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Lilly Steps In for AstraZeneca’s Secretase Inhibitor

Today brings news of a deal with AstraZeneca to help develop AZ’s beta-secretase inhibitor, AZD3293 (actually an Astex compound, developed through fragment-based methods). AZ has been getting out of CNS indications for some time now, so they really did need a partner here, and Lilly lost their own beta-secretase compound last year. So this move doesn’t come as too much of a shock, but it does reaffirm Lilly’s bet-the-ranch approach to Alzheimer’s.
This compound was used by AZ in their defense against being taken over by Pfizer, but (as that link in the first paragraph shows), not everyone was buying their estimated chances of success (9%). Since the overall chances for success in Alzheimer’s, historically, have ranged between zero and 1%, depending on what you call a success, I can see their point. But beta-secretase deserves to have another good shot taken at it, and we’ll see what happens. It’ll takes years, though, before we find out – Alzheimer’s trials are painfully slow, like the disease itself.
Update: I’ve had mail asking what I mean by AZ “getting out of CNS indications”, when they still have a CNS research area. That’s true, but it’s a lot different than it used to be. The company got rid of most of its own infrastructure, and is doing more of a virtual/collaborative approach. So no, in one sense they haven’t exited the field at all. But a lot of its former CNS people (and indeed, whole research sites) certainly exited AstraZeneca.

29 comments on “Lilly Steps In for AstraZeneca’s Secretase Inhibitor”

  1. Anonymous says:

    Zero to 1% is about right, and probably at the low end of this range.

  2. Anonymous says:

    Zero to 1% is about right, and probably at the low end of this range.

  3. MedChem says:

    Does anyone know the structure of AZD3293?

  4. Dr. Erlich says:

    #4) Thanks for the link to the structure. My initial thought on looking at the structure is to wonder about the stability / reactivity of the aminal part of the molecule?

  5. Dr Octopus says:

    If you look for it in Google Images, it looks like it should be an amidine rather than an aminal.

  6. Lane Simonian says:

    Good luck (and I say this only half facetiously). This is the last gasp for the amyloid hypothesis for Alzheimer’s disease.
    Alzheimer’s disease is not primarily driven not by amyloid and tangles but by oxidative stress. With mild oxidative stress one can have plaques and tangles but not Alzheimer’s disease. Look at children exposed to pollution in Mexico City.
    Front Pharmacol. 2013 Aug 22;4:104. doi: 10.3389/fphar.2013.00104. eCollection 2013.
    Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children.
    Calderón-Garcidueñas L1, Mora-Tiscareño A, Franco-Lira M, Cross JV, Engle R, Aragón-Flores M, Gómez-Garza G, Jewells V, Medina-Cortina H, Solorio E, Chao CK, Zhu H, Mukherjee PS, Ferreira-Azevedo L, Torres-Jardón R, D’Angiulli A.
    Author information
    Abstract
    Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9-24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases.
    Cocoa helps to alleviate the brain damage because it is a peroxynitrite scavenger.
    Toxicol Lett. 2003 Apr 11;140-141:125-32.
    Defenses against peroxynitrite: selenocompounds and flavonoids.
    Klotz LO1, Sies H.
    Author information
    Abstract
    The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite. Several selenocompounds serve this purpose and include selenoproteins such as glutathione peroxidase (GPx), selenoprotein P and thioredoxin reductase, or low-molecular-weight substances such as ebselen. Further, flavonoids, such as (-)-epicatechin, which occurs in green tea or cocoa as monomer or in the form of oligomers, can contribute to cellular defense against peroxynitrite.
    Peroxynitrites and hydrogen peroxide activate caspases that stimulate the beta secretase which leads to the c-terminal fragment of the amyloid precursor protein. Peroxynitrites stimulate the release of intracellular calcium which leads to the activation of the y secretase and the formation of amyloid oligomers. And it mediates the nitration of amyloid oligomers leading to amyloid plaques. Each form of amyloid is less toxic than the one which precedes. So the y secretase actually worsened conditions for people with Alzheimer’s disease primarily because they were left with more c terminal fragments in their brains.
    The c-terminal fragment leads to the production of more peroxynitrites, so a beta secretase may help slow down the progression of the disease, but the production (albeit at a slower pace) and damage done by peroxynitrites continues. To effectively treat Alzheimer’s disease early on, you have to work upstream of beta secretases, by limiting the formation of peroxynitrites:
    Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity.
    Take the example of another peroxynitrite scavenger: ferulic acid. Ferulic acid inhibits the beta secretase by limiting the formation of peroxynitrites and by scavenging peroxynitrites:
    As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a β-secretase modulator with therapeutic potential against AD.
    Ferulic acid also protect against excitoxicity which is a major problem in middle to late Alzheimer’s disease.
    Now the results of ferulic acid along with other peroxynitrite scavengers in the treatment of Alzheimer’s disease and other forms of dementia
    Ferulic acid and eugenol in lemon balm extract
    Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomised, placebo controlled trial
    S Akhondzadeh, M Noroozian, M Mohammadi, S Ohadinia, A Jamshidi, and M Khani
    Results: At four months, Melissa officinalis extract produced a significantly better outcome on cognitive function than placebo (ADAS-cog: df = 1, F = 6.93, p = 0.01; CDR: df = 1, F = 16.87, p

  7. TX raven says:

    … and the amidine gets in the brain?

  8. Iridium says:

    @5
    it isn´t stable.
    It is not the right structure.

  9. Anonymous says:

    @4 that is not azd3293
    @5 these molecules are indeed amidines
    @8 with judicious modulation of amidine basicity and overall tpsa, these later generation BACE inhibitors can get in the brain, and stay (that is avoiding pgp efflux)

  10. An Old Chemist says:

    AZD 3293 is not an amidine, it is an amino-benz-pyrrole:
    http://www.chemspider.com/Chemical-Structure.29315042.html
    It should be stable and able to cross BBB.

  11. TX raven says:

    @11
    You are correct…

  12. Anonymous says:

    @11, Old chemist:
    At the link you provide, the structural formula is drawn in a rather amusingly unfortunate way. Obviously, it is done algorithmically, and just happens to look in a way that strains (har har) credulity.

  13. Anonymous says:

    @11 the link provided is not azd3293. As said on the chemspider details, it is azd3839, a failed phI compound.
    In the field these are referred to generically as amidines, or cyclic amidines.
    For recent review including comments of molecules in clinic see here
    http://www.sciencedirect.com/science/article/pii/S0960894X14002418

  14. SteveM says:

    Whether 1% vs. 9%, the thing is AZ and Lilly have different assessments of the Expected Net Present Value (ENPV) of the molecule.
    If AZ thought the odds are that it would make money, they would have kept development in house. When push comes to shove, AZ thinks that they are passing a loser to Lilly to most likely validate.
    And since AZ is closer to what’s really going on, they are probably right.

  15. Nick K says:

    Lane Simonian: Why don’t you develop a clinical candidate for AD yourself as you seem to have all the answers? Vast wealth and quite possibly a Nobel Prize await you if you succeed.

  16. Lane Simonian says:

    I am not interested in a Nobel Prize. All I am interested in is an effective treatment for Alzheimer’s disease. And there are five clinical trials using compounds that are rather ubiquitous in the plant world that have effectively treated Alzheimer’s disease. All I have done is explained how these compounds work. In a different kind of world that is all I should have to do.

  17. DatamonitorMark says:

    In fact none of the structures linked to so far appears to be correct either for AZD3893 or for AZD3293.
    The correct structure of AZD3893 has been published in J Biol Chem 2012, 287(49):41245-41257. It’s not the trifluoromethyl shown in the chemspider record. Chemspider references Selleckchem.com, which is also wrong.
    As far as I’m aware, the structure of AZD3293 has not been disclosed.

  18. older chemist says:

    AZD3293 is not an astex compound although they recive royalties(modest) from providing a fragment startingpoint quit far away from the final candidates.

  19. Nick K says:

    Lane Simonian: We’re all looking forward to seeing your wishful thinking pan out.

  20. Lane Simonian says:

    On a small-scale it already has. The following are from care facilities using aromatherapy although other interventions were used as well.
    Ecumen Medical Consultant Dr. Tracy Tomac: A Psychiatrist Blazing New Trails in Dementia Care
    Date: Mar 27th, 2014 3:00pm Author: Ben Taylor
    As their collaboration progressed, Eva began to formalize the program. The entire staff of Ecumen Scenic Shores — including housekeepers, cooks and dining room servers — received training in methods to calm residents when they became agitated, using non-pharmaceutical techniques like redirection, exercise, activities, music, massage and aromatherapy. The staff was taught how to listen to residents and enter their reality, responding to them without insisting on facts that those with dementia can’t grasp or won’t recall.
    They started in the early spring of 2009 and by early fall that year, ALL inappropriate antipsychotics were discontinued and antidepressants were reduced by 30 percent. Ecumen Scenic Shores was no longer a quiet place. It had literally come alive. Residents who had been immobile began participating in balloon volleyball. People who had not spoken in years were becoming more verbal. Residents were smiling and participating in sing-alongs.
    The dramatic results prompted Ecumen to start exploring ways to make Ecumen Awakenings more widely available. Laurel Baxter, RN, an Ecumen quality improvement nurse now retired, was appointed to formalize the program so that it could be replicated in all 15 of Ecumen’s nursing homes. The State of Minnesota awarded Ecumen a performance incentive grant — essentially venture dollars to support innovation in long-term care— which financed the implementation. Carefully monitored results showed dramatic reductions in the use of antipsychotic medications and dramatic increases in alertness, mobility, and laughter, more restful sleep, fewer falls, enhanced verbal ability, singing, ability to exercise, and reductions or eliminations of erratic mood swings, hallucinations and outbursts.
    Also see video about ecumen on KARE 11.
    Maggie: A Case Study In Dementia Care
    Clues For Making Maggie Happier
    To try to make bathing more pleasant, staff decided to heat the bathroom before taking her in and dry her off with towels fresh from the dryer. They also installed a rolling shade over the sink mirror, as Maggie appeared to be fearful when she saw the person in the mirror.
    Another strategy they tried was intensive aromatherapy. Caregivers rubbed the essential oil of lavender on her skin every two hours to surround her in a familiar and comforting scent.
    Just in case Maggie was experiencing some level of pain, Clairmont’s staff made sure one of the essential oils that eases muscle stiffness, joint pain, and aches was rubbed into her body first thing in the morning when the elderly tend to be most stiff and uncomfortable.
    Staff noticed she had difficulty finding the right word when she wanted to express herself, so they worked hard to understand the particular way her mind tended to find a certain kind of word when reaching to express a completely different one.
    All of this required intensive one-on-one time getting to know Maggie very well.
    Because Maggie so clearly needed comfort, staff took every opportunity to give her a warm hug or sit or walk with her, holding her hand so that she might feel less alone in this strange new world her brain had drawn her inexorably into. Staff discovered that Christian music gave her joy, so they played it for her frequently.
    A couple of weeks passed, and gradually Maggie became calmer and more at ease.
    Their efforts were so successful that Maggie was able to go entirely off the lethargy-inducing Ativan she had been taking three times a day. She doesn’t even need it PRN (as needed) anymore. Staff even discover, to their delight, glimpses of joy in Maggie’s eyes.
    Lavender and Old Lace
    To calm agitated dementia patients some caregivers are turning away from sedatives and toward aromatherapy
    Benjamin Pearce, president of a chain of assisted living homes for people with dementia, puts his hand in a cardboard box, and in a split second has a string of rainbow-colored flowers around his neck. Here he stands in his office on a Monday morning, intense pale blue eyes set in a stern face, now wearing a white dress shirt, a tie — and a lei. “We use this sometimes as a delivery system,” he says, without cracking a smile. In a flash, the Hawaiian garland is back in the box.
    The lei is one way Pearce delivers aromatherapy to the elderly residents in his 12 New Jersey facilities. He also instructs his staff to spritz lavender on their pillows and mix six drops with their bathwater. Other natural oils, such as citrus blends and rosemary, are added to humidifiers, massaged into patients’ skin or pumped into the air via diffusers. “I’m the most pragmatic person you’ll ever meet, and I am totally sold on aromatherapy,” Pearce says.
    Aromatherapy is becoming an increasingly accepted treatment option for a group that frequently does not get the care it deserves: elderly, institutionalized dementia patients. Zoned out, without any appetite, dementia patients are sometimes agitated, violent, and driven to wander. They are often given sedatives or antipsychotics. But these drugs have serious side effects, including an increased risk that frail patients will fall and severely injure themselves.
    ECU therapist studies links between scent and memory
    Knapp’s daughter, Mary Langston, of Greenville, said she has noticed a marked change in the past few weeks in her mother’s attention span and ability to better remember relatives in photographs and scrapbooks.
    “It’s been nice. It makes it so much easier to sit down and talk to her. As a child, you can’t imagine your parent’s not being able to remember things. But lately, it’s like she has been reborn,” Langston said. “She doesn’t get upset that she can’t remember things. Her attention span certainly has improved and she enjoys being around people more. Noises aren’t as disturbing for her.”
    Beverly Health Care recreational therapist Amy Smith, who directs the study with nine patients at the care facility, said that keeping residents off medications helps them to be more alert and aware of their surroundings, and more willing to engage with others.
    “I’m glad we did this. We weren’t sure what to expect and in a few weeks we’ve noticed, she (Mary) is different now.”
    Of course, most scientists especially in the United States consider this pseudoscience. The people who have used aromatherapy in memory care facilities know better. My job is to show that the science supports their empirical observations

  21. Lane Simonian says:

    And back to the science (I should be able to avoid responding to sarcastic remarks, but unfortunately it is not in my nature).
    The two prinicipal compounds in essential oils that are helpful for the treatment of Alzheimer’s disease are eugenol and linalool. Essential oils containing eugenol include clove, bay laurel, rosemary, lemon balm, holy basil, and nutmeg. Essential oils containing linalool include orange, rose, patchouli, Ylang Ylang, bergamot, and lemon balm.
    The critical studies regarding eugenol and linalool.
    Abstract:
    Eugenol (4-allyl-2-methoxyphenol) is a fragrant compound that is commonly contained in various sorts of plants, especially in spices and medicinal herbs. Eugenol has been used for dental analgesic, which also has anticonvulsive and anti-microbial activities. Besides, anti-inflammatory and antioxidative activities of eugenol are known. A body of evidence suggests that eugenol can be used as a drug for treatment of Alzheimer’s disease (AD). According to recent reports, the extract of a medicinal plant Rhizoma Acori Graminei (RAG) alleviates neurotoxicity induced by amyloid beta peptides (Aβ) in vitro and the active constituent of RAG is eugenol. Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death. Moreover, eugenol possesses an antidepressant-like activity. Eugenol, like other antidepressants, increases expression of brain-derived neurotrophic factor (BDNF) gene in the hippocampus, which is necessary for an antidepressant to exhibit its activity. Furthermore, eugenol inhibits monoamine oxidase A (MAO-A) and may restore monoamines that are decreased in the brain of patients with depression. Thus, eugenol can be a good medicine for AD and depression. Here we suggest that eugenol and its analogs can be used also for other diseases of the central nervous system (CNS) including Parkinson’s disease (PD). This article reviews the previous investigations concerning effects of eugenol including its analogs on the CNS and describes perspectives of this highly potential compound.
    J Agric Food Chem. 2009 Jun 24;57(12):5480-5. doi: 10.1021/jf900420g.
    Stress repression in restrained rats by (R)-(-)-linalool inhalation and gene expression profiling of their whole blood cells.
    Nakamura A1, Fujiwara S, Matsumoto I, Abe K.
    Author information
    Abstract
    As an attempt to quantitatively analyze the physiopsychological effects elicited by odorants, white blood cells and gene expression were profiled in the whole blood of the rats exposed to (R)-(-)-linalool during restraint stress for 2 h. In neutrophils and lymphocytes, significant changes caused by the restraint were repressed by their exposure to the odorant. This indicates that inhalation attenuates stress-induced changes. Significant changes on the stress-induced variations were induced by inhalation in 115 gene expression levels. Of those, 109 genes were down-regulated, whereas the remaining 6 were up-regulated. These findings show that (R)-(-)-linalool inhalation represses stress-induced effects on the profiles of both blood cells and gene expression. Furthermore, these results suggest the possibility that the odorant-induced effects can be quantitatively evaluated by analyzing the profiles of blood cells and gene expression.
    And the clinical trial using rosemary, lemon, lavender, and orange to treat Alzheimer’s disease.
    Psychogeriatrics. 2009 Dec;9(4):173-9.
    Effect of aromatherapy on patients with Alzheimer’s disease.
    Jimbo D1, Kimura Y, Taniguchi M, Inoue M, Urakami K.
    RESULTS: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit’s score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.
    CONCLUSIONS:
    In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.
    It is often said that aromatherapy is without side effects, but it is not true. People can have allergic reactions to certain oils and essential oils containing eugenol can increase anxiety (perhaps in part because of the past use of clove oil in dental operations).
    The beauty of aromatherapy is that the chemicals in the oils pass nearly directly into the hippocampus and do not require the sense of smell. They are also highly effective antioxidants.

  22. Anonymous says:

    #7(LS): your insistence about the link between peroxynitrite and AD is not completely unfounded. See paper by B. De Strooper’s team: Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer’s disease. Guix FX et al. EMBO Mol Med. 2012 Jul;4(7): 660-73.

  23. Lane Simonian says:

    Thank you #23. Here are a couple of other articles establishing additional links between peroxynitrites and Alzheimer’s disease.
    FASEB J. 2006 Jul;20(9):1431-42.
    Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.
    Zhang YJ1, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ.
    Peroxynitrite-Induced Neuronal Apoptosis Is Mediated by Intracellular Zinc Release and 12-Lipoxygenase Activation
    Yumin Zhang, Hong Wang, […], and Paul A. Rosenberg
    Differential regulation of BACE1 expression by oxidative and nitrosative signals
    Young-Don Kwak1, Ruishan Wang1, Jing Jing Li1, Yun-Wu Zhang2, Huaxi Xu3 and Francesca-Fang Liao1*
    And to the larger picture:
    Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses
    Hyoung-gon Lee, Xiongwei Zhu, Rudy J. Castellani, Akihiko Nunomura, George Perry and Mark A. Smith
    The alternate hypothesis…is that Aβ simply represents a bystander or a protector rather than the causative factor of disease (Smith et al., 2002; Lee et al., 2003, 2004b). Notably, all therapeutic studies that have an effect on Aβ levels in cells or animals have shown extremely poor or no efficacy in subsequent clinical trials. This includes indomethacin (Weggen et al., 2001), ibuprofen (Lim et al., 2000), sulindac sulfide (Weggen et al., 2001), a nitric oxide-releasing nonsterodial anti-inflammatory drug (Jantzen et al., 2002), and estrogen (Zheng et al., 2002). Clearly, the alternate hypothesis points to greater therapeutic efficacy by directing efforts to the upstream metabolic and oxidative abnormalities that are what led to Aβ.
    A beta secretase inhibitor early on will limit oxidative stress but not prevent it. A beta secretase inhibitor without side effects should have some limited effectiveness in treating patients with early Alzheimer’s disease, but it is not likely to stop the ultimate progression of the disease.

  24. tangent says:

    Lane, I have a soft spot for enthusiasts, but you are not giving a good impression today for your objectivity in evaluating facts. You posted these news stories about a program of “redirection, exercise, activities, music, massage and aromatherapy” improving functioning and mood in some people with various dementias. And you want this as evidence that essential oils are affecting the organic disease process in AD? Step back, you know how weak that is.

  25. Chris Southan says:

    Aplogies for posting our link in 4 to AZD3839 where I mixed it up with AZD3293 (but the faux pa stimulated some intresting discussion)
    I guess its too much to expect someone from AZ (or their freinds) to just paste in the SMILES against the code numbers ?

  26. Lane Simonian says:

    Tangent, if not impressed by the results with aromatherapy in memory care facilities, see studies on eugenol and linalool in #22. Essential oils act like stimulants or sedatives depending on the chemical composition of the oil. More importantly certain essential oils help to reduce tyrosine nitration and scavenge peroxynitrites. Tyrosine nitration inhibits the synthesis of acetylcholine contributing to the loss of short-term memory. Tyrosine nitration inhibits the phosphatidylinositol 3-kinase/Akt pathway leading to reduced blood flow in the brain, the loss of internal antioxidants (particularly glutathione), and no further regeneration of neurons in the hippocampus.
    Fitoterapia. 2005 Jul;76(5):481-3.
    Essential oils of commonly used plants as inhibitors of peroxynitrite-induced tyrosine nitration.
    Chericoni S1, Prieto JM, Iacopini P, Morelli I.
    Abstract
    The essential oils obtained from fifteen relevant and commonly used plants belonging to Cruciferae, Lamiaceae, Lauraceae, Apiaceae, and Zingiberaceae were screened using an in vitro model of peroxynitrite-induced tyrosine nitration. Almost complete inhibition of 3-nitrotyrosine formation (91% at 300 microg/ml) was achieved only with the essential oil obtained from the leaves of Laurus nobilis. 1,8-Cineol, accounting for a 50% of this essential oil, which resulted as inactive in this model, thus evidencing a major role for the minor volatile compounds present in the leave.
    I went back and reviewed the Alzforum coverage of the study cited by #23. Here are a few excerpts.
    Aging trumps everything as a risk factor for sporadic AD, but after decades of study, researchers are still unclear why. One theory blames accumulating oxidative damage, a metabolic consequence of getting older. Three recent articles lend new support to that theory. Two cell culture studies point to mechanisms by which oxidative stress wreaks havoc on components of the γ-secretase complex and hence amyloid processing. Another reports that reducing oxidative damage in mice from birth alleviates amyloidβ accumulation. Together, the studies reveal that age-related oxidative stress is not just bad for neurons, it can specifically exacerbate AD pathology.
    The group wondered if peroxynitrite, an oxidant that accumulates during aging and irreversibly modifies protein tyrosine residues by nitrating them (a process called nitrotyrosination), might somehow alter γ-secretase to change Aβ processing. Guix found that between three and four weeks of age (the same at which Aβ processing went awry), protein nitrotyrosination tripled relative to two-week-old neurons. Nitration is widespread in AD brains (see Smith et al., 1997 and Castegna et al., 2003) and nitrotyrosination has been implicated in AD pathogenesis (see Tran et al., 2003).
    The various genetic mutations that cause amyloid aggregation and tangles are causing peroxynitrite formation first. Peroxynitrites mediate both the beta secretase (via caspases) and the gamma secretase (likely through the nitration of inositol 1,4,5 triphosphate receptors). But under conditions of mild oxidative stress (such as in children breathing particulate matter and other pollutants in Mexico City) you can have mainly the gamma secretase activated with amyloid oligomers and plaques and tangles without Alzheimer’s disease.
    The c-terminal fragment of the amyloid precursor protein and amyloid oligomers can increase oxidative stress but they are not the primary cause. Reduce oxidative stress and you delay the onset of Alzheimer’s disease. Reduce oxidative stress by inhibiting the beta secretase or removing amyloid oligomers (or transition metals) during the early stages of Alzheimer’s disease and you slow the progression of the disease. Partially reverse the damage done by oxidants with bioavailabe methoxyphenol antioxidants and you partially reverse Alzheimer’s disease. Combine the case studies, with the clinical trials, with the scientific explanation and you have a large part of the answer.

  27. Anonymous says:

    So Lilly finally settles for AZ’s BACE inhibitor? After they tries to buy Eisai’s of course

  28. Antwan says:

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    I would personally wish to study more information on this
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