), insulin signal substrate 1 (IRS-1) and phosphoinositide 3-kinase p85α (PI3K p85α), in primary cultured neurons. In the in vivo studies using mice with supplemented dietary iron, learning and memory was impaired. As well, hyperphosphorylation of tau and disrupted insulin signaling in the brain was induced in iron-overloaded mice. Furthermore, in our in vitro work we identified the activation of insulin signaling following exogenous supplementation of insulin. This was further attenuated by iron-induced hyperphosphorylation of tau in primary neurons. Together, these data suggest that dysfunctional insulin signaling participates in iron-induced abnormal phosphorylation of tau in AD. Our study highlights the promising role of insulin signaling in pathological lesions induced by iron overloading. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that abnormal deposition of amyloid-β (Ab) peptide in the brain is responsible for endothelial cell damage and consequently leads to blood-brain barrier (BBB) leakage. However, the mechanisms underlying BBB disruption are not well described. We employed an monolayer BBB model comprising bEnd.3 cell and found that BBB leakage was induced by treatment with Aβ1-42, and the levels of tight junction (TJ) scaffold proteins (ZO-1, Claudin-5, and Occludin) were decreased. Through comparisons of the effects of the different components of Aβ1-42, including monomer (Aβ1-42-Mono), oligomer (Aβ1-42-Oligo), and fibril (Aβ1-42-Fibril), our data confirmed that Aβ1-42-Oligo is likely to be the most important damage factor that results in TJ damage and BBB leakage in Alzheimer's disease. We found that the incubation of bEnd.3 cells with Aβ1-42 significantly up-regulated the level of receptor for advanced glycation end-products (RAGE). Co-incubation of a polyclonal antibody to RAGE and Aβ1-42-Oligo in bEnd.3 cells blocked RAGE suppression of Aβ1-42-Oligo-induced alterations in TJ scaffold proteins and reversed Aβ1-42-Oligoinduced up-regulation of RAGE, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, we found that these effects induced by Aβ1-42-Oligo treatment were effectively suppressed by knockdown of RAGE using small interfering RNA (siRNA) transfection. We also found that GM 6001, a broad-spectrum MMP inhibitor, partially reversed the Aβ1-42-Oligo-induced inhibitor effects in bEnd.3 cells. Thus, these results suggested that RAGE played an important role in Abinduced BBB leakage and alterations of TJ scaffold proteins, through a mechanism that involved up-regulation of MMP-2 and MMP-9. [ABSTRACT FROM AUTHOR]

Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Alzheimer's disease (AD) and attenuating the cognitive disorder. The blood-brain barrier (BBB) plays a critical role in maintaining homeostasis of the brain, and transporters e.g. P-glycoprotein (P-gp) are essential for Aβ clearance from the brain. In addition, the Wnt/β-catenin signaling pathway contributes to BBB formation, induction and maturation, and induces BBB function. Dysfunctional Wnt/β-catenin signaling in the BBB reveals the importance of this pathway, since this contributes to the neurodegeneration characteristic of AD. Based on the above evidence, we propose that targeting the canonical Wnt signaling pathway could be promising therapeutic approach for treatment of AD. [ABSTRACT FROM AUTHOR]

Studies have shown that misfolded proteins and endoplasmic reticulum (ER) stress play pivotal roles in the progression of Alzheimer's disease (AD). It has also been reported that ER stress is considered to be a common mediator of apoptosis in neurodegenerative disorders like AD. However, the precise mechanisms leading to neuronal cell death caused by ER stress in AD remain unclear. Hsp70, the major inducible form of the heat shock protein family, functions at the level of chaperone-mediated protein folding. Enhanced expression of Hsp70 suppresses the neurotoxicity caused by protein misfolding. EGb761, an accepted traditional Chinese medicine used to treat AD, was used here to examine the molecular mechanism underlying its protective effect on ER stress and Hsp70. Our study shows that pretreatment with EGb761 overcomes the neurotoxicity of the Aβ 1-42 oligomer by increasing Hsp70, Grp78, IRE1α and pAkt expression in a dose-dependent manner and significantly decreases cell apoptosis-related protein expression. Our findings suggest that the neuroprotective effect of EGb761 is related to ER stress activation and increased Hsp70 expression, and subsequent activation of Akt. However, the effect of EGb761 on these processes is not direct. [ABSTRACT FROM AUTHOR]