Kummer MP, Hermes M, Delekarte A, Hammerschmidt T, Kumar S, Terwel D, Walter J, Pape HC, König S, Roeber S, Jessen F, Klockgether T, Korte M, Heneka MT. Nitration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation. Neuron. 2011 Sep 8;71(5):833-44. PubMed.
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Duke University Medical Center and Cognosci
The Case for Personalized Alzheimer’s Medicine
Heneka and colleagues’ new report on the involvement of nitric oxide (NO) in Alzheimer’s disease (AD) serves to further underscore the need for properly matching the treatment to the unique patient. They report that APP/PS1 transgenic mice develop robust amyloid plaque pathology containing amyloid-β peptide (Aβ) that is modified by nitration of tyrosine at position 10. As did previous groups (Smith et al., 1997), they also find 3-nitrotyrosine-modified (3-NTyr) Aβ in the brains of AD patients and suggest that modifications to Aβ can seed or stimulate plaque formation. Similar to our earlier reports (Vitek et al., 1994; Smith et al., 1995), they also find that post-translational modifications of Aβ appear to occur at relatively younger ages when pathology is thought to begin developing. Interestingly, while deposited Aβ does appear to increase with time, the amount of nitrotyrosine-Aβ does not increase over time in this model. These data provoke the question of how nitric oxide, nitrative stress, and Aβ interact over the course of the disease.
At this point, there are simply many critical questions with no unambiguous answers. For example, it is not even clear if brain iNOS activity is meaningfully increased, particularly in humans, or if NO production is maintained in AD, if NO is, in fact, the sole product of iNOS activation. Coupled with the lack of arginine due to increased arginase 1 expression, NOS actually generates superoxide anion. It is not clear if iNOS is increased only at certain disease stages, or if the levels of NO generated by iNOS in vivo are sufficient to have the modifying effects demonstrated by direct application of nitrating/oxidizing agents to a protein. Furthermore, nitration of amino acids does not require enzymatically generated NO. It is now well known that 3-nitrotyrosine adducts can be formed by nitrite, hydrogen peroxide, and free metals, as well as by mechanisms that incorporate peroxidase activity (Thomas et al., 2002; Thomas et al., 2006). In AD or in mouse models of AD, the accumulation of Aβ fibrils that are also well known to bind to and produce a surface for reactive metals such as iron and copper (Dikalov et al., 2004) are highly likely to facilitate non-enzymatic nitration processes. That the 3-NTyr Aβ residue was localized to the core of the plaques in the present study further supports this possibility. In fact, because NO can be rapidly scavenged by superoxide anion, Aβ-mediated reactions are a mechanism by which bioavailability of NO is reduced and critical growth supporting/survival mechanisms mediated by NO are compromised. This loss of NO may account for the failure to observe an increase in 3-NTyr Aβ at the nine-month time point as shown in Figure 2.
With strong evidence that 3-NTyr-Aβ can stimulate aggregation and deposition of plaques, the experiments turn to understanding the consequences of removing nitric oxide from these APP/PS1 mice. Using both genetic knockout of the NOS2 gene, and the L-NIL inhibitor of iNOS, they find decreased 3-NTyr-Aβ, decreased Aβ deposits, and improved performance on a radial arm maze behavioral task with no change in tau pathology or neuronal loss reported. These findings are in stark contrast to our publications where APP transgenic mice on a NOS2 knockout background (Tg2576/NOS2 knockout or APP-SwDI/NOS2 knockout and, most recently, the 5xFAD/NOS2 knockout) develop robust plaque pathology, phospho-tau deposits, neuronal loss, and behavioral deficits (Colton et al., 2006; Wilcock et al., 2008; Colton et al., 2008). We’d like to note what we consider an inaccuracy in the paper’s discussion on this point. First, we do not see improved behavioral effects in our mouse models; rather, we see severe behavioral impairment with APP/NOS2-/-. Second, the concept of altered microglia was simply one of multiple possibilities given to explain the variance in data between Nathan et al., 2005, and our own. Similar to Nathan’s report that amyloid pathology of an APP/PS1 mouse was significantly reduced when placed on a NOS2 knockout background, the main difference between Heneka’s and our work is the presence of a mutated presenilin-1 gene. Given the contrasting findings, we conclude that the mutated PS1 gene is responsible for a differential response to the nitric oxide environment.
Mutated PS1 genes are found in less than 1 percent of all Alzheimer’s patients. Heneka and Nathan’s work suggests, importantly, that inhibitors of nitric oxide synthase may be appropriate for these patients. For the other 99 percent, our work clearly shows that nitric oxide exerts a protective effect that reduces plaque and tangle burdens, reduces neuronal loss, and improves behavior. With the ability to rapidly diagnose the presence of non-mutated and mutated PS1 genes in suspected AD patients, the field is poised to directly test the risks and benefits of NOS inhibitors and nitric oxide donors as potential therapies for this devastating disease.
References:
Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci. 1997 Apr 15;17(8):2653-7. PubMed.
Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4766-70. PubMed.
Smith MA, Sayre LM, Vitek MP, Monnier VM, Perry G. Early AGEing and Alzheimer's. Nature. 1995 Mar 23;374(6520):316. PubMed.
Thomas DD, Espey MG, Vitek MP, Miranda KM, Wink DA. Protein nitration is mediated by heme and free metals through Fenton-type chemistry: an alternative to the NO/O2- reaction. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12691-6. PubMed.
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Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Weinberg B, Dawson H. NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12867-72. PubMed.
Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA. Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci. 2008 Feb 13;28(7):1537-45. PubMed.
Colton CA, Wilcock DM, Wink DA, Davis J, Van Nostrand WE, Vitek MP. The effects of NOS2 gene deletion on mice expressing mutated human AbetaPP. J Alzheimers Dis. 2008 Dec;15(4):571-87. PubMed.
Nathan C, Calingasan N, Nezezon J, Ding A, Lucia MS, La Perle K, Fuortes M, Lin M, Ehrt S, Kwon NS, Chen J, Vodovotz Y, Kipiani K, Beal MF. Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase. J Exp Med. 2005 Nov 7;202(9):1163-9. PubMed.
Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE Tübingen
This is a very nice study by Heneka et al. Before readers reach conclusions about the nature of the amyloidogenic seed, I'd like to offer a note of caution. The authors used 0.25 mg/ml synthetic or synthetic nitrated Aβ. This is at least 50 times more Aβ than what is in the brain extract that we used for seeding in Meyer-Luehmann et al., 2006 (see Figure 4). Moreover, the brain extract we used induced much more amyloid induction than what is reported here; 0.25 mg/ml is 50,000 times more Aβ than what is contained in a 100,000 g supernatant of a brain, which also has significant seeding capacity (Langer et al., in press).
We also once used 0.5 mg/ml synthetic Aβ in Meyer-Luehmann et al. (supplemental Table). With that we also saw some amyloid after a four-month incubation period, but this was in large part the injected material similar to that reported in Heneka et al. However, in Heneka et al. it is very interesting to see some endogenous Aβ binding (or co-aggregating) to the injected nitrated Aβ.
Thus, in my view, from the presented results, the nitrated Aβ cannot (yet) be considered the magic seeding bullet, and more studies are necessary. But this is a very interesting paper.
References:
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.
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