European Review for Medical and Pharmacological Sciences 2016; 20: 2389-2403 Therapeutic approaches to Alzheimer’s disease through stimulating of non-amyloidogenic processing of amyloid precursor protein

Y.-Q. WANG, D.-H. QU, K. WANG

The Second Affiliated Hospital of Jilin University, Nanguan District, Changchun, Jilin, China Yanqiao Wang and Danhua Qu contributed equally to the work

Abstract. – (Aβ) plaques are Introduction pathological hallmarks of neurodegenerative Alzheimer’s disease (AD) that is predominant- Amyloid beta (Aβ) plaque deposition is a major ly characterized by clinical symptoms of demen- pathological feature of the neurodegenerative Al- tia. Therapies targeting Aβ are essential for pre- zheimer’s disease (AD)1. The amyloid precursor venting and treating AD. This review focuses on the non-amyloidogenic pathways that prevent the protein (APP), via stimulation of amyloidogenic generation of Aβ and thereby plaque for- processing, undergoes sequential proteolytic cle- mation in AD. An a-secretase-dependent cleav- avage by β-secretase and g-secretase to generate age of Amyloid Precursor Protein (APP) precludes Aβ2. Alternatively, a non-amyloidogenic pathway the amyloidogenic pathway of Aβ generation. This involving a-secretase activation generates sAP- non-amyloidogenic a-secretase activation thereby Pa3,4. The advantage of this a-secretase pathway secretes sAPPa with prominent neurotrophic and is that it causes proteolytic cleavage within Aβ memory-enhancing properties. Several “A Dis- integrin and Metalloprotease” (ADAM) proteins, peptide sequence of APP and, therefore, com- specifically ADAM17, ADAM10 and ADAM9, com- petitively inhibits activation of the detrimental prise active members of this a-secretase family. It amyloidogenic pathway5. Also, sAPPa is proven is conventionally accepted that whereas ADAM10 to possess neuroprotective and memory-enhan- executes constitutive APP cleavage, ADAM17 and cing properties, often being compared to cerebral ADAM9 are dedicated towards the regulated pro- growth stimulants6,7. Thus, these two features cessing. Therefore, promoting a-secretase activ- ity offers thorough neuroprotection against AD, of reduced Aβ generation and sAPPa-induced and emerges as a pertinent strategy in attenuat- neuroprotection point towards APP non-amyloi- ing Aβ. We discuss signaling pathways, particular- dogenic pathway as a suitable therapeutic target ly those mediated by protein kinase C and phorbol for AD. Intriguingly, although amyloidogenic esters, that enhance ADAM functioning and sAP- pathway is fairly well explored in relation to AD Pa release. We also elaborate upon the associat- therapy, the non-amyloidogenic neuroprotective ed M1 and M3-muscarinic acetylcholine receptors, pathway remained mostly ignored. This review ERK-MAP kinase, tyrosine kinase and calcium sig- naling pathways. Clinical studies suggest that reg- will bring forth the neuroprotective properties of ulated hormone and cholesterol levels are essen- sAPPa and a-secretase proteins and will focus tial for restricting neurodegeneration, and here we on important signaling pathways and therapeutic illustrate the role of estrogen and testosterone and targets that elevate non-amyloidogenic APP pro- that of cholesterol-attenuating statins in generat- cessing. We will also highlight the need for new ing sAPPa. We also emphasize the need for novel therapies and strategies that may promote a-se- ADAM activators that may be screened for target- ing the interleukin-1-responsive mRNA 5’-untrans- cretase activation. lated region of APP. This review offers an in-depth insight into pathways, strategies and probable APP Processing: Towards the therapies restricting AD pathology via its non-am- Non-Amyloidogenic Pathway yloidogenic route. sAPPa: Mode of Action Key Words: APP, ADAM, PKC, Estrogen, IL-1, APP5’UTR. The 695-amino acid sAPPa protein represen- ts the N-terminal domain of APP. It is functio-

Corresponding Author: Ke Wang, MD; e-mail: [email protected] 2389 Y.-Q. Wang, D.-H. Qu, K. Wang nally marked by 12-cysteine residues, active di- mily, characterized by a multi-domain structure sulfide bonds and heparin-binding sites which consisting of (1) pro-domain, (2) catalytic me- bind to copper, zinc and growth factors8. sAP- talloprotease domain, (3) domain, (4) Pa knock-in mice and transgenic mice mutated cysteine-rich domain, and (5) cytoplasmic tail for at sAPPa activation sites demonstrate aberrant binding adaptor proteins18 (Figure 1). Through neurobehavior and loss in memory and long-term knock-out, knock-down and silencing stu- potentiation (LTP)9. Particularly, the amino acid dies, the functional and comparative efficacy of 319-335 sequences of sAPPa proved essential in ADAM members in reducing Aβ pathology has preventing the neuronal loss and promoting neu- been investigated19,20. rite outgrowth10,11. sAPPa’s heparin-binding sites that interact with extracellular heparan sulfate ADAM17 proteoglycans participates in neuronal adhe- ADAM17, also known as Tumor Necrosis Fac- sion and dendritic and axonal outgrowth of the tor-α-converting (TACE), is believed to pro- brain8,12. Interestingly, sAPPa alone could rescue mote the regulated cleavage of APP towards sAPPα7. electrophysiological aberrations detected in the ADAM17 knock-down cell lines and ADAM17-de- APP knock-out mice, supporting its significant ficient mice could not promote non-amyloidogenic contribution in restoring the cognition9. Its effects processing of APP, whereas ADAM17 over-expres- include increased synaptic density and memory sion enhanced sAPPa, suggesting a regulated mode retention via stimulation of N-methyl-D-aspartate of action21,22. In support of this idea, ADAM17 inhi- currents13. Heparin-binding sites of sAPPa also bition in the Chinese Hamster Ovary cells (CHO) block the proximal copper and Zinc-binding sites, influences protein kinase C (PKC)-mediated sAPPa and inhibit generation of oxidative stress8,14. The generation23-25. In addition, ADAM17 over-expres- non-amyloidogenic pathway is involved in the sion in PKC-deficient LoVo cell lines fails to in- reduction of toxic calcium signaling, activation fluence constitutive sAPPa secretion26. of K+ channel, decrease of glutamate excitoxici- Apart from APP, ADAM 17 influences prote- ty and attenuation of glucose deprivation6,7,15. olytic cleavage of other substrates that directly or sAPPa also degrades Aβ aggregates through the indirectly reduce Aβ. Notably, ADAM17-media- lymphocyte immune defense mechanism, redu- ted shedding of microglial pro-inflammatory me- ces coagulation factor and enhances cytokine diators, like tumor necrosis factor-α, fractalkine release from activated astrocytes and microglia8. and interleukin-8 (IL-8), and stimulation of IL-1 Furthermore, sAPPa mimics epidermal growth and IL-6 receptors prompts phagocytosis that de- factor (EGF) functioning that promotes neuronal grades Aβ18,27. In addition, ADAM17-dependent proliferation and protects against AD pathology16. activation of Epidermal Growth Factor (EGF) family members28, especially heparin-binding A-secretase Members EGF-like growth factor, promotes neuronal proli- Zinc metalloproteases, mainly the members of feration and reduces cerebral damage in AD [29]. disintegrin and metalloprotease (ADAM) fami- However, as evident from studies on neurobla- lies, such as ADAM17, ADAM10 and ADAM9, stoma cells and mice in situ hybridization expe- are considered as a-secretases that activate the riments, ADAM17 only partially functions as non-amyloidogenic APP processing17. ADAMs a-secretase, and an overall non-amyloidogenic belong to type-1 integral membrane protein fa- APP processing essentially required the other

Figure 1. Structure of ADAM.

2390 Non-amyloidogenic mechanism of Alzheimer’s disease

ADAM family members as well7,30. Moreover, tion of ADAM17 and ADAM9 culminates in con- the reduced ability of ADAM17 to influence the stitutive ADAM10 functioning at the cell surfa- constitutive sAPPa release supports the view that ce44. This is indicative of an overlap or interaction other ADAM members are required for a-secre- of these important ADAM family members. Cli- tase functioning. nical trials are being carried out to verify specific role of ADAM9 and its connection with ADAM17 ADAM 10 and ADAM107. Overall, ADAM9 is relatively less Unlike ADAM17, ADAM10 functions throu- investigated and is believed to be of lesser signifi- gh a constitutive mode31. Enhanced sAPPα in cance in AD compared to ADAM17 and 1022. Ra- ADAM10 over-expressed cells and attenuated Aβ ther, ADAM9 mRNA having been first isolated plaque deposition in ADAM10 knock-out mice from lungs is considered more important for the brain support this constitutive concept32. ectodomain shedding of lung epithelia7. ADAM10 exists as a pro-enzyme in Golgi ap- It is interesting to note that distribution and paratus, and following cleavage and N-glycosyla- activation of the ADAM metalloproteases deter- tion acquires a activity at the plasma mine their specific activities7. Active ADAM17 is membrane32-34. ADAM10-mediated APP cleavage expressed at the cell surface and in perinuclear in- involves an altered APP interaction with adhesion tracellular compartment7. Biotinylated ADAM10 proteins and extracellular matrix35. In addition, was found to be located at cell surface and in in- the clathrin adaptor AP2-mediated endocytosis tracellular Golgi region32, and active ADAM9 is regulates ADAM10 expression36, and synapse-as- mainly localized in the Golgi apparatus47. Howe- sociated protein-97 (SAP-97) stimulates APP ver, distribution and localizations generally gui- cleavage by targeting the excitatory synapses in de the basal activities of ADAMs, and their re- AD brain37,38. Also, ADAM10, in association with gulated activities are governed distinctly48. It is AP2 and SAP-97, improves LTP and synaptic thoroughly proven that ADAM members fail to activity in AD patients36. function in isolation, and their combined impact The over-expression of ADAM10 in primary culminates in the ultimate a-secretase functions. neurons of knock-down and ADAM10-domi- nant-negative mutants reduce sAPPa, with a si- Stimulation of the non-amyloidogenic multaneous increase in BACE-121,39. In vivo stu- Pathway dies revealed that Q170H and R181G mutations in sAPPa promotes synaptic plasticity and neuro- ADAM10 gene are responsible for this reduced nal survival by stimulating several neurotrophic a-secretase activity40. Consistently, over-expres- signaling pathways. The most prominent among sion of this mutated gene inhibits Aβ deposition them is the protein kinase C (PKC) signaling (Fi- even in the APP transgenic animal models39, pro- gure 2) that results in increased level of anti-a- ving the importance of these two amino acid re- poptotic BCl2 and Bcl-xL proteins and attenuated sidues for the ADAM10 functioning. ADAM10 caspase-mediated in the AD brain [49]. also limits the AD vascular pathology, as evident Altered tyrosine kinase (TK), mitogen-activated from the shedding of lipoprotein receptor related protein kinase (MAPK)-extracellular signal-re- protein-1 (LRP1) that regulates Aβ transport and gulated kinase (ERK) signaling, and Ca2+ signa- clearance across the blood-brain barrier41. ling contributes to the anti-apoptotic mechanism of sAPPa50. In addition, acetylcholine, serotoner- ADAM9 gic and glutamatergic receptors, hormones and Like ADAM17, ADAM9 participates in the cholesterol-lowering statins enhance sAPPa rele- non-constitutive, regulated sAPPa processing42. ase. In the last few years, targeting of IL-1 and its ADAM9 activity mainly appears to be PKC-de- responsive element on the APP gene also emer- pendent43, and its cleavage sites were identified at ged as a useful strategy towards augmenting the His13-Lys16 and His14-Gln15 within Aβ peptide non-amyloidogenic APP processing (Figure 3). sequence43. Nonetheless, a constitutive role of ADAM9 where it closely mimicked the ADAM10 Promoting Signaling Pathways of sAPPa functions was also reported44,45. This report also claims that ADAM9 functions in the microglial PKC pathway cells only, targeting APP-HHQK sequence speci- Activation of PKC signaling emerged as the fic for microglia46. Comparative data on the three first promising strategy to manipulate and pro- ADAM proteins demonstrate that initial activa- mote a-secretase cleavage of APP24. In fact, in-

2391 Y.-Q. Wang, D.-H. Qu, K. Wang

Figure 2. Acetylcholine binding to M1/M3 receptors activates PKC and downstream MAPKs. The MAPKs phosphorylate ADAMs along the transmembrane that stimulates a-secretase cleavage of Al- zheimer’s Amyloid Precursor Protein (APP). formation on the role of PKC in sAPPa release compounds, bryostatin was the safest and showed appeared prior to characterization of ADAMs45. a consistent increasing effect on sAPPα release Supportively, almost all pharmacological pa- [56]. Bryostatin-1, even at sub-nanomolar con- thways promoting sAPPa release converged upon centrations, promoted sAPPα secretion and atte- PKC activators51. nuated Aβ deposition in transgenic mice without Phorbol esters that are prominent PKC activa- generating tumors56. However, differing from the tors are well-recognized stimulants of a-secretase ubiquitous PKC concept, some findings indicate pathway52. These PKC activators, in association that PKC signaling preferentially promotes regu- with cell-surface receptors and neurotransmitters lated sAPPα release and influences only 30-40% stimulate the activity of a-secretase ADAM fa- of basal or constitutive secretion51. This disparate mily members51. Phorbol 12-myristate 13-aceta- view on PKC in terms of constitutive and regula- te (PMA) and phorbol-12, 13-dibutyrate (PDBu), ted α-secretase activity awaits in-depth characte- even at nanomolar levels, increase PKCe synthe- rization57. sis, and inhibiting of PKCe activation blocks cho- Muscarinic (M1/M3) acetylcholine receptors linergic modulation of APP metabolism towards emerged as functional activators of PKC signaling sAPPa53. Thus, a direct or indirect regulation of that work in a dose and time-dependent manner45. PKCϵ appears to be promising in reducing the Existing evidence proves that PKC coupled to Aβ via the a-secretase pathway. However, the M1 and M3-muscarinic receptors stimulate sAP- use of PMA and PDBu is problematic due to Pa release58,59. In vitro observations revealed that their tumor promoting properties54. Thus, PKC this sAPPα and muscarinic receptor association activators, such as benzolactam (BL) and its re- preferentially involves PKCα and PKCε, rather lated compound, LQ12, as well as marine natural than PKCδ60. In support of this view, PKCα and macrocyclic polyketide, bryostatin, that causes a predominantly PKCε rather than PKCδ isoforms significant increase in sAPPα in clinical AD ca- demonstrated extensive activation at the pre-sy- ses, were investigated further55. Among all these naptic domain of central nervous system61.

2392 Non-amyloidogenic mechanism of Alzheimer’s disease

Blocking of acetylcholinesterase activity in- rived neurotrophic factor (BDNF) that activate creases PKC signaling and enhances sAPPa TK signaling contributes to the Aβ suppression release thus helping in restoring the cognitive via a-secretase pathway66. Suppressed TK signa- performances in AD57. Likewise, supplementing ling was reported in the frontal cortex and hip- a selective M1-muscarinic agonist, AF267B, pocampus of AD brain66. Conversely, activated through intraperitoneal route reduces acetyl- TK signaling via stimulated non-amyloidogenic cholinesterase activity and stimulates ADAM17, APP-processing was shown to protect against AD culminating in reduced AD pathology in a tran- pathology67-69. A synergistic PKC and TK signa- sgenic AD mice model62. A very similar M1 ling are also known in sAPPα release, where tyro- agonist, AF102B, inhibits neuronal apoptosis sine phosphate agonists appear to activate the M1/ via increased sAPPα58,63. A third M1/M3 recep- M3 muscarnic receptors70. Similarly, inhibiting tor agonist, RS86, elevates the sAPPa level in the non-receptor Src-TKs by protein phosphata- cerebrospinal fluid, with concomitant decrease se-1 (PP1) suppresses the PKC-induced sAPPa re- in cortical and hippocampal full-length APP and lease71, and inhibiting the EGFR trans-activation improved cognitive performance45. Here, fibro- via AG1478 blocks the EGF-induced sAPPα72. A blast growth factor (FGF) and EGF-activated combined application of FGF with PMA also re- serine/threonine-phosphorylation of ADAM17 sults in higher sAPPα release compared to their appear to mediate the a-secretase functions64,65. additive effects in human neuroblastoma cells, Phospholipase-C (PLC), diacylglycerol (DAG) thus supporting TK and PKC synergism73. PDGF and inositol 1,4,5-trisphosphate (IP3) participa- participates in sAPPα generation in astrocytes, tion in the PKC, M1/M3-muscarinic and sAPPa and suppressing the PDGF expression by using pathways has also been proposed66. genistein blocks TK activation as well as sAPPα release74. BDNF-Trkb interaction promotes the TK Pathway APP non-amyloidogenic pathways, whereas exo- A combined action of the EGF, platelet-deri- genous retinoic acid stimulation offers a signifi- ved growth factor (PDGF), FGF and brain-de- cant protection in AD75.

Figure 3. Factors stimulating a-secretase cleavage and therapeutic targets in sAPPa release.

2393 Y.-Q. Wang, D.-H. Qu, K. Wang

MAPK Pathway concomitant decrease in Ab expression in pri- Several independent experimental studies de- mary neurons and B104 neuroblastoma cel- monstrated that MAPK-ERK pathway is an im- ls84,85. The phorbol ester-mediated ADAM17 portant regulator of a-secretase activity76,77. It was increase also involves enhanced cytoplasmic demonstrated that ERK1 interaction with threo- Ca2+ signaling and activation of the calcium-de- nine-735 residue of ADAM17 promotes ADAM17 pendent , calpain86. Likewise, translocation along plasma membrane, linking the inhibiting calpain activity blocks α-secretase two pathways, i.e. ERK and non-amyloidogenic functioning. Based on this strong link between APP processing65. An intricate association is also ADAMs and calpain, it is presumed that cal- thought to exist between PKC-regulated a-secre- pain signaling mimics the α-secretase activities tase processing and ERK, where MAPK inhibitor, to certain extent87,88. PD 98059, blocks the impact of phorbol esters78. Similarly, pituitary adenylate cyclase-activating Acetylcholine, serotonergic and polypeptide (PACAP)-regulated a-secretase acti- Glutamatergic receptors, and sAPPa vity can be disrupted via synergistic interaction of PKC inhibitor, chelerythrine, and ERK inhibitor, Acetylcholine Receptor PD 9805979. The neuroprotective and anti-apopto- The loss of cholinergic neurons results in co- tic monoamine-oxidase inhibitor, rasagiline, also gnitive deficiencies, a major pathological feature requires PKC and ERK activation for stimulating of AD89. Thus, cholinesterase inhibition is one the sAPPα secretion80. Cisse et al45 showed that of the pharmacologic approaches that stimulate the PKC-regulated a-secretase pathway depends non-amyloidogenic APP processing and thereby significantly on the ERK and ADAM17 inte- restore cognition89. It is reported that the three raction. However, this PKC and ERK-ADAM in- main acetylcholinesterase inhibitors, physostig- teraction link need to be validated further. mine (PHY), heptyl-physostigmine (HEP) and Notably, unlike the PKC pathway, the ERK pa- 2,2-dichlorovinyldimethyl phosphate (DDVP) thway is proven to regulate equally both consti- significantly enhance the sAPPa release90. In tutive and regulated sAPPa release45. The discre- this study, the electrical stimulation frequency pant ERK and PKC responses could be explained of acetylcholine neurotransmission was used to by the fact that membrane lipid-rafts are key fac- determine the cholinergic activity that influences tors in choosing between regulated and constituti- sAPPa90. ve ADAM activities45. PKC activation is generally Loss of cholinergic primary cortical neurons localized in the cholesterol-rich domain, whereas suppressed the non-amyloidogenic processing constitutive ADAM activation demands non-lipid of APP, and thereby up-regulated Ab levels in sites45. ERK undergoes activation at both low and the brain. Likewise, mutation at the muscarinic high-cholesterol micro-domains, rationalizing its acetylcholine receptor in APP transgenic mice role in regulated as well as constitutive a-secreta- reduced sAPPa and increased Ab91. Clinical stu- se functioning81. dies also confirmed this acetylcholine receptor’s The ERK inhibitor, PD 98059, also inhibits participation in sAPPa release62. Investigating the Nerve growth factor (NGF)-induced TK signa- mechanism of action revealed that acetylcholine ling and sAPPa release, proving ERK participa- targets membrane trafficking of the ADAMs91. It tion in the TK-mediated a-secretase activation82. is assumed that muscarinic acetylcholinesterase Overall, the studies of these signaling pathways inhibitors function by drawing ADAM10 and APP highlighted the importance of PKC, MAPK, and substrate together on the plasma membrane59. For TK second-messenger pathways for a-secretase instance, treating SH-SY5Y neuroblastoma cells activation, where PKC and TK signals congregate with the muscarinic acetylcholinesterase inhibi- at ERK and ultimately drive the enhanced sAPPα tor, donepezil, not only increased sAPPa release, release74,80. but also led to the accumulation of ADAM10 and APP active forms in the close vicinity to plasma Ca2+ Signaling membrane59. Co-immunolabeling experimen- Calcium homeostasis is essential for the nor- ts validated this functional ADAM10 and APP mal sAPPα functioning, as it influences neuro- association59. However, it was proven that along nal plasticity and development and the release with muscarinic receptors, n-acetylcholine recep- of neurotransmitters83. The calcium ionophore, tors, or a combination of the two, participate in A23187, causes increased sAPPα release with the sAPPa formation. In support of this view, the

2394 Non-amyloidogenic mechanism of Alzheimer’s disease muscarinic-anticholinergic drug, atropine, failed ly safe EGCG and gallate compounds emerged to suppress fully sAPPa in experiments and ne- as reliable protectors against AD development eded involvement of n-acetylcholine receptor an- via activation of non-amyloidogenic pathway109. tagonist too92. EGCG mode of functioning via PKC also in- Serotoninergic agonists, via cyclic adenosine volves binding to the furin protein convertase monophosphate (cAMP)-dependent pathways enzyme that stimulates ADAM10 activation 110. or through coupling with IP3 and PLC pa- Here, up-regulation of ER1a/MAPK/ERK signa- thways increases sAPPα secretion93. Likewise, ling rather than the PI3k/AKT pathway has been serotonin-specific reuptake inhibitors suppress hypothesized110. sAPPα, which could be recovered via seroto- The phytoestrogen ginsenoside Rg1 promo- ninergic 5-hydroxytryptamine receptor acti- tes non-amyloidogenic APP processing111. PKC, vation94. In hippocampal neurons, the metabo- MAPK and PI3K inhibitors block ginsenosi- tropic glutamatergic pathway also accelerates de Rg1-mediated sAPPa release, indicating the non-amyloidogenic APP processing95. Here, the participation of these signaling pathways in the hippocampal and cortical PKC pathways play a phytoestrogens action111. Interestingly, although major role, as evident from the reduced sAPPa ginsenoside Rg1 failed to bind ERa directly, the levels upon PKC inhibition, even in the presen- PKC, MAPK and PI3K pathways phosphorylated ce of the glutamatergic agonists96,97. Glutama- AF-1 (Ser118) domain on the receptor, thereby tergic interplay with Ca2+ signaling also ap- arbitrating estrogen-mediated a-secretase acti- pears to be responsible for glutamate receptor vation112. Via enhanced a-secretase activity, Rg1 activation in sAPPa release 96,97. also inhibited ER withdrawal-mediated Ab accu- mulation in ovariectomized rats111. Hormonal Regulation and sAPPa A highly selective β1-adrenoceptor antagonist, Clinical findings reveal that steroid hormones Nebivolol, stimulated ADAM9 and reduced Ab have significant pharmacological relevance in upon co-treatment with E2 in N2Aswe cells, im- AD. Estrogen is one such hormone that alters APP plying combined estrogen and inactivated β1-ad- metabolism, promoting the shift towards sAPPα98. renoceptor-mediated functioning113. Co-treatment Estrogen attenuates Ab-induced apoptosis via re- with ER inhibitor, ICI182780, blocks Nebivolol duced oxidative stress and neuroinflammation98. and E2-mediated effects on Ab, verifying estro- Studies revealed the PKC pathway’s involvement gen receptor’s involvement in Nebivolol-induced as well, as apparent from the suppression of estro- anti-amyloidogenicity113. gen-induced sAPPa by PKC inhibitor, calphostin Apart from estrogen, the steroid hormone te- C99,100. Participation of MAPK-ERK1/2 in estro- stosterone influenced sAPPα in the GT1-7 cells gen-regulated a-secretase activation is also evi- and in N2a neuronal cell lines, as well as primary dent in hypothalamic HT22 cells101. MAPK and neurons. However, a testosterone to estrogen con- PKC together could also promote estrogen-indu- version involving MAPK activation is presumed ced sAPPα in the hypothalamic gonadotrophin, to be actually responsible for neuroprotection and GT-17 cells102. sAPPα increase100,114. Polyphenolic flavonoid from green tea, epigal- Suppression of luteinizing hormone (LH) at locatechin gallate (EGCG), activates ADAM10, the hypothalamic-pituitary-gonadal axis promo- enhances sAPPa release and suppresses Ab in tes a-secretase functioning, and thereby sup- SH-SY5Y and PC12 cell lines, as well as in N2a/ presses cognitive deficits and Ab deposition in APPsw cells103-106. Analysis of the mechanism Tg 2576 AD mice, indicating negative effects of EGCG action revealed that the gallate group of LH on sAPPa115. Growth hormones associa- of EGCG mimicks 7a-estrogen site, thereby al- ted with growth factor signaling participates in lowing EGCG binding to estrogen receptor-1-al- non-amyloidogenic pathway activation too116. pha (ERla)107. This gallate group was found to Insulin-like growth factor-1 is one such growth function by promoting maturation of ADAM10 stimulator that coordinates with growth hor- protein107. Further investigation proved that gal- mones in order to metabolize APP towards the late-dependent ERla activation involves PKC non-amyloidogenic pathway117. Melatonin and signaling107. Other phenolic compounds bearing thyroid hormones have also been linked to APP this gallate domain, including octyl gallate and metabolism; however, in-depth studies are nee- atranorin, could also activate sAPPa generation ded to investigate their exact participation in the via ERla and PKC108. Thus, pharmacological- a-secretase activity118,119.

2395 Y.-Q. Wang, D.-H. Qu, K. Wang

Statins and sAPPa APP5’UTR that affects APP metabolism and thus Cholesterol level affects the APP processing, sAPPa release134. and epidemiological data demonstrated that cho- As reported for U373MG astrocytoma cell lesterol-suppressing statins play a beneficial role line, short exposure to IL-l causes a dose-depen- by suppressing the amyloidogenic pathway7,120. dent increase in ADAM10 and ADAM17, both Reduced cholesterol disintegrates the functional at mRNA and protein levels that led to APP5’U- lipid rafts that promote Aβ formation, resulting TR-dependent Aβ reduction77. Supporting prior in a shift from amyloidogenic to non-amyloido- observations on these a-secretase members, IL-1 genic APP processing and thereby sAPPα gene- increased ADAM10 constitutively and ADAM17 ration121. Spatial separation of ADAM-10 and its in a regulated manner in U373MG astrocytoma physiological inhibitor, reversion-inducing cy- cells77. Further delving into the mechanism de- steine-rich protein with Kazal motifs (RECK), in monstrated that IL-1 significantly stimulates P38 the glycosylphosphatidylinositol-rich lipid rafts and ERK pathways and partially the PI3K/AKT governs the statin-mediated sAPPa generation19. pathway77. Overall, in this study the activated Supporting this view, lovastatin and atorvasta- P38 pathway appeared proximal to IL-1 that re- tin were demonstrated to separate RECK and gulates other kinases, proving the IL-1-mediated ADAM significantly and promote ADAM10 avai- P38®ERK®PI3K/AKT pathway of non-amyloi- lability122. The PKC stimulator, bryostatin, also dogenic APP processing77. A similar observation behaves in a similar manner19. Docosahexaenoic was reported in U251 neuroglioma cells, where acid (DHA), a well-known polyunsaturated fatty intermediate ERK and JNK pathway activations acid (PUFA) that reduces hypercholesterolemia stimulated a-secretase activity135,136. and cholesterol de novo, attenuates ADAM17 pro- Drug screen assays targeted towards APP5’UTR tein degradation in lipid rafts123. DHA was shown mRNA proved effective in identifying therapeuti- to promote the ADAM17 stability and the corre- cs for AD134. High Throughput Screening (HTS) sponding induction of a-secretase activity in SH- of 1200 FDA-approved drugs identified several se- SY5Y cells123. rotonin reuptake inhibitors, metal chelators, N-a- Statins that block 3-hydroxy-3-methylglutaryl cetyl cysteine antioxidants, macrolide antibiotics coenzyme A (HMG-CoA) reductase activity and anticholinesterases as APP suppressors137-139. and reduce hypercholesterolemia also enhances Of these, both in vitro and in vivo investigations sAPPa124-128. HMG-CoA inhibition involves the revealed M1 muscarinic agonist, AF102B, as an isoprenoid and Rho-GTPase pathways of sAP- enhancer of a-secretase activity140. The compound Pa modulation129,130. Rho-GTPase and its effector not only promoted sAPPa generation, but also sti- molecule, Rho-associated kinase (ROCK) ultima- mulated expression of neurotrophins and growth tely appears to be responsible for the statin-me- factors140. AF102B caused significant recovery in diated sAPPa shedding129. Supporting this idea, cholinergic functions, and restored cognitive per- farnesyl inhibitor, FTI-1, that inhibits formances such as escape latency and reversal ROCK enhances sAPPa and attenuates Aβ in the learning in mice140,141. The mechanism of AF10B N2a mouse cell line131. In addition, arachidonic action involved a synergistic association with NGF acid that stimulates ROCK expression attenuates and EGF, leading to inhibition of oxidative stress sAPPa131. Activated PI3K/Akt pathway, coupled and neuronal apoptosis140. to the insulin receptor, could also regulate sta- Stable SH-SY5Y cell transfectants expressing tin-mediated neuroprotection in AD132. Reduced the APP5′UTR-dependent luciferase reporter also calpain activation and calcium flux also demon- served as a target for 110,000 compounds from strate certain involvement133. the FDA drug library142. Green fluorescent protein under control of the viral ribosomal entry site was Targeting IL-1 and the APP 5’-Untranslat- used as an internal specificity control142. Around ed Region (APP5’UTR) Towards sAPPa twenty compounds from the screen modulated the The GC-rich APP mRNA 5’UTR-stem loop APP5’UTR-driven luciferase reporter expression. structure is a significant regulator of APP gene Prion protein-5′UTR that served as a negative expression. The loop bears an amyloid-specific control was unaffected, that prove specificity of CAGA sequence (+83/+86), IL-1 responsive ele- the screened compounds towards APP142. These ment (+55 to +144) and an iron responsive ele- compounds are presently being explored for fur- ment (+51 to +94). IL-1 binding to its responsive ther understanding of their efficacies in sAPPa element significantly impacts the functioning of generation.

2396 Non-amyloidogenic mechanism of Alzheimer’s disease

Conclusions and Future Perspectives References

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