In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-beta domain by alpha-secretase precluding deposition of intact amyloid-beta peptide. The large ectodomain released from the cell surface by the action of alpha-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that alpha-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-alpha convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of alpha-secretase. We review the evidence for each of these ADAMs acting as the alpha-secretase. What seems to be emerging from numerous studies, including those with mice in which each of the ADAMs has been knocked out, is that there is a team of zinc metalloproteinases able to cleave APP at the alpha-secretase site. We also discuss how upregulation of alpha-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease.

Numerous transmembrane proteins, including the blood pressure regulating angiotensin converting enzyme (ACE) and the Alzheimer's disease amyloid precursor protein (APP), are proteolytically shed from the plasma membrane by metalloproteases. We have used an antisense oligonucleotide (ASO) approach to delineate the role of ADAM10 and tumour necrosis factor-a converting enzyme (TACE; ADAM17) in the ectodomain shedding of ACE and APP from human SH-SY5Y cells. Although the ADAM10 ASO and TACE ASO significantly reduced (> 81%) their respective mRNA levels and reduced the a-secretase shedding of APP by 60% and 30%, respectively, neither ASO reduced the shedding of ACE. The mercurial compound 4-aminophenylmercuric acetate (APMA) stimulated the shedding of ACE but not of APP. The APMA-stimulated secretase cleaved ACE at the same Arg-Ser bond in the juxtamembrane stalk as the constitutive secretase but was more sensitive to inhibition by a hydroxamate-based compound. The APMA-activated shedding of ACE was not reduced by the ADAM10 or TACE ASOs. These results indicate that neither ADAM10 nor TACE are involved in the shedding of ACE and that APMA, which activates a distinct ACE secretase, is the first pharmacological agent to distinguish between the shedding of ACE and APP.Keywords: ADAM; antisense oligonucleotide; metalloprotease; secretase; tumour necrosis factor-a converting enzyme.Angiotensin converting enzyme (ACE) is critically involved in blood pressure regulation due to its action in generating angiotensin II and in inactivating bradykinin [1]. The enzyme also has a role in the development of vascular pathology and endothelium remodelling in some disease states [2]. Inhibitors of ACE have emerged as first-line therapy for a range of cardiovascular and renal diseases, including hypertension, congestive heart failure, myocardial infarction and diabetic nephropathy. The transmembrane protein ACE is proteolytically shed from the cell surface by its cognate secretase with the resulting soluble form circulating in the blood and present in other body fluids [3].In addition to ACE, a number of other integral membrane proteins are shed from the cell surface by a post-translational proteolytic cleavage event mediated by zinc metalloproteases [4,5]. Another such shedding process is the nonamyloidogenic processing of the Alzheimer's disease amyloid precursor protein (APP) [6]. Cleavage of APP within the neurotoxic amyloid b region by a-secretase precludes the deposition of intact amyloid b [7] and releases the large soluble ectodomain of APP, sAPPa, which has been shown to have neuroprotective and memory enhancing properties [8]. The APP a-secretase is a membrane-associated metalloprotease [9] that is inhibited by hydroxamic acid-based compounds such as batimastat [10]. Members of the ADAMs (a disintegrin and metalloprotease) family have been put forward as candidate a-secretases, in particular ADAM10 and ADAM17 (tumour necrosis factor-a converting enzyme; TACE) ([11,12] and reviewed in [13]). Although the ACE secretase has no...

p(25-35) is a fragment of P-amyloid, that retains its properties. N-methylated derivatives of P(25-35) can block hydrogen bonding on the outer edge of the assembling amyloid, so preventing the aggregation and inhibiting the toxicity of the wild type peptide.The effects are assayed by Congo red and Thioflavin T binding, electron microscopy and an MTT toxicity assay. N-methyl Gly 25 has similar properties to wild-type, while five have varying effects on prefolded fibrils and fibril assembly. In particular, N-methyl Gly33 is able to completely prevent fibril assembly and reduces the toxicity of prefolded amyloid. With N-methyl Leu34 the fibril morphology is altered and toxicity reduced. P(25-35) structure in aqeuous solution was studied by small angle neutron reflection (SANS). The protofibrillar aggregates are best described by a cylindrical or toroidal model with radius of 140 Angstroms and height of 53 Angstroms. No aggregates form in the presence of N-methyl Gly33. We suggest that the use of N-methylated derivatives of amyloidogenic peptides and proteins could provide a general solution to the problem of amyloid deposition and toxicity, and that SANS is a unique technique for the direct observation of protofibril formation and destruction in solution.28 Chronic nicotine treatment reduces beta-amyloidosis L Court, E.Alzheimer's disease is characterised by beta-amyloid plaques, and inhibition of beta-amyloid accumulation may be essential for effective therapy in this disorder. Previous in vitro studies have indicated protective effects of nicotine against amyloid beta peptide deposition and toxicity. In the present study the effect of long term nicotine on human age related Alzheimer-like pathology was assessed by comparison of non-demented elderly tobacco smokers and non-smokers. In tobacco users there was reduced beta-amyloid plaque deposition in the hippocampus and entorhinal cortex compared with age-matched non-smokers, but no significant change in neurofibrillary tangles. Chronic nicotine treatment of transgenic mice (APPsw)(from 9 months of age for 5.5 months), which also develop beta-amyloid plaques, caused greatly reduced plaque density in the neocortex and hippocampus, together with reduced levels of insoluble, but not soluble, 1-40 and 1-42 amyloid peptides. Chronic nicotine can therefore reduce beta-amyloid deposition in both elderly humans and a mouse model of Alzheimer-like pathology and nicotinic drugs may be a feasible neuroprotective therapeutic approach in Alzheimer's disease.29 Proteolytic processing of the amyloid precursor protein by a-secretase Alzheimer's Disease is the most common form of dementia in the elderly and is characterised by the deposition of plaques of a 4kDa peptide called AP. AP is cleaved from a larger protein called the amyloid precursor protein by the action of two proteases termed the P and y secretases. Another protease, the a-secretase prevents the formation of AP by cleaving APP in the centre of the AP region. The a-secretase has been independently identified as being on...