The role of presenilin cofactors in the γ-secretase complex

Takasugi, Nobumasa; Tomita, Taisuke; Hayashi, Ikuo; Tsuruoka, Makiko; Niimura, Manabu; Takahashi, Yasuko; Wang, Shuai; Iwatsubo, Takeshi

doi:10.1038/nature01506

Cited by 836 publications

(855 citation statements)

References 28 publications

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“…[15][16][17] Similar to the results obtained with reduced Aph-1a expression, knockdown or knockout of either of the g-secretase components PS1, Nct or PEN-2 in the mouse led to affected levels of most of the nonsilenced g-secretase subunits. [18][19][20][21][22][23][24] In contrast, ablation of mouse PS2 expression had little effect on the expression levels of the other g-secretase components, 20,24,25 comparable to what we have observed in the I/I, II/II and III/III rat lines concerning the effect of reduced Aph-1b expression. 7 These findings suggest that PS2 and Aph-1b are somehow related.…”

Section: Discussionsupporting

confidence: 83%

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

et al. 2006

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Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the c-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about csecretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre-and postnatal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in c-secretase cleavage activity towards one of its best-known substrates, the amyloid-b precursor protein APP. We conclude that the low levels of Aph-1b mRNA and c-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

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Section: Discussionsupporting

confidence: 83%

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

et al. 2006

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“…Given that PS1 is a major component of the g-secretase that cleaves amyloid precursor protein and contributes to the generation of Ab (Takasugi et al, 2003), activation of STAT3 might affect memory impairment related to AD via transcriptional regulation of PS1.…”

Section: Discussionmentioning

confidence: 99%

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Yamada

Chiba

Sasabe

et al. 2007

Neuropsychopharmacol

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Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-b (Ab) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Ab induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

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“…3d). There is recent evidence to suggest that specific proteins within tetrameric complexes provide stability and enhance enzymatic function [34].…”

Section: Discussionmentioning

confidence: 99%

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

et al. 2004

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DNA microarray profiling of CD4 + and CD8 + cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4 + cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion. Secondly, CYFIP2 knock-down experiments using antisense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4 + cells. Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4 + cells. Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4 + cells from MS patients to levels similar to controls. These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.

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The role of presenilin cofactors in the γ-secretase complex

Cited by 836 publications

References 28 publications

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion

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The role of presenilin cofactors in the γ-secretase complex

Cited by 836 publications

References 28 publications

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion

Contact Info

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CYFIP2 is highly abundant in CD4⁺ cells from multiple sclerosis patients and is involved in T cell adhesion