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Topic: Secretase

In the News (Fri 1 Jan 10)

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	Elan: Alzheimer's Research
		Beta and gamma secretases are proteases (enzymes that break down other proteins) that appear to clip the amyloid precursor protein (APP), resulting in the formation of beta amyloid.
		Beta secretase is believed to initiate the first step in the formation of beta amyloid, the precursor to plaque development in the brain.
		Gamma Secretase is an unusual multi-protein complex that is thought to play a significant role in the formation of beta amyloid.
	www.elan.com /research_development/Alzheimers (1212 words)

	Alpha-Secretase (TACE)
		To initiate Ab formation, b-secretase cleaves APP at the N-terminus of Ab to release APPsb (~100 kDa soluble NT-fragment), and C99, a 12-kDa CT membrane fragment.
		Alternatively, a-secretase cleaves within the Ab to prevent the formation of Ab.
		Cleavage by a-secretase produces a soluble N-terminal fragment, APPsa, and a 10-kDa membrane C-terminal fragment, C83.
	www.gencompare.com /alpha-secretase_(tace).htm (1074 words)

	MSN Encarta - Alzheimer’s Disease
		Researchers have isolated the enzyme beta-secretase, which is believed to make one of the cuts in the amyloid precursor protein.
		Researchers also identified another enzyme, called gamma secretase, that makes the second cut in the amyloid precursor protein.
		These mutated proteins apparently trigger the activity of the enzyme gamma secretase, which splices the amyloid precursor protein.
	encarta.msn.com /encyclopedia_761577591/Alzheimer%e2%80%99s_Disease.html (1380 words)

	Research detail
		In the original application we proposed to establish assays for quantification of secretase mRNA to determine whether factors shown to affect APP processing also affect expression of the proteases involved.
		The mechanism of this effect is unclear, and Paul aims to determine whether it is receptor-mediated by using a range of breast cancer cells lines that differ with respect to the number of oestrogen receptors present.
		In view of this, and of the original proposal to study any secretases that should be identified during the course of the project, I have recently decided to focus on aspects of BACE processing, as described above.
	www.qrd.alzheimers.org.uk /researchdetail.asp?GrantsID=8 (3072 words)

	Current Medicinal Chemistry, Volume, 9 No. 11, 2002 (Site not responding. Last check: 2007-10-12)
		Studies with a range of hydroxamic acid-based compounds, such as batimastat, indicate that a-secretase is a zinc metalloproteinase, and members of the adamalysin family of proteins, TACE, ADAM10 and ADAM9, all fulfil some of the criteria required of a-secretase.
		The constitutive a-secretase activity is primarily at the cell surface, while the regulated activity is predominantly located within the Golgi.
		As the a-secretase cleavage of APP both precludes the deposition of the amyloid b peptide and releases the neuroprotective sAPPa, pharmacological up-regulation of a-secretase may provide alternative therapeutic approaches for Alzheimer’s disease.
	www.bentham.org /cmc/cmc9-11.htm (784 words)

	body4/4
		As an alternative, recent studies have shown that regulating the subcellular localization of BACE may control beta-C-fragment formation and thus affect the proliferation of AD [44].
		Alpha secretase destroys the beta amyloid fragment by cleaving on C-terminal side of residue 16 of beta amyloid sequence in APP, yielding an 83 residue C-terminal fragment (C83) and sAPP alpha [45].
		Alpha secretase cleavage of APP yields a C83 fragment and sAPP alpha.
	www.arches.uga.edu /~lyles/bcmb8010/body4-4.htm (580 words)

	International Conference on Prevention of Dementia \| Corporate symposia schedule
		This symposium will examine the Amyloid hypothesis in the treatment of AD.
		Potential therapeutic agents such as secretase inhibitors, processing modulators, antibodies and aggregation inhibitors will be discussed.
		In addition biomarker (animal models and also human data) and clinical data for selected agents in clinical development will be discussed.
	www.alz.org /preventionconference/pc2007/symposia_schedule.asp (166 words)

	RÉFÉRENCES BIBLIOGRAPHIQUES
		"Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early-onset Alzheimer's disease." Neurosci Lett 313(1-2): 105-7.
		Dingwall, C. "Spotlight on BACE: the secretases as targets for treatment in Alzheimer disease." J Clin Invest 108(9): 1243-6.
		Evidence for a yeast secretase activity." J Biol Chem 269(45): 27799-802.
	www.theses.ulaval.ca /2003/21411/apa.html (3487 words)

	The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor ... (Site not responding. Last check: 2007-10-12)
		secretase was similar as that towards TACE [14], we considered
		Oppong, S.Y. and Hooper, N.M. (1993) Characterization of a secretase activity which releases angiotensin-converting enzyme from the membrane.
		-secretase is inhibited by hydroxamic acid-based zinc metalloprotease inhibitors: similarities to the angiotensin converting enzyme secretase.
	content.febsjournal.org /cgi/content/full/271/12/2539 (4277 words)

	Aging research; molecular concepts of aging, related diseases and cloning.
		The rather small effects on total Aβ peptide generation as compared to amyloid deposition suggest that relatively minor changes in Aβ peptide production may be sufficient to induce AD pathology.
		This provides hope, since secretase modifiers (regardless of whether they are inhibitors of α- and β-secretase or activators of γ-secretase) may only be required at rather low dose.
		Most importantly, the study also provides evidence that overexpression of ADAM10 not only reduces amyloid plaque formation but also alleviates the deficits in spatial learning and synaptic plasticity observed in the control animals, suggesting that an activation of α-secretase cleavage may also improve cognitive status in humans.
	www.innovitaresearch.org /news/05031001.html (1723 words)

	Protein aggregates and dementia: is there a common toxicity? -- Lovestone and McLoughlin 72 (2): 152 -- Journal of ...
		Secretase cleavage sites are indicated by dashed lines and the location of pathogenic mutations in APP are shown.
		Membrane-anchored aspartyl protease with Alzheimer's disease ß- secretase activity.
		Purification and cloning of amyloid precursor protein ß- secretase from human brain.
	jnnp.bmjjournals.com /cgi/content/full/72/2/152 (6253 words)

	Alpha-Secretase (TACE), Beta-Site APP-Cleaving Enzymes (BACE/Asp2/Asp1), Nicastrin Antibodies
		Alternatively, a-secretase cleaves within the Ab to prevent the formation of Ab.
		Cleavage by a-secretase produces a soluble N-terminal fragment, APPsa, and a 10-kDa membrane C-terminal fragment, C83.
		Both C99 and C83 can be further cleaved by g-secretase releasing Ab and a nonpathogenic p3 peptide, respectively.
	www.4adi.com /flr/baceflr.html (963 words)

	Take five--BACE and the {gamma}-secretase quartet conduct Alzheimer's amyloid {beta}-peptide generation -- Haass 23 ... (Site not responding. Last check: 2007-10-12)
		of the secretases are not all discovered yet.
		Shirotani K, Edbauer D, Capell A, Schmitz J, Steiner H, Haass C (2003) Secretase activity is associated with a conformational change of nicastrin.
		Steiner H, Kostka M, Romig H, Basset G, Pesold B, Hardy J, Capell A, Meyn L, Grim MG, Baumeister R, Fechteler K, Haass C (2000) Glycine 384 is required for presenilin-1 function and is conserved in polytopic bacterial aspartyl proteases.
	embojournal.npgjournals.com /cgi/content/full/23/3/483 (4261 words)

	New model of Alzheimer's enzyme may help refine future treatments
		Next, the team examined how the same enzyme is responsible for clipping each molecule at two separate sites.
		A breakthrough came from observing the activity of a particular mutation in Notch that is protected from gamma secretase cleavage.
		As expected, Kopan's team found that this fragment does not compete with C99.
	www.eurekalert.org /pub_releases/2003-10/wuso-nmo102703.php (1243 words)

	Enzyme offers promise of Alzheimer's drugs, Science News Online (11/6/99)
		Many scientists, but not all, believe that these amyloid plaques kill or damage brain cells, producing memory loss and other symptoms of the illness.
		The brain makes beta-amyloid by chopping up a larger molecule, amyloid precursor protein (APP), with enzymes called secretases.
		Since beta-secretase makes the first cut on APP, scientists predict that drugs blocking its action will reduce the brain's beta-amyloid burden.
	www.sciencenews.org /pages/sn_arc99/11_6_99/fob5.htm (715 words)

	Assay Kits/Secretase Assay Kits/EnzoLyte 520 β-Secretase Assay Kit
		Assay Kits > Secretase Assay Kits >> EnzoLyte 520 β-Secretase Assay Kit
		The enzyme has been implicated to be an excellent target for anti-amyloid therapy of Alzheimer's disease.
		The EnzoLyte Secretase Assay Kit provides a sensitive and efficient method for screening potential β-Secretase inhibitors.
	www.anaspec.com /products/product.asp?id=9503 (132 words)

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