588 Studies on inhibition of βA4 formation in APP-751 transfected IMR-32 cells, and SPA4CT transfected SHSYSY cells

Christie, G.S.; Gray, C.; Holmes, Sandra L.; Markwell, Roger E.; Owen, David; Smith, Laurens H.; Wadsworth, Harry J.; Ward, Robin V.; Hartmann, Thomas; Lichtenthaler, Stefan F.; Evin, Geneviève; Fuller, Steven A.; Masters, CL; Beyreuther, Konrad; Roberts, G.W.

doi:10.1016/s0197-4580(96)80590-2

Cited by 6 publications

(11 citation statements)

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“…1A, G93A, and data not shown). Increased APP levels were confirmed with additional antibodies that recognize the amyloid domain (1E8), 2 an N-terminal epitope (22C11 that also recognizes the APP homolog APLP2), 34 and a C-terminal epitope of APP (Ab54). 18 By contrast, in nontransgenic wild-type mice (Fig.…”

Section: Resultsmentioning

confidence: 94%

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease

et al. 2006

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by motor neuron loss. Transgenic mouse models show features that closely mimic those seen in the clinical situation, reflected in the molecular changes observed in mouse models and in tissues from patients. We report a dramatic increase in the expression of amyloid precursor protein (APP) in the hindlimb muscles, but not the spinal cord of the G93A transgenic mouse model, significantly before the appearance of clinical abnormalities. APP levels were unchanged in nontransgenic mice and in mice overexpressing human wild-type Cu/Zn-dependent superoxide dismutase 1 (SOD1). Preliminary results indicate a similar change in APP expression in human deltoid muscle samples from ALS patients compared with age-matched controls. The inhibitory role of APP in innervation at the neuromuscular junction and increased expression in inclusion-body myositis suggest that presymptomatic upregulation of APP may be consistent with a potential role for APP in ALS pathology.

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Section: Resultsmentioning

confidence: 94%

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease

et al. 2006

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“…Total A ␤ levels in the medium were determined as follows. Total A ␤ was captured using a midregion A ␤ antibody, 1E8 [17] , precoated on Nunc Maxisorb microtitre plates (Thermo Fischer Scientific, Roskilde, Denmark). Detec-tion was by means of biotinylated 6E10 (Signet Laboratories, Dedham, Mass., USA) and binding of streptavidin-europium (Perkin Elmer, Waltham, Mass., USA), permitting quantification by DELFIA (Delayed Enhanced Lanthanide Fluorescence Immunoassay; Perkin Elmer).…”

Section: A ␤ Enzyme-linked Immunosorbent Assaysmentioning

confidence: 99%

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

Hussain

Harrison²,

Hawkins³

et al. 2010

Neurodegener Dis

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Background: Cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-β (Aβ) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aβ₄₂ peptide while avoiding deleterious activity on Notch processing. Objective: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aβ peptides to induce neurotoxicity in rat primary cortical neurons. Methods: The effect of GSM-10h on Aβ levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. Results:In cells, GSM-10h decreased levels of Aβ₄₂ while concomitantly increasing levels of Aβ₃₈ in the absence of effects on Aβ₄₀ levels. In TASTPM mice, GSM-10h effectively lowered brain Aβ₄₂ and increased brain Aβ₃₈, with no effect on Notch signalling. Unlike Aβ₄₂, which causes neuronal cell death, neither Aβ₃₇ nor Aβ₃₈ were neurotoxic. Conclusions: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.

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“…IMR‐32 cells transfected with pCEP4 incorporating the coding sequence for APP‐751 (IMR‐32 APP‐751) were obtained from Dr. Chris Morris (MRC Neurochemical Pathology Unit, Newcastle upon Tyne, U.K.). These have been described previously by Allsop et al (1997) and Parvathy et al (1998) as human IMR‐32 cells but have recently been characterised as a murine tetraploid neuronal cell line (C. Morris, personal communication). Untransfected human IMR‐32 cells were obtained from ECACC.…”

Section: Methodsmentioning

confidence: 98%

“…Several small peptide aldehydes of the type known to inhibit both cysteine and serine proteases have been shown to inhibit Aβ formation from cells (Higaki et al, 1995; Klafki et al, 1995, 1996; Citron et al, 1996; Allsop et al, 1997). Compounds of this type (such as the peptide aldehyde inhibitor N ‐acetyl‐Leu‐Leu‐Nle‐H or ALLN) are known to be potent inhibitors of the chymotrypsin‐like activity of the proteasome (CLIP) (Lowe et al, 1995).…”

mentioning

confidence: 99%

Alzheimer’s Disease

Christie

Markwell

Gray

et al. 1999

Journal of Neurochemistry

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Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as Nacetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of ␤-amyloid peptide (A␤) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A␤ formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of ␤-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A␤ formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A␤ formation. Key Words: Alzheimer's disease -Amyloid-␤-Amyloid peptide -Proteasome -Inhibitor. J. Neurochem. 73, 195-204 (1999).The accumulation of the 39 -43-residue ␤-amyloid peptide (A␤) (Glenner and Wong, 1984) in senile plaques and in the walls of cerebral blood vessels is an important pathological feature of Alzheimer's disease. A␤ is derived by proteolytic processing of the ␤-amyloid precursor protein (APP), an integral type 1 membranespanning glycoprotein. There is considerable interest in the proteolytic enzymes involved in this process, as the formation and aggregation of A␤ are likely to be key pathological events in the development of Alzheimer's disease (Hardy and Allsop, 1991). Early studies (Esch et al., 1990;Anderson et al., 1991) showed that the majority of APP is cleaved by ␣-secretase at the Lys 16 -Leu 17 bond in the middle of the A␤ sequence, to produce a large, soluble, N-terminal fragment, which is referred to here as sAPP␣. An alternative pathway of APP processing has been implicated in the formation of A␤, involving an initial cleavage by ␤-secretase at the Met 596 -Asp 597 bond (numbered according to APP-695) to derive the N terminus of A␤ (Seubert et al., 1993), followed by a second ␥-secretase-mediated cleavage within the membrane-spanning domain of APP to release the C terminus of A␤. Several forms of A␤ of different length have been described, with A␤40 and A␤42 being prominent species (see, for example, Asami-Odaka et al., 1995). The longer forms of A␤ seem to be particularly important in the pathogenesis of Alzheimer's disease (Younkin, 1995).The identity of the ␣-, ␤-, and ␥-secretases is unknown, although the effects of various class-specific protease inhibitors suggest that ␣-secretase is a zinc metalloproteinase, with similarities to the angiotensin converting enzyme secretase and other related membrane-associated secretases (Parvathy et al., 1998). As far as ␤-secretase is concerned, the proteasome has been implicated (Ishiura et al., 1989), as have several chymotrypsin-like serine proteinases (Nelson et al., 1993;Sahasrabudhe et al., 1993;Savage et al., 1994), the metallopeptidase thimet (McDermott et al., 1992), and Received November 4, 1...

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588 Studies on inhibition of βA4 formation in APP-751 transfected IMR-32 cells, and SPA4CT transfected SHSYSY cells

Cited by 6 publications

References 0 publications

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease

Elevated levels of amyloid precursor protein in muscle of patients with amyotrophic lateral sclerosis and a mouse model of the disease

TASTPM Mice Expressing Amyloid Precursor Protein and Presenilin-1 Mutant Transgenes Are Sensitive to γ-Secretase Modulation and Amyloid-β<sub>42</sub> Lowering by GSM-10h

Alzheimer’s Disease

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