Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer’s disease

Richardson, Jill C.; Kendal, Claire; Anderson, Richard B.; Priest, F; Gower, Elaine; Soden, Peter E.; Gray, Roy; Topps, S.; Howlett, David; Lavender, Debbie; Clarke, Nigel J.; Barnes, Julie C.; Haworth, Richard; Stewart, Michael G.; Rupniak, H. T.

doi:10.1016/s0306-4522(03)00389-0

Cited by 77 publications

(64 citation statements)

References 59 publications

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“…Depletion of CD147 from the γ secretase complex through RNA interference in cell lines resulted in an increase in amyloid β peptide production but had no effect on the expression levels of other complex components or complex substrates suggesting that CD147 may regulate γ secretase activity (Zhou et al 2005). Interestingly, neurological abnormalities observed in CD147 null mice including spatial learning and memory deficits (Naruhashi et al 1997) are similar to those observed in mouse models of Alzheimer's disease (Higgins et al 2003;Richardson et al 2003). Although the mechanism by which CD147 attenuates the production of amyloid β peptides is unknown, further study of CD147 function within the γ secretase complex may aid Alzheimer's disease therapy.…”

Section: Alzheimer's Diseasementioning

confidence: 82%

CD147 immunoglobulin superfamily receptor function and role in pathology

Iacono

Brown

Greene

et al. 2007

Experimental and Molecular Pathology

242

206

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The immunoglobulin superfamily member CD147 plays an important role in fetal, neuronal, lymphocyte and extracellular matrix development. Here we review the current understanding of CD147 expression and protein interactions with regard to CD147 function and its role in pathologic conditions including heart disease, Alzheimer's disease, stroke and cancer. A model linking hypoxic conditions found within the tumor microenvironment to up-regulation of CD147 expression and tumor progression is introduced.

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Section: Alzheimer's Diseasementioning

confidence: 82%

CD147 immunoglobulin superfamily receptor function and role in pathology

Iacono

Brown

Greene

et al. 2007

Experimental and Molecular Pathology

242

206

View full text Add to dashboard Cite

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“…Moreover, the correlation between plaque burden and cognitive impairment (Guillozet et al, 2003) and between A␤ 1-42 and synaptic loss in humans are rather weak (Lue et al, 1999). Recent studies in animals have established links between natural, as well as synthetic, soluble A␤ oligomers and cognitive impairment (Richardson et al, 2003;Cleary et al, 2005), and A␤ oligomers have been shown to induce disruption of LTP (Q. S. Walsh et al, 2002;Kamenetz et al, 2003;Klyubin et al, 2004;Wang et al, 2004) but not LTD (Wang et al, 2002) induction. These observations suggest that excitatory synapses might be the early targets of soluble A␤, a view supported by evidence that oligomerized A␤ can bind to synaptic sites, namely, PSD-95-containing postsynaptic sites (Lacor et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Soluble β-Amyloid_1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

Roselli¹,

Tirard²,

Lu³

et al. 2005

J. Neurosci.

266

199

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Amyloid-␤ (A␤) has been implicated in memory loss and disruption of synaptic plasticity observed in early-stage Alzheimer's disease. Recently, it has been shown that soluble A␤ oligomers target synapses in cultured rat hippocampal neurons, suggesting a direct role of A␤ in the regulation of synaptic structure and function. Postsynaptic density-95 (PSD-95) is a postsynaptic scaffolding protein that plays a critical role in synaptic plasticity and the stabilization of AMPA (AMPARs) and NMDA (NMDARs) receptors at synapses. Here, we show that exposure of cultured cortical neurons to soluble oligomers of A␤ 1-40 reduces PSD-95 protein levels in a dose-and time-dependent manner and that the A␤1 1-40 -dependent decrease in PSD-95 requires NMDAR activity. We also show that the decrease in PSD-95 requires cyclin-dependent kinase 5 activity and involves the proteasome pathway. Immunostaining analysis of cortical cultured neurons revealed that A␤ treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2. Together, these data suggest a novel pathway by which A␤ triggers synaptic dysfunction, namely, by altering the molecular composition of glutamatergic synapses.

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“…Interestingly, deletion of CD147 in mice was found to result in various neurological abnormalities, including severe defects in nervous system development, pronounced spatial learning deficits in the Morris water maze testing, and working memory deficits (43), a behavior phenotype similar to those observed in transgenic mouse models of AD (44,45). With the discovery of CD147 as an integral subunit of the native ␥-secretase complex, obtaining details of the molecular mechanism of CD147 through atomic structure determination of the complex and subsequent functional studies of selected structure-directed mutants will be a crucial step in understanding the molecular processes involved in multiple-site cleavage of a constellation of substrates and in the design of AD therapeutics.…”

Section: Discussionmentioning

confidence: 99%

CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production

Zhou

Walian

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

182

168

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␥-Secretase is a membrane protein complex that cleaves the ␤-amyloid precursor protein (APP) within the transmembrane region, after prior processing by ␤-secretase, producing amyloid ␤-peptides A␤40 and A␤42. Errant production of A␤-peptides that substantially increases A␤ 42 production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1, which contains the proteolytic active site, and three other membrane proteins [nicastrin, anterior pharynx defective-1 (APH-1), and presenilin enhancer-2 (PEN-2)] are required to form the core of the active ␥-secretase complex. Here, we report the purification of the native ␥-secretase complexes from HeLa cell membranes and the identification of an additional ␥-secretase complex subunit, CD147, a transmembrane glycoprotein with two Ig-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through coimmunoprecipitation studies of the purified protein from HeLa cells and of solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of A␤ peptides without changing the expression level of the other ␥-secretase components or APP substrates whereas CD147 overexpression had no statistically significant effect on A␤-peptide production, other ␥-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the ␥-secretase complex down-modulates the production of A␤-peptides.aspartyl protease ͉ membrane protein complex ͉ membrane protein purification

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Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer’s disease

Cited by 77 publications

References 59 publications

CD147 immunoglobulin superfamily receptor function and role in pathology

CD147 immunoglobulin superfamily receptor function and role in pathology

Soluble β-Amyloid_1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production

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Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer’s disease

Cited by 77 publications

References 59 publications

CD147 immunoglobulin superfamily receptor function and role in pathology

CD147 immunoglobulin superfamily receptor function and role in pathology

Soluble β-Amyloid1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses

CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production

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Soluble β-Amyloid_1-40Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses