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Alzheimer's disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata , as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5',7'-dichloro-8'-quinolyloxy)-3,19-acetonylidene (compound 9 ) behave as moderate α-secretase activators, while 14α-(2'-methyl-5',7'-dichloro-8'-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9 , stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.

The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on- andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease-modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β-amyloid precursor protein (βAPP) and β-amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed., (© 2019 Wiley Periodicals, Inc.)

Methamphetamine is a potent and highly addictive psychostimulant whose abuse has turned out to be a global health hazard. The multitudinous effects it exerts at the cellular level induces neurotoxic responses in the human brain, ultimately leading to neurocognitive disorders. Strikingly, brain changes, tissue damage and neuropsychological symptoms due to Meth exposure compels and necessitates to link the probability of risk of developing premature Alzheimer's disease, a progressive neurodegenerative disorder characterized by amyloid plaques composed of amyloid-β peptides and clinical dementia. These peptides are derived from sequential cleavages of the β-amyloid precursor protein by β- and γ-secretases. Previous studies reveals evidence for both positive and negative effects of Meth pertaining to cognitive functioning based on the dosage paradigm and duration of exposure revealing a beneficial psychotropic profile under some conditions and deleterious cognitive deficits under some others. In this context, we proposed to examine the effect of Meth on βAPP metabolism and βAPP-cleaving secretases in the human neuroblastoma SH-SY5Y cell line. Our results showed that Meth dose-dependently increases BACE1 expression and catalytic activity, while its effect on the α-cleavage of βAPP and on the expression and catalytic activity of the main α-secretase ADAM10 display a bell-curve shape. To our knowledge, the present study is the first to demonstrate that Meth can control βAPP-cleaving secretases. Moreover, we propose from these findings that the deleterious effect of Meth on cognitive decline might be an outcome of high dosage paradigm whereas acute and short-term drug use which stimulated sAPPα might produce improvements in cognition in disorders such as AD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Alzheimer's disease is characterized by the deposition of insoluble amyloid-β peptides produced from the β-amyloid precursor protein (βAPP). Because α-secretase cleavage by ADAM10 and ADAM17 takes place in the middle of Aβ, its activation is considered as a promising anti-AD therapeutic track. Here we establish that the polyherbal Wattana formula (WNF) stimulates sAPPα production in cells of neuronal and non-neuronal origins through an increase of both ADAM10 and ADAM17 catalytic activities with no modification of BACE1 activity and expression. This effect is blocked by specific inhibition or genetic depletion of these disintegrins and we show that WNF up-regulates ADAM10 transcription and ADAM17 maturation. In addition, WNF reduces Aβ40 and Aβ42 generation in human cell lines. Altogether, WNF presents all the characteristics of a potent preventive anti-Alzheimer formula. Importantly, this natural recipe, currently prescribed to patients for the treatment of other symptoms without any secondary effect, can be tested immediately for further clinical studies., Competing Interests: The authors have declared that no competing interests exist.

Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer-related amyloid β-peptide (Aβ) triggers oxidative stress through hydroxyl radical-induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Aβ is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Aβ peptides are produced via the sequential cleavage of β-secretase β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase (PS1/PS2), while α-secretase (ADAM10) prevents the production of Aβ peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH-SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration-dependent manner and mediated via melatonin G protein-coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor-κB phosphorylation (pNF-κB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated β-secretase catalytic activity. The present data show that melatonin is not only a potential regulator of β/γ-secretase but also an activator of α-secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, melatonin levels strongly decrease as we age and patients with Alzheimer's disease (AD) display lower melatonin than age-matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid-β peptides that are produced from the β-amyloid precursor protein (βAPP). However, whether melatonin can directly regulate the βAPP-cleaving proteases ('secretases') has not been investigated so far. In this study, we establish that melatonin stimulates the α-secretase cleavage of βAPP in cultured neuronal and non-neuronal cells. This effect is fully reversed by ADAM10- and ADAM17-specific inhibitors and requires both plasma membrane-located melatonin receptor activation, and ERK1/2 phosphorylation. Moreover, we demonstrate that melatonin upregulates both ADAM10 and ADAM17 catalytic activities and endogenous protein levels. Importantly, genetic depletion of one or the other protease in mouse embryonic fibroblasts prevents melatonin stimulating constitutive and PKC-regulated sAPPα secretion and ADAM10/ADAM17 catalytic activities. Furthermore, we show that melatonin induces ADAM10 and ADAM17 promoter transactivation, and we identify the targeted promoter regions. Finally, we correlate melatonin-dependent sAPPα production with a protection against staurosporine-induced apoptosis. Altogether, our results provide the first demonstration that melatonin upregulates the nonamyloidogenic ADAM10 and ADAM17 proteases through melatonin receptor activation, ERK phosphorylation and the transactivation of some specific regions of their promoters and further underline the preventive rather than curative nature of melatonin regarding AD treatment., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The extracellular senile plaques observed in Alzheimer's disease (AD) patients are mainly composed of amyloid peptides produced from the β-amyloid precursor protein (βAPP) by β- and γ-secretases. A third non-amyloidogenic α-secretase activity performed by the disintegrins ADAM10 and ADAM17 occurs in the middle of the amyloid-β peptide Aβ and liberates the large sAPPα neuroprotective fragment. Since the activation of α-secretase recently emerged as a promising therapeutic approach to treat AD, the identification of natural compounds able to trigger this cleavage is highly required. Here we describe new curcumin-based modified compounds as α-secretase activators. We established that the aminoacid conjugates curcumin-isoleucine, curcumin-phenylalanine and curcumin-valine promote the constitutive α-secretase activity and increase ADAM10 immunoreactivity. Strickingly, experiments carried out under conditions mimicking the PKC/muscarinic receptor-regulated pathway display different patterns of activation by these compounds. Altogether, our data identified new lead natural compounds for the future development of powerful and stable α-secretase activators and established that some of these molecules are able to discriminate between the constitutive and regulated α-secretase pathways., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Proteases regulate numerous physiological functions in all living organisms. Because of their contribution to βAPP processing, α-, β- and γ-secretases have focused particular attention of researchers in the field of Alzheimer's disease (AD) during the past 20 years. Whereas the β-secretase BACE1 and the heterotetrameric presenilin-dependent γ- secretase complex were identified between 1995 and 2002, α-secretase activity was attributed to previously described ADAM10 and ADAM17, two members of the type I integral membrane protein family called ADAMs (A Disintegrin And Metalloprotease). ADAM10 and/or ADAM17 target numerous substrates through various modes of action. This review focuses on the complex physiology of these α-secretases and will document their contribution to cancers, diabetes, rheumatoid arthritis, and prion diseases besides their well characterized role in Alzheimer's disease.

The α-secretases A disintegrin and metalloprotease 10 (ADAM10) and ADAM17 trigger constitutive and regulated processing of the cellular prion protein (PrP(c)) yielding N1 fragment. The latter depends on protein kinase C (PKC)-coupled M1/M3 muscarinic receptor activation and subsequent phosphorylation of ADAM17 on its intracytoplasmic threonine 735. Here we show that regulated PrP(c) processing and ADAM17 phosphorylation and activation are controlled by the extracellular-regulated kinase-1/MAP-ERK kinase (ERK1/MEK) cascade. Thus, reductions of ERK1 or MEK activities by dominant-negative analogs, pharmacological inhibition, or genetic ablation all impair N1 secretion, whereas constitutively active proteins increase N1 recovery in the conditioned medium. Interestingly, we also observed an ERK1-mediated enhanced expression of PrP(c). We demonstrate that the ERK1-associated increase in PrP(c) promoter transactivation and mRNA levels involve transcription factor AP-1 as a downstream effector. Altogether, our data identify ERK1 as an important regulator of PrP(c) cellular homeostasis and indicate that this kinase exerts a dual control of PrP(c) levels through transcriptional and post-transcriptional mechanisms.

The amyloid precursor protein (βAPP) undergoes several proteolytic cleavages. While β- and γ-secretases are responsible for the production of the 40-43 amino-acid long amyloid β peptide (Aβ), the α-secretase cut performed by the disintegrins ADAM10 and ADAM17, occurs in the middle of the Aβ sequence, thereby preventing its formation and leading to the secretion of the large sAPPα neuroprotective fragment. Here we showed that a series of M1 muscarinic receptor agonists dose-dependently stimulated sAPPα secretion without interfering with βAPP subcellular distribution. Carbachol- and PDBu-induced sAPPα secretions were blocked by the general PKC inhibitor GF109203X. We established that HEK293 and rhabdhomyosarcoma cells overexpressing constitutively active (CA) PKCα or PKCε secrete increased amounts of sAPPα while those expressing PKCδ were unable to modify sAPPα recovery. Conversely, the overexpression of PKCα or PKCε dominant negative (DN) constructs abolished PDBU-stimulated sAPPα secretion, whereas DN-PKCδ remained inert. In agreement, PKCα knockout lowered sAPPα recovery in primary cultured fibroblasts. We also demonstrated that the regulated α-secretase processing of βAPP is not controlled by the Extracellular-Regulated Kinase-1/MAP-ERK Kinase (ERK1/MEK) cascade and likely does not require ADAM17 phosphorylation on its threonine735 residue. Because the muscarinic-dependent α-secretase-like processing of PrP(c) is fully dependent on ADAM17 phosphorylation on its threonine735 residue by ERK1, these results indicate that a single extracellular signal triggers ADAM17-dependent regulated cleavages of βAPP and PrP(c) through distinct signalling cascades. This opens new potential therapeutic strategies aimed, in the context of Alzheimer's disease, at selectively activating ADAM17 towards βAPP without affecting the cleavages of its numerous other substrates., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is by far the main cause of dementia in the aged population. Because the amyloid-β peptide (Aβ) is the main component of senile plaques that develop in the brain of affected patients, numerous studies aimed at preventing its production or aggregation were conducted during the past 25 years. The inhibition of Aβ production via pharmacological inhibition of β- and γ-secretases is, with vaccination, one of the two main current challenges aimed at curing AD. However, the fact that there exist numerous substrates of these two activities renders this approach problematic since treatments with β- or γ-secretase inhibitors can cause deleterious effects. An alternative to the inhibition of the amyloidogenic enzymes would be to activate the α-secretase processing of AβPP. This cleavage is performed by two members of the disintegrin family of metalloproteases (ADAM10 and ADAM17). It is noteworthy that this cleavage can be seen as doubly beneficial regarding AD since it both occurs in the middle of the Aβ sequence and triggers the release of the neuroprotective sAβPPα product. However, similarly to β- and γ-secretases, ADAM10 and ADAM17 are responsible for the cleavage of a large number of proteins, the processing of some of them being tightly associated with important physiological functions but also with severe pathologies. This review focuses on our current knowledge of the various natural or synthetic compounds able to trigger α-secretase activities and on the possible ways to circumvent the deleterious side effects that would result from their broad activation.

Alzheimer's disease (AD) is by far the most common form of dementia in the elderly and concerns one out of three individuals over 85. Like other neurodegenerative disorders such as Parkinson, Hungtington or prion diseases, AD is characterized by the formation of amyloid plaques in the central nervous system. In the brain of AD patients, the main component of these abnormal deposits is an aggregated form of the so-called amyloid beta-peptide (Abeta), which is produced from a large trans-membrane type-1 protein, the beta-amyloid precursor protein (betaAPP), by the sequential action of the beta- and gamma-secretases. Beside these two amyloidogenic proteolytic attacks, betaAPP is targeted by a third enzyme termed alpha-secretase. Of utmost importance, this cleavage, which can be of constitutive or regulated origin, occurs right in the middle of the Abeta sequence, thus precluding its production. For this reason, and because the sAPPalpha secreted fragment derived from this cleavage displays beneficial effects, tremendous efforts have been made recently in order to both identify the proteases involved and the way they are regulated. More recently, it emerged that alpha-secretase was also responsible for the physiological processing of the cellular prion protein (PrP(c)) in the middle of its toxic 106-126 sequence. This review will focus on the recent advances in the alpha-secretase pathways regulation and will discuss the putative therapeutic approaches that could be envisioned concerning the treatment of two apparently distinct diseases that share common denominators according to their metabolism.

Amyloid beta-peptide (Abeta), which plays a central role in Alzheimer Disease, is generated by presenilin-dependent and presenilin-independent gamma-secretase cleavages of beta-amyloid precursor protein (betaAPP). We report that the presenilins (PS1 and PS2) also regulate p53-associated cell death. Thus, we established that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors and betaAPP or APLP2 depletion reduced the expression and activity of p53, and lowered the transactivation of its promoter and mRNA levels. p53 expression was also reduced in the brains or betaAPP-deficient mice or in brains where both PS had been invalidated by double conditional knock out. AICDC59 and AICDC50, the gamma- and epsilon-secretase-derived C-terminal fragments of betaAPP, respectively, trigger the activation of caspase-3, p53-dependent cell death, and increase p53 activity and mRNA. Finally, HEK293 cells expressing PS1 harboring familial AD (FAD) mutations or FAD-affected brains, all display enhanced p53 activity and p53 expression. Our studies demonstrate that AICDs control p53 at a transcriptional level, in vitro and in vivo and unravel a still unknown function for presenilins.