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Madrid: Highs and Lows of The Insulin Connection
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This is Part 3 of a three-part report. See also Intro/Part 1 and Part 2 of this clinical trials update. Also see PDF of Part 3.
14 September 2006. Frequently in Alzheimer research, new trends take form when epidemiologic studies suggest an association between the risk of developing Alzheimer disease and some second factor. One such area that is growing in strength is the overlap between type 2 diabetes and Alzheimer disease. More broadly, all components of what is loosely called metabolic syndrome—hypertension, high blood lipids, high blood sugar, insulin resistance, obesity—are linked with increased risk for age-related dementia. While mechanistic studies are ongoing and the epidemiologic connection is still growing in strength, some groups are already beginning to report results of some initial clinical trials (see below). Unfortunately, also frequently in AD research, tantalizing hints of a therapeutic effect show up in small pilot trials, only to fall flat when tested subsequently in larger, better-controlled studies. One problem is that, sometimes, trials are designed without sufficient input from basic scientists before underlying biologic processes of the new association, and specific biologic markers for it, are worked out for clinical trials to measure. The insulin/diabetes connection so far is no different.
One pilot trial reported at ICAD tested insulin itself. The underlying rationale is that plasma hyperinsulinemia and insulin resistance in the periphery paradoxically lead to a deficiency of insulin in the brain, probably because the peripheral condition changes the receptor-mediated transport of insulin at cells of the blood-brain barrier. Addressing this issue, Suzanne Craft and colleagues at the University of Washington, Seattle, attempted to deliver insulin directly to the brain by way of the nose. This route might be able to avoid the low blood sugar that would result from systemic insulin treatment (see also Born et al., 2002). The scientists used electronic atomizers to spray insulin into the noses of people with early AD or amnestic MCI for 3 weeks.
Of 25 patients, 13 were randomized to receive 20 international units of insulin daily and 12 to placebo. Plasma glucose and insulin levels happily did not change in insulin sniffers, nor did they suffer other side effects, Craft reported. The placebo and insulin group performed equally on verbal recall tests at baseline, but at the end of the trial the insulin group outperformed the placebo group. Older patients responded less well than younger patients. Intriguingly, intranasal insulin appeared to change plasma Aβ and cortisol levels.
Instead of using insulin, perhaps current type 2 diabetes drugs might work for AD? After all, AD is sometimes called “type 3 diabetes,” and some widely used drugs effectively increase the body’s sensitivity to insulin and lower blood glucose levels. GlaxoSmithKline’s rosiglitazone and Takeda Pharmaceutical/Lilly’s pioglitazone both are thiazolidinedione compounds that act as agonists of the PPARγ nuclear receptors. First, consider rosiglitazone. A small trial by Craft and colleagues had suggested a cognitive benefit in AD patients (Watson et al., 2005), and in Madrid, scientists from GlaxoSmithKline presented data for a large follow-up study. In a 6-month double-blind, placebo-controlled, dose-ranging trial of an extended-release form of rosiglitazone in 518 non-diabetic AD patients, the drug showed a similar safety profile as was previously established for diabetic patients. Edema and cardiac complications occurred as anticipated (see also ARF related news story), but no additional side effects cropped up in this AD population. The trial at first looked good: the patients were newly diagnosed, did not also take cholinesterase inhibitors or memantine, and 85 percent completed the trial. Unfortunately, the drug did not significantly improve their ADAS-Cog or CIBIC scores, reported Marina Zvartau-Hind of GlaxoSmithKline in Greenford, United Kingdom. There was no significant difference between the rosiglitazone and the placebo group. (The placebo group barely declined, as sometimes happens in 6-month trials of this slow-moving disease.)
This disappointing result could have ended the effort. Yet when the investigators analyzed, as planned, the ApoE4-positive and negative trial participants separately, they found a ray of hope. Patients without an E4 allele had, in fact, improved on the highest dose given, whereas people with one ApoE4 allele showed no benefit, and people with two ApoE4 alleles declined (Risner et al., 2006). Subgroup analysis is weaker than the result on the primary endpoint. Zvartau-Hind noted that this exploratory finding can’t help a doctor decide whether to prescribe rosiglitazone to a given AD patient. It also is not sufficient to encourage patients to find out their ApoE status. But the finding has swayed GlaxoSmithKline to continue testing rosiglitazone for AD, and larger trials powered to study its effect both in ApoE4 carriers and non-carriers are planned.
Rosiglitazone’s competitor pioglitazone also was put to the test, though a smaller one. David Geldmacher of the University of Virginia, Charlottesville, with colleagues at University Hospitals and Case Western Reserve University in Cleveland, Ohio, reported results of their 18-month trial of this drug in 29 non-diabetic AD patients. They were randomized to take either the drug or placebo but unlike in the GlaxoSmithKline trial, also took cholinesterase inhibitors and/or memantine. More than a quarter of the people in the treatment group developed edema; otherwise, they tolerated the drug well. Cognition, function, and behavior did not improve significantly, but there was a positive trend that the investigators interpret to warrant a larger trial on this drug, as well.
If those drugs are no home run, how about going after the signal transduction cascade downstream of insulin, to boost the hormone’s downstream effects? The literature is ripe with evidence implicating reduced levels of insulin-like growth factor-1 (IGF-1) in aging, cognitive decline, AD, and amyloid degradation (e.g., Rivera et al., 2005; for a recent review, see Messier and Teutenberg, 2005). Led by J.
Michael Ryan, scientists at Merck Research Laboratories in North Wales, Pennsylvania, took a cue from that body of work and tested MK-0677, a compound that induces secretion of IGF-1. They randomized 563 AD patients with baseline MMSE scores between 14 and 26 to take either MK-0677 or placebo daily for a year. In this double-blind trial, MK-0677 did increase
IGF-1 serum levels by 60 percent. Sadly, this failed to move any of the clinical treatment endpoints. Both CIBIC-plus and ADAS-Cog scales showed little change; neither did secondary endpoints.
What gives? Does the failure of large trials mean the epidemiological data are wrong? No, scientists across the field generally agree. Epidemiologists cautioned that one possible reason why trials have shown little effect is that epidemiology data are converging to show a link between components of the diabetic syndrome in mid-life and elevated risk for AD a decade or two later. As happened with anti-inflammatory drugs and estrogen, the trials tested drugs that are based on a mid-life risk factor in the hope that the drug will still be able to help a much older brain that has since degenerated considerably. To design better intervention—or even prevention—trials in younger people, more mechanistic insight in the underlying processes of metabolic syndrome components in AD is needed. This is particularly urgent because most patients have mixed forms of AD and vascular dementia, said Monique Breteler of Erasmus University in Rotterdam, The Netherlands. Echoing a similar story for estrogen, Kristin Yaffe of University of California, San Francisco, noted that after the disheartening failure of conjugated horse estrogen in the Women’s Health study, researchers have tried to focus on a critical period of dementia initiation in late mid-life, when endogenous sex hormone levels decline. They are beginning to test designer estrogens such as raloxifene for their ability to protect against MCI, not dementia (Yaffe et al., 2005).
The association between a history of diabetes and risk for AD is undisputed, but the mechanisms are nebulous, agreed Richard Mayeux of Columbia University, New York. Leads for possible mechanisms include insulin’s role in Aβ clearance by competition for the enzyme IDE, its downregulation of the tau kinase GSK3β, and its effect on the neuroprotective Akt signaling pathway. Does insulin resistance change the outcome of these pathways toward AD? Insulin-resistant adults have lower CSF Aβ42 levels, which other work has suggested foreshadows future AD. Research should focus on how increased CSF insulin might damage the brain’s microvasculature and blood-brain barrier and, in turn, lower insulin signaling inside the brain. More broadly, mechanisms accounting for microvascular damage could explain some of the established overlap between vascular dementia and AD. The focus in this area is slowly shifting away from ischemia and toward small hemorrhages and vascular amyloid, noted Breteler.
Research also should focus on a clear delineation between the effect of central insulin on Aβ and peripheral insulin on Aβ. If blood insulin levels increase peripheral Aβ, especially large amounts produced in muscle, then the direction of transport could shift toward Aβ import into the brain. Insulin is one of several factors that affect APP metabolism, Mayeux added, all of which deserve a clear description of the mechanistic pathway. Examples include dietary factors and stress. Hormones released by fat in that dangerous potbelly, as well as elevated glucocorticoids, cause insulin resistance and can lead to the same functional hypoglycemia in the brain that is seen in diabetes (see also Green et al., 2006; see ARF Madrid story). Understanding these mechanisms could pay off not only in better trial design but also in early detection and, eventually, prevention. The scientists agreed that epidemiology and basic science need to move in concert toward this goal.
A final note on the anti-inflammatory treatment front, which has suffered from similar problems. A trial of triflusal, an antithrombotic drug that also appears to inhibit NF-κB in the brain, showed a hint of promise toward reducing progression from MCI to AD in 257 people. However, slow recruitment forced a premature end to this trial, led by Teresa Gomez-Isla of the Hospital Santa Creu i Sant Pau in Barcelona, Spain, and conducted there and in Lisbon, Spain. An Italian trial of ibuprofen, conducted by researchers in Brescia, Pavia, Turin, and Rome, failed to slow cognitive decline in patients with mild-to-moderate AD in 132 patients. A longer-term follow-up of R-flurbiprofen confirmed and extended a moderate positive effect on cognition in patients with mild AD reported earlier (see ARF related conference story).—Gabrielle Strobel.
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Related News: Madrid: Pooled Antibody Cocktail, New Metal Quencher
Comment by: Mary Reid
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Submitted 18 September 2006
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Posted 19 September 2006
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IVIg is also used to treat hyper-IgM syndrome. Grewal and colleagues (1) report that protein glycosylation by alpha2,6-sialyltransferase (ST6Gal-I) restricts access of antigen receptors and Shp-1 to CD22 and operates by a CD22-dependent mechanism that decreases the basal rate of IgM antigen receptor endocytosis. Kitazume and colleagues (2) report that BACE1 transgenic mice have increased levels of ST6Gal I in plasma. Has anyone looked at IgM receptor endocytosis in AD?
It's interesting that PIR-B recruits Shp-1 and provides an alternative inhibitory pathway for B calls which is complementary to CD22 (3). Would you expect increased recruitment of Shp-1 by PIR-B in BACE1 transgenics? Does BACE1 restrict synaptic plasticity as is reported for PIR-B in the news comment by Pat McCaffrey (4)?
References:
1. Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling. Mol Cell Biol. 2006 Jul;26(13):4970-81. Abstract
2. Kitazume S, Nakagawa K, Oka R, Tachida Y, Ogawa K, Luo Y, Citron M, Shitara H, Taya C, Yonekawa H, Paulson JC, Miyoshi E, Taniguchi N, Hashimoto Y. In vivo cleavage of alpha2,6-sialyltransferase by Alzheimer beta-secretase. J Biol Chem. 2005 Mar 4;280(9):8589-95. Epub 2004 Sep 13. Abstract
3. Blery M, Kubagawa H, Chen CC, Vely F, Cooper MD, Vivier E. The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2446-51. Abstract
4. Immune Receptor Controls Synaptic Plasticity; LTP Makes Memories
 View all comments by Mary Reid |
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Related News: Mitochondrial Mayhem—PGC-1α, Respiration, and Neurodegeneration
Comment by: Victor V. Pineda
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Submitted 10 November 2006
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Posted 10 November 2006
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PGC-1α’s Emerging Roles—Neuroprotection and Neurodegeneration
Four recent articles focus on the importance of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), a transcriptional regulator involved in mitochondrial biogenesis, tissue differentiation, and energy homeostasis. One paper illustrates the protein’s neuroprotective role while three implicate its loss of function as a cause of neurodegeneration. St-Pierre and colleagues (1) show that PGC-1α transcription is upregulated in response to reactive oxygen species (ROS). Consequently, this increase in PGC-1α leads to higher expression of genes that are involved in suppressing ROS toxicity. In addition, their study showed that ablation of PGC-1α increased susceptibility to neuronal insults induced by ROS-generating toxins and depolarizing agents. In contrast, PGC-1α overexpression protected against ROS insults, further cementing the important role this protein plays in neuroprotection.
The other studies present evidence that decreased...
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PGC-1α’s Emerging Roles—Neuroprotection and Neurodegeneration
Four recent articles focus on the importance of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), a transcriptional regulator involved in mitochondrial biogenesis, tissue differentiation, and energy homeostasis. One paper illustrates the protein’s neuroprotective role while three implicate its loss of function as a cause of neurodegeneration. St-Pierre and colleagues (1) show that PGC-1α transcription is upregulated in response to reactive oxygen species (ROS). Consequently, this increase in PGC-1α leads to higher expression of genes that are involved in suppressing ROS toxicity. In addition, their study showed that ablation of PGC-1α increased susceptibility to neuronal insults induced by ROS-generating toxins and depolarizing agents. In contrast, PGC-1α overexpression protected against ROS insults, further cementing the important role this protein plays in neuroprotection.
The other studies present evidence that decreased expression and/or loss of function of PGC-1α underlie the neurodegenerative and metabolic deficits in Huntington disease (HD) and Leigh syndrome French Canadian variant (LSFC). In the Cooper paper(2), the authors report that loss of the 130 kDa leucine-rich protein (LRP130), an adaptor protein for PGC-1α, results in transcriptional dysregulation of specific PGC-1α targets. In Cui et al. (3), transcriptional repression of PGC-1α by the polyglutamine-expanded huntingtin (htt) protein causes mitochondrial deficits and neurodegeneration. In a study we published recently in Cell Metabolism (4), we implicated mutant htt-mediated transcriptional dysregulation of PGC-1α targets as the underlying cause of the thermoregulatory, neurodegenerative and metabolic dysfunctions in an HD mouse model. Furthermore, we showed that PGC-1α target genes are downregulated in the caudate of human HD patients compared to normal controls as additional evidence of the importance of PGC-1α in HD pathogenesis.
These papers present the importance of PGC-1α in maintaining neuronal integrity, either when faced with exogenous environmental insults or with toxic mutant proteins. Collectively, these reports point to a key player that can be viewed as an attractive drug target for the treatment of HD or perhaps other neurodegenerative disorders. A pharmacological agent that can increase neuronal expression or transcriptional activity of PGC-1α may be able to ameliorate the toxic effects of mutant proteins or perhaps reverse the accumulated oxidative damage associated with the aging process.
References:
1. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.
Cell. 2006 Oct 20;127(2):397-408.
Abstract
2. Cooper MP, Qu L, Rohas LM, Lin J, Yang W, Erdjument-Bromage H, Tempst P, Spiegelman BM. Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex.
Genes Dev. 2006 Nov 1;20(21):2996-3009. Epub 2006 Oct 18.
Abstract
3. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.
Cell. 2006 Oct 6;127(1):59-69.
Abstract
4. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration.
Cell Metab. 2006 Nov;4(5):349-62. Epub 2006 Oct 19.
Abstract
View all comments by Victor V. Pineda
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Related News: Longevity Tied to Insulin Action in Brain
Comment by: Suzanne Craft (Disclosure)
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Submitted 22 July 2007
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Posted 22 July 2007
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Taguchi and colleagues’ recent studies suggest that reducing insulin signaling through deletion of insulin receptor substrate 2 in brain (bIRS2) increases longevity even though it induces increased peripheral insulin resistance and hyperinsulinemia. Neuronal IRS2 is known to mediate critical aspects of systemic energy homeostasis (1); thus, the peripheral metabolic derangement caused by genetic deletion of bIRS2 is not surprising. It is of interest, however, that the typical life-shortening effects of peripheral insulin resistance can be reversed by inactivation of bIRS2-mediated insulin signaling. The authors make a good case that retention of youthful fat and carbohydrate metabolism and postprandial superoxide dismutase response may contribute to the resilience of bIRS2 -/- and +/- animals.
There are mixed implications of these results for understanding the potential contribution of insulin signaling abnormalities to Alzheimer disease (AD) pathogenesis. The finding that brain size is reduced in the bIRS2 -/- both supports the role of IRS2 in brain development and raises the...
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Taguchi and colleagues’ recent studies suggest that reducing insulin signaling through deletion of insulin receptor substrate 2 in brain (bIRS2) increases longevity even though it induces increased peripheral insulin resistance and hyperinsulinemia. Neuronal IRS2 is known to mediate critical aspects of systemic energy homeostasis (1); thus, the peripheral metabolic derangement caused by genetic deletion of bIRS2 is not surprising. It is of interest, however, that the typical life-shortening effects of peripheral insulin resistance can be reversed by inactivation of bIRS2-mediated insulin signaling. The authors make a good case that retention of youthful fat and carbohydrate metabolism and postprandial superoxide dismutase response may contribute to the resilience of bIRS2 -/- and +/- animals.
There are mixed implications of these results for understanding the potential contribution of insulin signaling abnormalities to Alzheimer disease (AD) pathogenesis. The finding that brain size is reduced in the bIRS2 -/- both supports the role of IRS2 in brain development and raises the question of potential behavioral deficits in these animals. Further behavioral testing with this model will provide useful data in that regard. There are additional direct implications of this work for Aβ regulation, given suggestions that IRS2 is required for insulin/IGF1-mediated switching from TrkA to the p75NTR neurotrophin receptor, which then stabilizes BACE1 and increases Aβ generation (2). Reducing IRS2-mediated insulin signaling may thus conceivably reduce brain amyloid levels.
One final caveat is needed regarding the extreme plasticity of the ancient and complex insulin signaling pathway. Knockout models of insulin/IGF1 signaling are highly susceptible to effects of reorganization that may not always be easy to discern and control. Replicative findings with conditional knockout models or techniques such as siRNA will help solidify the relevance of these interesting results for human aging and AD.
References:
1. Pardini AW, Nguyen HT, Figlewicz DP, Baskin DG, Williams DL, Kim F, Schwartz MW. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 2006 Sep 27;1112(1):169-78. Epub 2006 Aug 22.
Abstract
2. Constantini C, Scrable H, Puglielli L. An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation. EMBO. 2006;25:1997-2006.
View all comments by Suzanne Craft |
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Related News: Longevity Tied to Insulin Action in Brain
Comment by: Kun Ping Lu
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Submitted 22 July 2007
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Posted 22 July 2007
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Comment by Kazuhiro Nakamura and Kun Ping Lu
Aging, Cancer, and Neurodegeneration
Matheu et al. (1) have made the important discovery that overexpression of both Arf and p53 under normal regulation can confer cancer resistance, reduce aging-associated damage, and delay normal aging in mice. These results are especially interesting because these authors have previously shown that overexpression of either Arf or p53 alone can confer cancer resistance, but not longevity (2,3), highlighting the tight regulation of the aging process. The authors have provided a rationale for the co-evolution of cancer resistance and longevity, suggesting that it may be possible to live longer without worrying about cancer.
These results have a general impact on many age-related disorders, including neurodegeneration, which also result from age-related cellular damage in the nervous system. Interestingly, p53-mediated cell death has been associated with the progressive neuronal death in Huntington disease, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis...
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Comment by Kazuhiro Nakamura and Kun Ping Lu
Aging, Cancer, and Neurodegeneration
Matheu et al. (1) have made the important discovery that overexpression of both Arf and p53 under normal regulation can confer cancer resistance, reduce aging-associated damage, and delay normal aging in mice. These results are especially interesting because these authors have previously shown that overexpression of either Arf or p53 alone can confer cancer resistance, but not longevity (2,3), highlighting the tight regulation of the aging process. The authors have provided a rationale for the co-evolution of cancer resistance and longevity, suggesting that it may be possible to live longer without worrying about cancer.
These results have a general impact on many age-related disorders, including neurodegeneration, which also result from age-related cellular damage in the nervous system. Interestingly, p53-mediated cell death has been associated with the progressive neuronal death in Huntington disease, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis (4). For instance, p53 mediates cellular dysfunction and behavioral abnormalities in Huntington disease (5). In addition, increased expression of Arf and p16ink4a has been shown to decrease brain stem/progenitor cells and neurogenesis during aging and in Bmi1-deficient mice (6-9). Reduced stem/progenitor cell function may be a major cause of the decline in regenerative capacity and contribute to degenerative diseases observed in aging tissues. Thus, it would be of interest to examine whether this Arf/p53 longevity pathway would affect the development of stem/progenitor and progression of neurodegeneration.
The concept of the co-evolution of cancer resistance and longevity is intriguing and significant. However, there are many other examples where longevity and cancer resistance may be antagonistic (10). For example, overexpression of truncated (constitutively active?) p53 leads to premature aging and cancer resistance in mice (11,12). Similarly, we and others have shown that ablation of the prolyl isomerase Pin1 in mice leads to many premature aging phenotypes including neurodegeneration, and also protects against cancer development even induced by overexpression of certain oncogenes or ablation of p53 (13-18). These results are relevant because Pin1 appears to regulate p53 function in response to genotoxic stress (19-21). Therefore, it would be extremely interesting and important to understand how and why cancer resistance and longevity are antagonistic under some conditions, but compatible under some other conditions, and also to investigate the relationship among aging, cancer, and neurodegeneration.
References
1. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M. Delayed aging through damage protection by the Arf/p53 pathway. Nature. 2007 Jul 19;448(7151):375-9.
Abstract
2. Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, Weill JC, Blasco MA, Serrano M. "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally.
EMBO J. 2002 Nov 15;21(22):6225-35.
Abstract
3. Matheu A, Pantoja C, Efeyan A, Criado LM, Martin-Caballero J, Flores JM, Klatt P, Serrano M. Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging.
Genes Dev. 2004 Nov 15;18(22):2736-46. Epub 2004 Nov 1.
Abstract
4. Jacobs WB, Kaplan DR, Miller FD. The p53 family in nervous system development and disease.
J Neurochem. 2006 Jun;97(6):1571-84. Review.
Abstract
5. Bae BI, Xu H, Igarashi S, Fujimuro M, Agrawal N, Taya Y, Hayward SD, Moran TH, Montell C, Ross CA, Snyder SH, Sawa A. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease.
Neuron. 2005 Jul 7;47(1):29-41.
Abstract
6. Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, Sharpless NE, Morrison SJ. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during aging.
Nature. 2006 Sep 28;443(7110):448-52. Epub 2006 Sep 6.
Abstract
7. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. Stem-cell aging modified by the cyclin-dependent kinase inhibitor p16INK4a.
Nature. 2006 Sep 28;443(7110):421-6. Epub 2006 Sep 6.
Abstract
8. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways.
Genes Dev. 2005 Jun 15;19(12):1432-7.
Abstract
9. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation.
Nature. 2003 Oct 30;425(6961):962-7. Epub 2003 Oct 22.
Abstract
10.
Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors.
Cell. 2005 Feb 25;120(4):513-22. Review.
Abstract
11. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA. p53 mutant mice that display early aging-associated phenotypes.
Nature. 2002 Jan 3;415(6867):45-53.
Abstract
12. Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, Sutherland A, Thorner M, Scrable H. Modulation of mammalian life span by the short isoform of p53.
Genes Dev. 2004 Feb 1;18(3):306-19.
Abstract
13. Lu, K. P., and X. Z. Zhou. 2007. The prolyl isomerase Pin1: a pivotal new twist in phosphorylation signalling and human disease. Nat Rev Mol Cell Biol (in press).
14. Liou YC, Ryo A, Huang HK, Lu PJ, Bronson R, Fujimori F, Uchida T, Hunter T, Lu KP. Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes.
Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1335-40. Epub 2002 Jan 22.
Abstract
15. Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration.
Nature. 2003 Jul 31;424(6948):556-61.
Abstract
16. Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production.
Nature. 2006 Mar 23;440(7083):528-34. Erratum in: Nature. 2007 Mar 15;446(7133):342.
Abstract
17. Wulf G, Garg P, Liou YC, Iglehart D, Lu KP. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis.
EMBO J. 2004 Aug 18;23(16):3397-407. Epub 2004 Jul 15.
Abstract
18. Takahashi K, Akiyama H, Shimazaki K, Uchida C, Akiyama-Okunuki H, Tomita M, Fukumoto M, Uchida T. Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1.
Oncogene. 2007 May 31;26(26):3835-45. Epub 2006 Dec 11.
Abstract
19. Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP. Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage.
J Biol Chem. 2002 Dec 13;277(50):47976-9. Epub 2002 Oct 17.
Abstract
20. Zheng H, You H, Zhou XZ, Murray SA, Uchida T, Wulf G, Gu L, Tang X, Lu KP, Xiao ZX. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response.
Nature. 2002 Oct 24;419(6909):849-53. Epub 2002 Oct 2. Erratum in: Nature 2002 Nov 28;420(6914):445.
Abstract
21. Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S, Ronai Z, Blandino G, Schneider C, Del Sal G. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults.
Nature. 2002 Oct 24;419(6909):853-7. Epub 2002 Oct 2.
Abstract
View all comments by Kun Ping Lu
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Related News: Longevity Tied to Insulin Action in Brain
Comment by: Frédéric Checler
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Submitted 23 July 2007
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Posted 23 July 2007
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It is well established that p53 is an oncogene, many mutations on which are responsible for the development of various types of cancer. It has been proposed that this pathology is due to the impairment of the ability of p53 to eliminate damaged cells. Aging also results from damaged cells which accumulate, and it is therefore tempting to postulate that p53 could be an endogenous “life prolongator.” Accordingly, in C. elegans, mutations which increase longevity also confer cancer resistance likely via p53 activation. Therefore, longevity and cancer resistance could have in common the potent ability of p53 to clear damaged cells.
The paper by Matheu and colleagues very interestingly documents that in mice, overexpression of p53 and Arf (a p53 stabilizer) triggers cancer resistance and decreases age-associated damage. Therefore, the study gives support to the idea that the control of p53 could be central in aging and provides a rationale to the unexplained observation that long lifetime is apparently associated to increased cancer resistance.
This very interesting and...
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It is well established that p53 is an oncogene, many mutations on which are responsible for the development of various types of cancer. It has been proposed that this pathology is due to the impairment of the ability of p53 to eliminate damaged cells. Aging also results from damaged cells which accumulate, and it is therefore tempting to postulate that p53 could be an endogenous “life prolongator.” Accordingly, in C. elegans, mutations which increase longevity also confer cancer resistance likely via p53 activation. Therefore, longevity and cancer resistance could have in common the potent ability of p53 to clear damaged cells.
The paper by Matheu and colleagues very interestingly documents that in mice, overexpression of p53 and Arf (a p53 stabilizer) triggers cancer resistance and decreases age-associated damage. Therefore, the study gives support to the idea that the control of p53 could be central in aging and provides a rationale to the unexplained observation that long lifetime is apparently associated to increased cancer resistance.
This very interesting and well-performed study raises a few questions. Particularly striking is the observation that the coexpression of both Arf and p53 slightly increases the median lifespan (by 16 percent) but that the shapes of the two survival/age curves are different (see Fig. 2a,b). Although the Arf/p53 mice begin to die later than wild-type mice, the decay in survival seems accelerated for the former mice and finally, both curves gather to give 100 percent mortality at about 150 weeks. In other words, there is not a subset of Arf/p53 mice which survives the group of wild-type mice. Whether the cooperative function of Arf and p53 is efficient at early stages of “old age” but remains ineffective at later stages is a matter of reflection.
Has the work by Matheu implications for the understanding of neurodegenerative diseases? In Parkinson disease-affected brains, an increased p53-dependent cell death has been well documented. In both Parkinson and Alzheimer diseases, proteins responsible for familial cases, such as presenilins or α-synuclein, control p53-dependent cell death, and this function is increased by pathogenic mutations. Even if the demonstration that exacerbated p53-dependent apoptosis is causal in early death observed in genetic cases of AD or PD remains to be established, increased p53 expression accompanying early death would appear paradoxical with respect to Matheu’s work indicating that p53 overexpression triggers enhanced longevity. Close examination of data gives simple explanations. Thus, Matheu and colleagues show that the p53 or Arf overexpression alone did not mimic the phenotype triggered by coexpression of the two protein partners. No data are yet available concerning the levels of Arf in AD or PD brains and whether decreased levels of Arf could account for altered p53-dependent control of the longevity bestowed by p53. It should be noted that if this is the case, such alteration should be topologically restricted to cerebral areas lesioned in these pathologies (which are sometimes very narrow) in contrast to more widely distributed brain zones affected during normal aging. It is therefore more likely that the very nicely documented functional collaboration between Arf and p53 in the control of lifespan is not a central alteration responsible for neurodegenerative diseases associated with exacerbated apoptotic cell death.
View all comments by Frédéric Checler |
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Related News: How Does Aβ Do Harm? New Clues on Insulin Signaling, Spines, Inflammation
Comment by: Sanjay W. Pimplikar
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Submitted 17 September 2007
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Posted 18 September 2007
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The two papers that report the effects of “oligomeric” Aβ on insulin signaling pathways display a curious discrepancy. Townsend et al. add their oligomeric Aβ preparation to mouse hippocampal neuronal cultures and observe no effect of Aβ alone on S473 phosphorylation of Akt. Zhao et al. add their oligomeric Aβ preparation to rat hippocampal neurons and observe a whopping increase in S473 phosphorylation of Akt. Aren't these observations inconsistent, or are we missing something? These findings would seem to mean that the “Selkoe-mers” and the “Klein-mers” elicit their effects through different mechanisms? If so, which pathway is followed by the “real-mers”' implicated in human AD? At this point, we have no data yet on how the “star-oligomers” will affect the phosphorylation of Akt.
Zhao et al. state that phosphorylation of Akt at S473 is a hallmark of insulin resistance. I'd like to point out that phosphorylation of Akt at S473 is an indicator of its activation and widely accepted as such in the field (Hemmings,...
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The two papers that report the effects of “oligomeric” Aβ on insulin signaling pathways display a curious discrepancy. Townsend et al. add their oligomeric Aβ preparation to mouse hippocampal neuronal cultures and observe no effect of Aβ alone on S473 phosphorylation of Akt. Zhao et al. add their oligomeric Aβ preparation to rat hippocampal neurons and observe a whopping increase in S473 phosphorylation of Akt. Aren't these observations inconsistent, or are we missing something? These findings would seem to mean that the “Selkoe-mers” and the “Klein-mers” elicit their effects through different mechanisms? If so, which pathway is followed by the “real-mers”' implicated in human AD? At this point, we have no data yet on how the “star-oligomers” will affect the phosphorylation of Akt.
Zhao et al. state that phosphorylation of Akt at S473 is a hallmark of insulin resistance. I'd like to point out that phosphorylation of Akt at S473 is an indicator of its activation and widely accepted as such in the field (Hemmings, 1997). So, could one interpret these findings to suggest that the oligomeric Aβ activates the Akt signaling pathway and promotes cell survival (Chan et al., 1999)? That would run against everything we were told about Aβ. To be fair, the authors do speculate about “a possible negative feedback loop,” but their observations, at first glance, demonstrate activation of Akt by “oligomeric Aβ.”
View all comments by Sanjay W. Pimplikar |
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Related News: How Does Aβ Do Harm? New Clues on Insulin Signaling, Spines, Inflammation
Comment by: Dennis Selkoe, ARF Advisor, Matthew Townsend
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Submitted 27 September 2007
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Posted 27 September 2007
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Comment by Matt Townsend and Dennis Selkoe
In response to Sanjay Pimplikar's comment, we fully agree that it will be important to clarify the differences between our manuscripts—whether it's the source of Aβ, the concentration, the age of the neurons, etc.
Nevertheless, the basic conclusion of both papers is consistent, namely, that Aβ oligomers interfere with insulin receptor function in neurons.
The
purpose of neuronal insulin receptors is largely unexplored, although C.
Ronald Kahn and colleagues have reported significant tauopathy (but not memory deficits) in the NIRKO mice ( Schubert et al., 2004).
We find two important differences between our work and that of Zhao et al.
The
first, of course, is the opposite effects on Akt phosphorylation; the second is the issue of whether Aβ prevents insulin receptor signaling by blocking the receptor versus causing receptor internalization. The simplest explanation is a subtle difference in methods. However, a perhaps more satisfying possibility is that...
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Comment by Matt Townsend and Dennis Selkoe
In response to Sanjay Pimplikar's comment, we fully agree that it will be important to clarify the differences between our manuscripts—whether it's the source of Aβ, the concentration, the age of the neurons, etc.
Nevertheless, the basic conclusion of both papers is consistent, namely, that Aβ oligomers interfere with insulin receptor function in neurons.
The
purpose of neuronal insulin receptors is largely unexplored, although C.
Ronald Kahn and colleagues have reported significant tauopathy (but not memory deficits) in the NIRKO mice ( Schubert et al., 2004).
We find two important differences between our work and that of Zhao et al.
The
first, of course, is the opposite effects on Akt phosphorylation; the second is the issue of whether Aβ prevents insulin receptor signaling by blocking the receptor versus causing receptor internalization. The simplest explanation is a subtle difference in methods. However, a perhaps more satisfying possibility is that picomolar concentrations of Aβ simply shut down insulin receptor signaling cascades, while nanomolar concentrations have a more dire effect, such as inducing insulin receptor internalization and stimulating an Akt-driven checkpoint as to whether to survive or undergo apoptosis. If this is the case, both observations may be relevant for Alzheimer disease.
A second notable possibility pertains to our unpublished observation that monomeric Aβ may act as a weak agonist at the insulin receptor.
Depending
on the exact levels of monomeric Aβ in both of our preparations, we might expect to see precisely the opposite effect. A distinct effect of monomeric versus oligomeric Aβ on the insulin receptor may conform with widely accepted notions that the conformation of Aβ is important for toxicity. In this scenario, monomeric Aβ may mildly stimulate insulin receptor activity, while oligomeric Aβ antagonizes its function.
Following this line of reasoning into speculation, it's conceivable that the common sequence and conformational elements that enable insulin degrading enzyme (IDE) to degrade both insulin and monomeric Aβ are common to the insulin receptor, as well. Should this be the case, the evolutionary importance of IDE in degrading Aβ may outweigh its unfortunate side effects in the insulin receptor.
View all comments by Dennis Selkoe
View all comments by Matthew Townsend
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Related News: How Does Aβ Do Harm? New Clues on Insulin Signaling, Spines, Inflammation
Comment by: Fernanda De Felice, William Klein, Wei-Qin Zhao
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Submitted 8 October 2007
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Posted 8 October 2007
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We acknowledge Dr. Pimplikar's understandable concern regarding Akt. We would like to call attention to the very nice editorial by Rong Tian in Circulation Research ( Tian, 2005), which explains the emerging complexities of Akt ("Another Role for the Celebrity: Akt and Insulin Resistance"). Tian's is an important commentary. In his words, "Although thr 308 phosphorylation of the Akt resulted in increased glucose uptake, Akt activation by Ser 473 phosphorylation acted as a negative regulator that phosphorylated a threonine on the insulin receptor β-subunit causing decreased autophosphorylation of the receptors…. This finding suggests a likely mechanism for insulin resistance...." In our Results section, we cite this commentary, and we state that "Inhibition of IR autophosphorylation can occur physiologically through negative feedback regulation by Akt." In our Discussion, we include further citations germane to this topic to provide a knowledge base relevant to insulin receptor resistance in the context of elevated Akt-pSer473....
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We acknowledge Dr. Pimplikar's understandable concern regarding Akt. We would like to call attention to the very nice editorial by Rong Tian in Circulation Research ( Tian, 2005), which explains the emerging complexities of Akt ("Another Role for the Celebrity: Akt and Insulin Resistance"). Tian's is an important commentary. In his words, "Although thr 308 phosphorylation of the Akt resulted in increased glucose uptake, Akt activation by Ser 473 phosphorylation acted as a negative regulator that phosphorylated a threonine on the insulin receptor β-subunit causing decreased autophosphorylation of the receptors…. This finding suggests a likely mechanism for insulin resistance...." In our Results section, we cite this commentary, and we state that "Inhibition of IR autophosphorylation can occur physiologically through negative feedback regulation by Akt." In our Discussion, we include further citations germane to this topic to provide a knowledge base relevant to insulin receptor resistance in the context of elevated Akt-pSer473. Observations are presented " suggesting the possibility that elevated Akt-pSer473 induced Aβ oligomers could contribute to insulin resistance in AD-affected brain." Our hypothesis concerning possible involvement of Akt phosphorylation in ADDL-induced insulin resistance thus derives from published precedents.
The correlation between oligomer structures and neurotoxic activities is of fundamental concern. It would be appropriate to address this important issue at length at a meeting or online. We would be interested in carrying out a compare-and-contrast discussion, or better yet, collaborative experimentation. Historically, we note that with our colleagues Tuck Finch and Grant Krafft, we introduced evidence that small soluble oligomers of the fibrillogenic Aβ peptide could be potent CNS neurotoxins, capable of rapidly attacking synaptic plasticity (LTP) and ultimately killing neurons (Lambert et al., 1998). We coined the ADDL nomenclature to distinguish globular oligomeric toxins from fibrillar Aβ and to introduce a mechanism for dementia based on pathogenic ligand binding and disrupted signal transduction. Using conformation-specific antibodies generated by ADDLs (Lambert et al., 2001), we found that Alzheimer’s-affected human brain (Gong et al., 2003) and CSF (Georganopoulou et al., 2005) present significantly elevated ADDL levels.
The relationship between various oligomers needs further investigation, but synthetic and brain-derived ADDLs show overlapping features. Both show prominent 12mers (54 kDa) that react with the conformation-specific antibodies (Gong et al., 2003). Both bind with great specificity to particular synapses, acting as gain-of-function pathogenic ligands (Lacor et al., 2004). Both stimulate AD-type tau hyperphosphorylation (De Felice et al., 2007). Given the structural diversity of Aβ oligomers (Chromy et al., 2003), we are open-minded about the possibility that distinct brain-derived oligomers could interact differentially with brain cells to produce unique aspects of neural damage.
View all comments by Fernanda De Felice
View all comments by William Klein
View all comments by Wei-Qin Zhao |
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Related News: IGF-1 Disappoints in Trials for AD, ALS
Comment by: Deborah Gattoni
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Submitted 20 December 2008
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Posted 23 December 2008
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It would be appropriate to try doing a trial of IGF-1 BP3
(Iplex) at a
higher dose. As ALS patients, many of us do not have two years
to waste on
stupidity. I used Iplex briefly before the lawsuit rendered it
unavailable. My "anecdotal" evidence supported slight improvement
in a short period of
time. Worth a shot when it comes to people waiting to die,
isn't it?
View all comments by Deborah Gattoni |
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Related News: Peptide Brace Against AD—Insulin, Neuropeptide Y Tame Aβ Toxicity
Comment by: Tony Turner
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Submitted 17 February 2009
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Posted 2 March 2009
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The comment that the cleavage of neuropeptide Y to generate a biologically active fragment by neprilysin (Neutral EndoPeptidase-24.11) is the first such example for the enzyme is incorrect. At least one example has previously been reported in the metabolism of calcitonin gene-related peptide (CGRP) (Davies et al., 1992).
References: Davies D, Medeiros MS, Keen J, Turner AJ, Haynes LW. Endopeptidase-24.11 cleaves a chemotactic factor from alpha-calcitonin gene-related peptide. Biochem Pharmacol. 1992 Apr 15;43(8):1753-6. Abstract
View all comments by Tony Turner |
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Related News: Boston: Drug Development Strategies for Neuro Diseases
Comment by: Ashley Bush
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Submitted 29 April 2009
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Posted 29 April 2009
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Barry Greenberg is quoted as saying “...[NAP] and Dimebon are the only [drugs] that have been reported in Phase 2 to improve patients over background rather than just slow the rate of decline....”
PBT2 should be added to this small but important list. It improved cognitive function above baseline within 12 weeks in a recent Phase 2 trial.
Ashley Bush on behalf of the PBT2 study group.
References:
Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW; PBT2-201-EURO study group. Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial.
Lancet Neurology 2008; 7, 779-786. Abstract
View all comments by Ashley Bush |
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Related News: Medical Foods—Fallback Option for Elusive AD Drug Status?
Comment by: Suzanne Craft (Disclosure)
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Submitted 14 October 2009
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Posted 14 October 2009
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As noted in this interesting article, I think the approach of supplying alternate forms of bioenergetic substrates to patients with Alzheimer disease is worth further exploration, and future studies must be designed and powered to test a differential APOE response, which we have observed in our own studies of insulin/energy-modulating agents. In the interest of full disclosure, as the article described, I received a small grant from Accera to conduct an acute dosing study of an MCT formulation in 2004; additionally, I also serve as a consultant for Accera, a fact that was not mentioned in the article. View all comments by Suzanne Craft |
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Related News: Medical Foods—Fallback Option for Elusive AD Drug Status?
Comment by: Steve Orndorff (Disclosure)
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Submitted 28 October 2009
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Posted 30 October 2009
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The premise of this article is the notion that companies are using the medical food route as a “fallback” or backup strategy if their drug compound fails in the clinic. As I will discuss below, this premise is flawed. I wish to point out that this was never the intent for Axona (AC-1202). As I stated in the Tangled Neuron interview, Axona was originally intended to be a surrogate for testing our new therapeutic approach (ketone treatment for neuronal hypometabolism) in AD patients so the company could secure venture funding for its drug development platform.
Based on our research, we found evidence that the dietary addition of ketones can delay and reduce the magnitude of cognitive dysfunction in patients with mild to moderate AD and can be an effective part of the dietary management of the disease. As a result, we concluded that the product could be appropriately marketed as a medical food.
The company never filed an IND for Axona or intended to develop it as a drug. However, we did perform our clinical studies to pharmaceutical standards with industry and FDA-accepted...
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The premise of this article is the notion that companies are using the medical food route as a “fallback” or backup strategy if their drug compound fails in the clinic. As I will discuss below, this premise is flawed. I wish to point out that this was never the intent for Axona (AC-1202). As I stated in the Tangled Neuron interview, Axona was originally intended to be a surrogate for testing our new therapeutic approach (ketone treatment for neuronal hypometabolism) in AD patients so the company could secure venture funding for its drug development platform.
Based on our research, we found evidence that the dietary addition of ketones can delay and reduce the magnitude of cognitive dysfunction in patients with mild to moderate AD and can be an effective part of the dietary management of the disease. As a result, we concluded that the product could be appropriately marketed as a medical food.
The company never filed an IND for Axona or intended to develop it as a drug. However, we did perform our clinical studies to pharmaceutical standards with industry and FDA-accepted outcomes for safety and efficacy. These data have been presented at major scientific conferences such as AAN and ICAD, and have been reviewed by internationally acclaimed experts on AD. The clinical data are also incorporated into our 10,000+ page product dossier that supports its positioning as a medical food.
As a result of our laboratory and clinical studies with Axona during the past seven years we now have two preclinical New Chemical Entity compounds in development as drugs that work through the ketosis therapeutic mechanism.
In terms of the article’s overall premise, there were some significant inaccuracies. First, NCEs and drug products cannot be marketed as medical food since medical food must meet the general food requirement of having ingredients that are either GRAS or approved food additives. Additionally, as noted in the Q&A with Sue Anderson from the FDA, medical food “is not a product that is merely provided to sick people … It is a formulated product that contains ingredients shown to be directly linked biochemically or metabolically to the disease or condition in humans.” I would also note that Vivimind (aka Alzhemed) is a dietary supplement, not a medical food. Supplements and medical food have distinct definitions and regulatory requirements. We are not aware of any examples of a product in the marketplace that was switched from drug development to medical food.
While it is true that medical food is not required to report adverse events to FDA, this statement holds true for all food products. Nevertheless, Accera has in place a full medical information and safety system that compiles safety-related information and relays all serious adverse events via MedWatch to the FDA. We believe this is a responsible way to identify and address potential side effects and drug interactions in an elderly patient population that often has many comorbidities.
Lastly, I wish to point out that the discussion of “what’s in a label” shows a fundamental misunderstanding of the key features that distinguish a medical food from a drug. As Ms. Anderson notes in the Q&A discussion, the product’s intended use and the provision of nutritional support distinguish medical food from a drug. In other words, to be considered a medical food, a product must be intended for the specific dietary management of a disease or condition and must be an integral part of the clinical treatment of patients. It may not, however, state or imply that the product treats, cures, or prevents a disease. Those are drug claims. To imply that the Axona label is insufficient or indicates that the product failed drug trials is simply inaccurate. The Axona label appropriately reflects the product’s intended use as a medical food.
View all comments by Steve Orndorff |
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Related News: Medical Foods—Fallback Option for Elusive AD Drug Status?
Comment by: Frederic Calon
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Submitted 12 November 2009
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Posted 12 November 2009
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I think it would have been a major advantage to get Ketasyn/AC1202 FDA-approved as a drug. Ketasyn/AC1202 could have then been used by health professionals and prescribed to the right persons. There is a strong rationale in using medium chain triglycerides (MTCs) as a source of ketone bodies to boost brain metabolism. It is likely that certain specific patients in “energy crisis”, such as very old persons for example, could benefit from MCTs. Unfortunately, the use of Ketasyn/AC1202 as a medical food will dilute its true therapeutic benefit.
In summary, I might be wrong but I think Ketasyn would have had more chance to achieve its full therapeutic potential as a drug than as a medical food.
View all comments by Frederic Calon |
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Related News: ApoE and Brain Networks—The Anatomy of a Risk Factor
Comment by: Robert Peers
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Submitted 2 June 2010
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Posted 2 June 2010
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 I recommend the Primary Papers
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Related News: Honolulu: Intranasal Insulin Trial Claims Promise in MCI, AD
Comment by: J. Lucy Boyd
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Submitted 12 August 2010
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Posted 12 August 2010
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I look forward to Phase 3 trial results. I think many of us have dismissed the fact that insulin might play a role in dementia, instead looking only at hyperglycemia and its devastating effects throughout the body. We've known that obesity and diabetes harm brain function long-term, without properly considering that low levels of insulin might be damaging to memory or brain function—something that can be corrected more easily than getting a generation of people to stick to their ideal body weight. View all comments by J. Lucy Boyd |
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