The α5β1 Integrin Mediates Elimination of Amyloid-β Peptide and Protects Against Apoptosis

Matter, Michelle L.; Zhang, Zhuohua; Nordstedt, Christer; Ruoslahti, Erkki

doi:10.1083/jcb.141.4.1019

Cited by 90 publications

(74 citation statements)

References 56 publications

(66 reference statements)

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“…This sequence is also reported to be responsible for binding of Ab to a5b1 integrin. 47 Our results showing IF 1 -sensitive extracellular generation of ATP by the glioma C6 cell line lead us to the conclusion that in this cell type there must also be a competent F 1 F 0 -ATP synthase complex at the cell surface, which could also be shown for other cell types. [20][21][22]35 Another known inhibitor of ATP synthase subunit a activity is angiostatin, a proteolytically derived 38 kDa fragment of plasminogen.…”

Section: Discussionmentioning

confidence: 67%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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Amyloid precursor protein (APP) and amyloid b-peptide (Ab) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit a as a binding partner of the extracellular domain of APP and Ab. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit a reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit a. The extracellular domain of APP and Ab partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Ab is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF 1 ), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Ab and IF 1 similarly impair both short-and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Ab regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Ab-mediated Alzheimer's disease pathology.

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Section: Discussionmentioning

confidence: 67%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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“…23 However, as it was shown for global hypoxia, 24 we can hypothesize that a5 integrin has been upregulated acutely after jTBI, and then returned to baseline after 2 and 6 months. Moreover, a5b1 integrin was previously shown to be involved in the clearance of Ab, 30 therefore the absence of increase of a5b1 integrin may also contribute to Ab accumulation observed in our model. To the best of our knowledge, the level of expression of a5b1 integrin after jTBI has never been studied before.…”

Section: Discussionmentioning

confidence: 85%

“…4 Interestingly, several other proteins have been proposed to participate in Ab clearance like other transporters (ABCA1 and ABCA2) 28,29 or like the receptor a5b1 integrin. 30 In addition, various basement membrane proteins, Figure 4. a5b1 integrin levels are not modified long term after a juvenile traumatic brain injury (jTBI).…”

Section: Discussionmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Ab clearance. Rodent-Ab staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood-brain barrier alongside vascular dysfunction and altered Ab trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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“…Integrin subunits have been linked to the ability of cells to generate resistance to apoptosis (Faraldo et al, 1998 ;Matter et al, 1998 ;Rozzo et al, 1997 ;Scatena et al, 1998). We compared the ability of HaCaT-E6 cells to resist anchorage-independent induced apoptosis and found that HaCaT-E6 cells generate lower resistance to anchorage-independent induced apoptosis compared to HaCaT-Ras cells (data not shown).…”

mentioning

confidence: 99%

Pleiotropic effects of human papillomavirus type 16 E6 oncogene expression in human epithelial cell lines.

Mythily¹,

Krishna²,

Tergaonkar³

1999

Journal of General Virology

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Two human papillomavirus (HPV)-negative epithelial cell lines, HaCaT and C33A, were transfected with HPV-16 E6 and analysed for functional consequences which are relevant to invasive tumour progression. After transfection with E6, both cell lines invaded collagen matrices, in contrast to vector-transfected control cells. The E6-expressing cells showed a marked increase in expression of the β1 integrin subunit, with no or relatively minor alterations in the levels of a range of integrin subunits. In addition, the epithelial cell lines expressing E6 displayed resistance to apoptosis generated by serum starvation. This resistance is comparable to that generated by ras and is not generated by HPV-11 E6 or HPV-16 E7. Both C33A and HaCaT cells have mutations in the p53 loci and hence these functional consequences of E6 are probably independent of wild-type p53 function.The persisting presence of human papillomavirus (HPV) types 16 and 18 E6 and E7 oncogene expression is a hallmark of most cervical tumours (zur Hausen, 1996). To elucidate the function of these two oncogenes, several groups have attempted to identify host proteins that interact with the products encoded by these two oncogenes. The bestdocumented function of HPV-16 E6 is the ability to bind (Storey et al., 1998 ;Werness et al., 1990) and degrade the p53 protein (Scheffner et al., 1990). More recently, largely using the yeast two-hybrid system, several host proteins, which include E6BP, paxillin, hDLG and AP-1, have been identified as interacting with the E6 product of different papillomavirus types (Chen et al., 1995 ;Kiyono et al., 1997 ;Lee et al., 1997 ;Tong et al., 1998 ;Tong & Howley, 1997 ;Vande Pol et al., 1998). In this report, we have explored the phenotypic consequences of E6 expression per se in epithelial cell lines. In general, transformed cells are generated following the cumulative effects of changes in apoptosis induction, cell cycle control, motility, integrin expression and function. These processes are linked in intricate feedback loops and the deregulation of the feedback controls during tumorigenesis is currently under investigation by several groups (Meredith & Schwartz, 1997 ;Schwartz, 1997). In this report, we have focused on an analysis of the role of the HPV-16 E6 oncogene in altering motility, integrin patterns and generating resistance to apoptosis induction in human epithelial cell lines.We have used two HPV-negative cell lines, C33A (Crook et al., 1991), a cervical tumour-derived cell line, and HaCaT (Lehman et al., 1993), a spontaneously immortalized epithelial line. Using plasmid LXSN-16E6 (Etscheid et al., 1994), we generated HaCaT-E6 and C33A-E6, which are HaCaT and C33A cells that constitutively express HPV-16 E6. Our approach using pooled transfectants is similar to that used in a recent study undertaken to analyse the role of cdc42 and Rac1 in integrin-mediated cell motility and invasiveness through PI(3)K (Keely et al., 1997). LXSN-neomycin-expressing cells, i.e. HaCaT-Neo and C33A-Neo, were used as controls in all e...

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The α5β1 Integrin Mediates Elimination of Amyloid-β Peptide and Protects Against Apoptosis

Cited by 90 publications

References 56 publications

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Pleiotropic effects of human papillomavirus type 16 E6 oncogene expression in human epithelial cell lines.

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