Amyloid- peptide (A) plays an important role in the pathogenesis of Alzheimer's disease (AD). A is generated by proteolysis of -amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against A. HSP70 activity in relation to inhibition of A oligomerization and stimulation of A phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of A, A plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of -and ␥-secretase activity suggested that overexpression of HSP70 does not affect the production A. In contrast, HSP70 overexpression did lead to upregulation of the expression of A-degrading enzyme and TGF-1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.
Tight junctions (TJs), the most apical intercellular structures in epithelial and endothelial cells, create a physiological intercellular barrier separating the apical and basolateral spaces, as well as regulating the paracellular permeability of various solutes. They also act as a divide between the apical and basolateral membranes, thereby maintaining cell polarity. TJs contain transmembrane proteins such as claudins, occludin and junctional adhesion molecules. The C-terminal regions of these proteins interact with cytosolic proteins, such as zonula occludens (ZO)-1, -2 and -3, which are linked to the actin cytoskeleton and are potentially involved in signal transduction.1-6) Among these transmembrane proteins, the claudin family of proteins (claudin-1 to -24) play a major role in maintaining the intercellular barrier. 7,8) Given that a loss of TJ structure and function is frequently observed in epithelium-derived cancers, [9][10][11][12] TJs have attracted considerable attention in relation to this disease. The loss of TJ structure and function is thought to promote cancer cell proliferation by allowing constitutive accessibility of cancers to nutrients and growth factors. As TJs function as a barrier against cancer cell invasion, loss of TJ structure and function could also stimulate the metastasis of tumors. 11,[13][14][15] Alteration in the expression of the constituent proteins of TJs, in particular claudins, is frequently observed in tumors clinically isolated from various types of tissues, including colon, breast, pancreas, prostate, uterus and ovary. [9][10][11][12][16][17][18][19][20] It was initially believed that these alterations in expression affect cancer development only through the modulation of the barrier function of TJs. However, a number of recent studies suggest that the expression of certain claudins modulates the invasiveness and migration of cancer cells through various mechanisms.9,11) For example, we recently reported that overexpression of claudin-4 or claudin-2 causes a decrease or an increase, respectively, in the migration activity of gastric carcinoma (AGS) cells. 21,22) Studies from other groups have also shown that claudin overexpression (claudin-1, 3, 4, 5) can affect the invasiveness and migration of various types of cancer cells. 16,[23][24][25][26] Thus, an alteration in claudin expression appears to play a role in the progression of tumors, both by modulating the barrier function of TJs and by altering the migration and invasiveness of the cancer cells. However, the overall relationship between claudin expression and these cell functions have not been fully elucidated, partly due to the different types of cells and different cell culture conditions (i.e. cell density) used in the various studies. For example, although we showed that overexpression of claudin-4 decreases cell migration activity in AGS cells, other groups have reported that the overexpression stimulates cell invasion and migration in human ovarian cancer cells, 25) but inhibits the invasiveness of pancreatic...
Clostridium perfringens iota-toxin and Clostridium botulinum C2 toxin are composed of two non-linked proteins, one being the enzymatic component and the other being the binding/translocation component. These latter components recognize specific receptors and oligomerize in plasma membrane lipid-rafts, mediating the uptake of the enzymatic component into the cytosol. Enzymatic components induce actin cytoskeleton disorganization through the ADP-ribosylation of actin and are responsible for cell rounding and death. This review focuses upon the recent advances in cellular internalization of clostridial binary toxins.
Although granulopoiesis is accelerated to suppress bacteria during infection, some bacteria can still cause life-threatening infections, but the mechanism behind this remains unclear. In this study, we found that mature neutrophils in bone marrow cells (BMCs) were decreased in C. perfringens-infected mice and also after injection of virulence factor α-toxin. C. perfringens infection interfered with the replenishment of mature neutrophils in the peripheral circulation and the accumulation of neutrophils at C. perfringens-infected sites in an α-toxin-dependent manner. Measurements of bacterial colony-forming units in C. perfringens-infected muscle revealed that α-toxin inhibited a reduction in the load of C. perfringens. In vitro treatment of isolated BMCs with α-toxin (phospholipase C) revealed that α-toxin directly decreased mature neutrophils. α-Toxin did not influence the viability of isolated mature neutrophils, while simultaneous treatment of BMCs with granulocyte colony-stimulating factor attenuated the reduction of mature neutrophils by α-toxin. Together, our results illustrate that impairment of the innate immune system by the inhibition of neutrophil differentiation is crucial for the pathogenesis of C. perfringens to promote disease to a life-threatening infection, which provides new insight to understand how pathogenic bacteria evade the host immune system.
Amyloid- (A) peptides, generated by the proteolysis of -amyloid precursor protein by -and ␥-secretases, play an important role in the pathogenesis of Alzheimer disease. Inflammation is also important. We recently reported that prostaglandin E 2 (PGE 2 ), a strong inducer of inflammation, stimulates the production of A through EP 2 and EP 4 receptors, and here we have examined the molecular mechanism. Activation of EP 2 and EP 4 receptors is coupled to an increase in cellular cAMP levels and activation of protein kinase A (PKA). We found that inhibitors of adenylate cyclase and PKA suppress EP 2 , but not EP 4 , receptor-mediated stimulation of the A production. In contrast, inhibitors of endocytosis suppressed EP 4 , but not EP 2 , receptor-mediated stimulation. Activation of ␥-secretase was observed with the activation of EP 4 receptors but not EP 2 receptors. PGE 2 -dependent internalization of the EP 4 receptor was observed, and cells expressing a mutant EP 4 receptor lacking the internalization activity did not exhibit PGE 2 -stimulated production of A. A physical interaction between the EP 4 receptor and PS-1, a catalytic subunit of ␥-secretases, was revealed by immunoprecipitation assays. PGE 2 -induced internalization of PS-1 and co-localization of EP 4 , PS-1, and Rab7 (a marker of late endosomes and lysosomes) was observed. Co-localization of PS-1 and Rab7 was also observed in the brain of wild-type mice but not of EP 4 receptor null mice. These results suggest that PGE 2 -stimulated production of A involves EP 4 receptor-mediated endocytosis of PS-1 followed by activation of the ␥-secretase, as well as EP 2 receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease. Alzheimer disease (AD)2 is the most common neurodegenerative disorder of the central nervous system and the leading cause of adult onset dementia. AD is characterized pathologically by the accumulation of tangles and senile plaques. Senile plaques are composed of the amyloid- (A) peptides A40 and A42 (1, 2). To generate A, -amyloid precursor protein (APP) is first cleaved by -secretase and then by ␥-secretase. Cleavage of APP by ␣-secretase produces non-amyloidogenic peptides (3, 4). The ␥-secretase is an aspartyl protease complex composed of four core components, including presenilin (PS) 1 and PS2 (5). Early onset familial AD is linked to three genes, APP, PS1, and PS2 (5, 6), strongly suggesting that ␥-secretasedependent production of A is a key factor in the pathogenesis of AD. Therefore, cellular factors that affect the ␥-secretase-dependent production of A may be good targets for the development of drugs to prevent and treat AD.Both APP and PS-1 are transmembrane proteins, and their intracellular localization is controlled by secretory and endocytic pathways. These proteins are modified in the endoplasmic reticulum and trafficked to the cell surface through the transGolgi network (TGN). Then, they are internalized again and traf...
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