We invite you to participate in this offline Forum discussion led by Vincent Marchesi of Yale University. A close observer of the AD field, Marchesi regularly contributes commentary and original hypotheses. Here he invites researchers to consider and critique a new idea on a mechanism driven by oxidative stress that could bridge a knowledge gap between some rare genetic forms of AD and some cases of the common sporadic forms of the disease. How can this hypothesis be tested? Have you already worked on similar ideas, and have some preliminary data to share? Is this a new link between oxidative mechanisms and specific targets in AD? Or has the hypothesis been proposed previously, tested, and found wanting?—Gabrielle Strobel.

View Comments By:
Pablo Dolz — Posted 15 January 2008
Tao Lu, Bruce Yankner — Posted 1 February 2008
Michael Lardelli — Posted 5 February 2008
Vincent Marchesi — Posted 11 February 2008
Mark A. Smith, Hyoung-gon Lee, Rudy Castellani, George Perry, Akihiko Nunomura, Xiongwei Zhu, Paula Moreira — Posted 28 February 2008

By Vincent Marchesi, Yale University
The single most convincing piece of evidence linking amyloid Aβ peptides to Alzheimer disease has come from the analysis of human mutants of the amyloid precursor protein (APP) and their obvious connections to rare familial forms of early-onset dementia. Here I am proposing a hypothesis that builds on this genetic data to offer a testable model for how some cases of sporadic AD might arise. First, a brief perspective on the known types of APP mutation.

Some of the different germ line mutations of APP that have been described are shown below.

APP Germ Line Mutations in Early-onset AD

 
Wt. KM DAEFRHDSGYEVHHQKLVFFA ED VGSNKGAIIGLMVGGVVIAT VIV

Swe NI                 Dutch QD               French MIV           
                     Italian KD              Florida VVV
                        Iowa EN              Indiana VIL
                      Arctic GD               London VII

APP Mutations That Affect Wild-type Aβ
We now know that these mutations either affect the rates of Aβ production and/or accumulation, or they generate potentially toxic forms of Aβ peptides. The mutations that coincide with sites where the secretases cleave APP almost certainly affect production of the Aβ peptides, while others are not associated with any known cleavage sites and do not appear to result in overproduction of their peptides in experimental animals.

One of the first and most important APP mutations studied, and still widely used to induce AD-like syndromes in experimental animals, is the so-called Swedish mutation. Two amino acids, lysine and methionine, at the site of β-secretase cleavage, are mutated to glutamine and leucine. The increased cleavage at this site is coupled in some unknown way to an increase in γ-secretase cleavage, resulting in the accumulation of the same Aβ peptide that is normally generated in the brain during physiologic synaptic transmission. These are generally referred to as wild-type Aβs. Another cluster of mutations has been described on APP sites related to γ-secretase cleavage, and they also produce increased amounts of wild-Aβ, presumably due to enhancement of γ-secretase activity. The site of γ-secretase cleavage of APP includes the amino acid sequence VIV, and this is changed in several mutants to MIV, VVV, VIL, VII, and others like them. Each of these changes involves a remarkably conservative shift of one hydrophobic amino acid to another. These are subtle changes in a polypeptide chain that is thought to be an α helical coil within the lipid bilayer. They suggest that the γ-secretase reaction is tightly regulated, which may account for the fact that so many diverse mutations in the presenilins affect Aβ production.

Aβ Oligomers as Toxic Factors
To understand how APP mutations that result in the accumulation of wild-type Aβ relate to the pathogenesis of dementia, many investigators have tried to determine why increased amounts of Aβ peptides are toxic to neurons. Since patients with late-stage AD have decreased numbers of neurons in critical areas of the brain, one idea was that too much Aβ is potentially toxic to neurons, although it was also recognized that Aβ peptides are likely to affect neuronal functions such as synaptic transmission before killing the cells.

One answer to the conundrum of why too much Aβ peptides could be toxic was the realization that they have a remarkable (and vexing) capacity to aggregate into higher forms once they are released from the lipid bilayer (1).

No one knows whether the cleaved peptides are released from the membrane as monomers or dimers, or whether they assemble into higher forms within the cytosol of neurons before they are released. Even the release mechanism is poorly defined. But two facts are clear. Aβ peptides do accumulate in the extracellular spaces of the brain, and, if they are present at high enough concentration, they are likely to aggregate into higher forms.

The question now is which of the many possible aggregation states that have been described is responsible for neuronal dysfunction? This is more than just academic interest, since many new therapies are being proposed based on the assumption that the most important targets have been identified. The question of which aggregation state is the toxic principle is complicated by how difficult it is to isolate and characterize the different forms, and the problem is compounded by their tendency to change from one form to another depending on experimental conditions. Two recent studies (2,3) show that oligomeric forms (also called ADDLs) of Aβ, composed of both natural and synthetic peptides, are not inherently toxic when added at low concentrations, contrary to earlier reports, but instead can effect subtle changes in dendritic spines of post-synaptic terminals. Such effects support the idea that Aβ aggregates can affect synaptic dysfunction without killing the neurons outright. A complicating feature of these studies was the fact that the natural Aβ peptides appeared to act as dimers and trimers (2), while the synthetic ones appeared to be much larger aggregates, ranging from 50 to100K (3). It is difficult to understand how two sets of oligomers of such varying size can act on the same membrane site unless there is in both cases an active element that has not yet been identified, in which case it would be premature to claim that the active element is one of the oligomers added to the system.

APP Mutations That Generate Toxic Aβs
A second set of APP mutants that cluster together, as shown above, has been described in families with early-onset AD. The families are scattered throughout the world and named after the sites of the founder families. These include Dutch, Iowa, and Arctic mutations (D/I/A), as well as others, and they generate Aβ peptides with unusual properties. These peptides are more fibrillogenic than regular Aβ, and they are relatively resistant to proteolytic digestion by neprilysin and IDE. Patients who have these mutations have extensive deposits of Aβ around their blood vessels, a condition known as cerebral amyloid angiopathy (CAA), which predisposes them to cerebral micro-hemorrhages in addition to the amyloid plaques seen in patients with sporadic AD. Many investigators (4-6) have found that transgenic mice that express versions of these APP mutants develop profound cerebral angiopathy with extensive deposits of altered Aβ. Unlike other transgenic animals that express mutant forms of APP or the presenilins, D/I/A mutant Aβ peptides are not overexpressed in brain tissue, nor can they be found in the blood of affected animals. Their remarkable capacity to localize around blood vessels marks them as potentially toxic vasculotropic agents.

These D/I/A-type mutations cluster at what might be called the "middle" segment of the Aβ domain of the APP molecule. These sites are not within the hydrophobic domain itself but are at what is presumed to be at a membrane surface interface. Peptides that are generated from these mutants have single amino acid substitutions, involving either a glutamic or aspartic residue. The relevant sequences of three of these mutant forms are given below. The changes in the Dutch/Iowa/Arctic forms involve a substitution of one of the two negatively charged amino acids, glutamic (E22) or aspartic (D23), to either a non-charged one or a lysine. Because of these amino acid changes, such peptides may not be able to fold into the same hairpin-like structures postulated for the native Aβ forms, since the latter are believed to be stabilized by long-range Coulombic interactions between Glu22/Asp23 and Lys28.

How these changes might contribute to increased aggregation propensity of the isolated peptides is not clear, but their increased toxicity is expressed both in the affected patients and in experimental animals. These A/I/D-type Aβ peptides have three properties that may enhance their toxicity: (i) they are resistant to proteolytic digestion by neprilysin and IDE (7); (ii) they collect around blood vessels (8); and (iii) they can damage vessel walls leading to amyloid angiopathy, which over time induces inflammatory and thrombotic complications. The accumulations of Aβ that concentrate around small blood vessels appear by histological analysis to resemble the amyloid angiopathy of small vessels that is commonly found in brains of sporadic AD patients.

Another important property of these peptides is their ability to enhance the fibrillization of wild-type Aβs both in vitro and in experimental animals. Large macromolecular complexes are created when the two forms are incubated together, and they have a discrete ultrastructure (9), an indication that these mixed forms are not simply non-specific aggregates.

Can Oxidative Stress Generate Toxic Forms of Aβ?
A close look at the amino acid sequences of these mutant peptides provides grounds for some interesting speculation as to how these rare germ line mutations might relate to the pathogenesis of sporadic AD. This speculation forms the core of my hypothesis. Each of the changes at the E, D sites shown above could be generated by a single base change in the coding sequence of either DNA or mRNA that involves either a G—C or a G—A switch. Oxidized guanine residues are well known to produce such transversions (10,11). Patients with sporadic AD would not normally have these changes in their germ line DNA, but specific guanine residues could be oxidized, either directly, by exposure to reactive oxygen species (ROS), or if the oxidized trinucleotide precursor, ox-GTP, was incorporated into the DNA during synthesis or repair. If ox-GTP is also incorporated into APP mRNA, it could conceivably lead to the production of Aβ peptides with the same toxic potential as the E, D germ line mutant forms.

How could this happen? It has been known for many years that large amounts of oxidatively modified RNA and lesser amounts of such DNA are present in neurons of AD patients (12,13) and even in patients with mild cognitive impairment (14). Guanine is widely regarded as the most sensitive of the bases to oxidative damage, and 8-OHG is produced, both as the oxidized triphosphonucleotide (8-OH-GTP) and in mRNA itself. A recent study shows that oxidized mRNA can direct the synthesis of polypeptide chains of varying length and changes in amino acid sequence (15). Others have reported high levels of oxidized mRNA in the brains of AD patients (16,17). If mRNAs that code for APP have oxidized guanines at appropriate sites, possibly at exposed loops, they could in principle code for APP molecules that contain one of the E, D changes. If specific guanines in the coding regions of APP DNA are modified, over time such DNA in long-lived neurons could generate substantial amounts of modified mRNAs.

One of the obvious objections to such a proposal is the low probability that enough mRNA that codes for modified APP will be generated at a level high enough to make a difference, and indeed studies of DNA samples from patients with sporadic AD have not detected such changes (18). But low levels of modified DNA that represent minor fractions of the total would not be detected by routine measurements, and for the same reason small amounts of modified Aβ would also escape detection by conventional methods. However, because of their resistance to degradation, small amounts of modified peptides could accumulate around blood vessels, possibly over decades, leading to destruction of small blood vessels and localized ischemic changes. They might also act through their capacity to enhance the fibrillization of wild-type Aβ. Cells also have well-developed DNA repair mechanisms, one being OGG1, an enzyme that specifically and efficiently removes oxo-guanine from modified DNA (19), and enzymes that hydrolyze oxidized triphosphonucleotides. While these activities would be expected to minimize the impact of oxidized guanine and other modified nucleotides, recent reports indicate that base excision repair mechanisms may be defective in a subset of AD patients (20) and even in the brains of those diagnosed with minimal cognitive impairment (21).

This idea that oxidized DNA or RNA might generate toxic forms of Aβ and other proteins has many interesting implications. It identifies specific targets for oxidative damage as a cause of dementia, long postulated by others (22), and raises the possibility that attempts to reduce levels of oxidized nucleotides through enzymes, which hydrolyze 8-ox-GTP, or other approaches that focus on anti-oxidation mechanisms should be pursued. If the modification is at the DNA level, which is likely, ways to enhance DNA repair might be pursued as new therapeutic initiatives. This discussion has focused largely on the possibility that toxic Aβ peptides might be generated through oxidative damage of two specific codons, but the same hypothetical argument could be applied to the other APP mutations, as well. Is it conceivable that somatic mutations can also be generated at sites that increase Aβ production?

References:
1. Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. Review. Abstract

2. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14;27(11):2866-75. Abstract

3. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem. 2007 Apr 13;282(15):11590-601. Abstract

4. Prelli F, Levy E, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays. Biochem Biophys Res Commun. 1990 Jul 16;170(1):301-7. Abstract

5. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Stürchler-Pierrat C, Bürki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004 Sep;7(9):954-60. Epub 2004 Aug 15. Abstract

6. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004 May 7;279(19):20296-306. Abstract

7. Tsubuki S, Takaki Y, Saido TC. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet. 2003 Jun 7;361(9373):1957-8. Abstract

8. Monro OR, Mackic JB, Yamada S, Segal MB, Ghiso J, Maurer C, Calero M, Frangione B, Zlokovic BV. Substitution at codon 22 reduces clearance of Alzheimer's amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into blood. Neurobiol Aging. 2002 May-Jun ;23(3):405-12. Abstract

9. Lashuel HA, Hartley DM, Petre BM, Wall JS, Simon MN, Walz T, Lansbury PT. Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores. J Mol Biol. 2003 Sep 26;332(4):795-808. Abstract

10. Cheng X, Kelso C, Hornak V, de los Santos C, Grollman AP, Simmerling C. Dynamic behavior of DNA base pairs containing 8-oxoguanine. J Am Chem Soc. 2005 Oct 12;127(40):13906-18. Abstract

11. Kamiya H, Suzuki A, Kawai K, Kasai H, Harashima H. Mutagenic properties of oxidized GTP and ATP in in vitro transcription-reverse transcription. Nucleic Acids Symp Ser (Oxf). 2006;(50):99-100. Abstract

12. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999 Mar 15;19(6):1959-64. Abstract

13. Sekiguchi M, Tsuzuki T. Oxidative nucleotide damage: consequences and prevention. Oncogene. 2002 Dec 16;21(58):8895-904. Abstract

14. Wang J, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem. 2006 Feb 1;96(3):825-32. Abstract

15. Tanaka M, Chock PB, Stadtman ER. Oxidized messenger RNA induces translation errors. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):66-71. Epub 2006 Dec 26. Abstract

16. Shan X, Tashiro H, Lin CL. The identification and characterization of oxidized RNAs in Alzheimer's disease. J Neurosci. 2003 Jun 15;23(12):4913-21. Abstract

17. Shan X, Lin CL. Quantification of oxidized RNAs in Alzheimer's disease. Neurobiol Aging. 2006 May 1;27(5):657-62. Abstract

18. Scacchi R, Gambina G, Moretto G, Corbo RM. A mutation screening by DHPLC of PSEN1 and APP genes reveals no significant variation associated with the sporadic late-onset form of Alzheimer's disease. Neurosci Lett. 2007 May 18;418(3):282-5. Abstract

19. David SS, O'Shea VL, Kundu S. Base-excision repair of oxidative DNA damage. Nature. 2007 Jun 21;447(7147):941-50. Abstract

20. Mao, G, Pan, X, Zhu, B-B, Zhang, Y, Yuan, F, Huang, J, Lovell, MA, Lee, MP, Markesbery, WR, Li, G-M, Gu, L (2007) Identification and characterization of OGG1 mutations in patients with Alzheimer's disease. Nucleic Acids Res. Advance Access published April 10, 2007, 1-8.

21. Weissman L, Jo DG, Sørensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, Bohr VA. Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res. 2007 Jan 1;35(16):5545-55. Abstract

22. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug 1;60(8):759-67. Abstract

	Comments on Live Discussion
	Comment by:  Pablo Dolz
	Submitted 14 January 2008  |  Permalink	Posted 15 January 2008
	This hypothesis can be merged with the fact that amyloid beta affects mitochondria, causing a rise of ROS as hydrogen peroxide. (Viña et al., 2007). Therefore, this would act as a feedback: little amounts of ROS would lead to the production of a mutated form of APP, which would be processed as amyloid beta, which would rise the amounts of ROS, an so on. This would make it more likely that the mutation escapes the repair mechanisms in normal brain. As AD is considered also a tauopathy, it would be interesting to see whether the DNA or mRNA encoding tau is also affected by ROS, and if this can enhance tau's hyperphosphorylation. References: Viña J, Lloret A, Vallés SL, Borrás C, Badía MC, Pallardó FV, Sastre J, Alonso MD. Mitochondrial oxidant signalling in Alzheimer's disease. J Alzheimers Dis. 2007 May;11(2):175-81. Abstract View all comments by Pablo Dolz
	Comment by:  Tao Lu, Bruce Yankner, ARF Advisor
	Submitted 1 February 2008  |  Permalink	Posted 1 February 2008
	The idea that age-related oxidative damage to DNA might introduce mutations into APP that affect its processing to Aβ is intriguing. This could occur through replication of DNA containing 8-oxoguanine introducing G:C to T:A transversion mutations, or by errors introduced through non-homologous end-joining. We tested this hypothesis by sequencing the Aβ region of APP transcripts cloned from AD cases and controls, including three young adults, three aged cognitively intact individuals, three individuals with MCI, and three with sporadic AD. Initially, we identified quite a few putative mRNA mutations in clones derived by RT-PCR. However, when we used very high-fidelity reverse transcriptase for the cloning, the putative mutations disappeared. Importantly, direct sequencing of APP exon 17 failed to reveal any somatic mutations in 97 clones. This does not rule out the possibility of somatic APP mutations, but suggests that the frequency in this region of the gene would have to be less than 1 percent. View all comments by Tao Lu View all comments by Bruce Yankner
	Comment by:  Michael Lardelli
	Submitted 3 February 2008  |  Permalink	Posted 5 February 2008
	Why focus on APP as a target for somatic mutation when PSEN1 (and PSEN2) represents arguably a better one? The target region for the proposed somatic mutation of APP is small compared to PSEN1, where missense mutations over a broad area of the coding frame promote Alzheimer disease. Focusing on PSEN1 rather than APP also explains more easily the hyperphosphorylation of tau. A recent paper (Chen et al., 2008) points out a number of interesting observations in its discussion: “…a fundamental issue is not whether Aβ is neurotoxic under certain experimental conditions, but whether the defined neurotoxicity is able to trigger AD neurodegeneration. As described above, the transgenic expression of FAD-linked PS1 mutations in the mouse could only produce partial AD phenotypes. Furthermore, this incomplete AD pathology did not significantly get worse following the increase in Aβ loading, such as coexpression of mutant APP/PS1 (Marjanska et al., [2005]; Lazarov et al., [2006]; van Groen et al., [2006]), APP/multiple PS mutations...  Read more Why focus on APP as a target for somatic mutation when PSEN1 (and PSEN2) represents arguably a better one? The target region for the proposed somatic mutation of APP is small compared to PSEN1, where missense mutations over a broad area of the coding frame promote Alzheimer disease. Focusing on PSEN1 rather than APP also explains more easily the hyperphosphorylation of tau. A recent paper (Chen et al., 2008) points out a number of interesting observations in its discussion: “…a fundamental issue is not whether Aβ is neurotoxic under certain experimental conditions, but whether the defined neurotoxicity is able to trigger AD neurodegeneration. As described above, the transgenic expression of FAD-linked PS1 mutations in the mouse could only produce partial AD phenotypes. Furthermore, this incomplete AD pathology did not significantly get worse following the increase in Aβ loading, such as coexpression of mutant APP/PS1 (Marjanska et al., [2005]; Lazarov et al., [2006]; van Groen et al., [2006]), APP/multiple PS mutations (Oakley et al., [2006]), or direct expression of Aβ peptide (McGowan et al., [2005]). It should be noted that the direct expression of the Aβ42 fragment in the mouse leads to a huge increase in Aβ42 deposition (more than 100-fold) in the brain (McGowan et al., [2005]).” There is now a growing appreciation that many of the mutations in PSEN1 causing familial Alzheimer disease may be hypomorphic, i.e., reduce PSEN1 activity; see Wolfe, 2007. Using a zebrafish model, we have recently shown that truncations of either zebrafish Psen1 or Psen2 protein in the region encoded by exon 7 can produce potent dominant- negative peptides that interfere with the activity of both Psen1 and Psen2 (Nornes et al., 2008). In effect, a somatic cellular event that creates the appropriate truncation of PSEN1 or PSEN2 protein (such as molecular misreading, aberrant splicing, de-novo mutation, etc.) could significantly reduce cellular presenilin activity, thus affecting the numerous signaling pathways and other processes that depend upon it. Conclusion: Maybe the AD research community needs to broaden its focus away from APP and Aβ and look at the presenilins. The 160+ mutations in the presenilins are telling us that reduced presenilin activity causes Alzheimer disease. This means that somatic changes that reduce presenilin activity in aging brains also have the potential to produce Alzheimer disease. The presenilins lie at the center of a complex web of cellular processes. Molecular data link the presenilins to both changes in Aβ production and tau phosphorylation, and so much more. Could reduced presenilin activity be a common factor connecting familial and sporadic Alzheimer disease? [Editor’s note: For more on this topic, see Presenilin Loss of Function—Plan B for AD?]. View all comments by Michael Lardelli
	Comment by:  Vincent Marchesi, ARF Advisor
	Submitted 10 February 2008  |  Permalink	Posted 11 February 2008
	Dr. Nardelli may have heard of the infamous Willie Sutton, a notorious American bank robber. When caught by the police, he was asked why he robbed banks so often. He replied "because that's where the money is". Many of us focus on APP and Aβ for obvious reasons, but Dr. Lardelli does raise an interesting point. Since presenilins seem so susceptible to germ line mutations, why aren’t they also prone to somatic ones? My own feeling is that in the case of AD, presenilin mutations seem to be expressed through their effects on Aβ production. If they do have other consequences that contribute to disease, independent of APP, I would expect the 160 plus mutations that have been described to have other non-APP related effects, since the presenilins seem to be involved in so many different intramembraneous cleavages. View all comments by Vincent Marchesi
	Comment by:  Rudy Castellani, Hyoung-gon Lee, Paula Moreira, Akihiko Nunomura, George Perry, ARF Advisor (Disclosure), Mark A. Smith (Disclosure), Xiongwei Zhu
	Submitted 28 February 2008  |  Permalink	Posted 28 February 2008
	Comment by George Perry, Akihiko Nunomura, Paula I. Moreira, Rudy J. Castellani, Hyoung-gon Lee, Xiongwei Zhu, Mark A. Smith Alzheimer in the Wind The focus of Alzheimer disease (AD) research, as well as research into most diseases, has been the determination of the most solid foundation of biology: genes. Alternately, Vincent Marchesi proposes something as ephemeral as an oxidizing breeze as the culprit. While genetic material is involved, it is RNA that is at the center—rRNA as well as mRNA. Instead of deterministic changes, Marchesi proposes that the balance between sickness and health rests with the accumulation of errors, and that it is the ratio of errors that determines the fate of our brain as we age. This is a little disheartening for reductionism and the black box of genetic mutations and Aβ oligomers. However, seen in the context of the aging process, accumulation of random errors tied to lifestyle and environment is about the only thing we know about aging and perhaps, according to Marchesi, its most common mind-robbing disease, i.e.,...  Read more Comment by George Perry, Akihiko Nunomura, Paula I. Moreira, Rudy J. Castellani, Hyoung-gon Lee, Xiongwei Zhu, Mark A. Smith Alzheimer in the Wind The focus of Alzheimer disease (AD) research, as well as research into most diseases, has been the determination of the most solid foundation of biology: genes. Alternately, Vincent Marchesi proposes something as ephemeral as an oxidizing breeze as the culprit. While genetic material is involved, it is RNA that is at the center—rRNA as well as mRNA. Instead of deterministic changes, Marchesi proposes that the balance between sickness and health rests with the accumulation of errors, and that it is the ratio of errors that determines the fate of our brain as we age. This is a little disheartening for reductionism and the black box of genetic mutations and Aβ oligomers. However, seen in the context of the aging process, accumulation of random errors tied to lifestyle and environment is about the only thing we know about aging and perhaps, according to Marchesi, its most common mind-robbing disease, i.e., AD. Supporting Marchesi’s assertion is the elegant work of Fred van Leeuwen showing an increase in +1 mutations in proteins in AD (van Leeuwen et al., 1998). +1 mutations mark random errors in protein sequence, just like those likely to result from oxidative damage to RNA species. How cells handle these random errors, especially their degradation, is poorly understood but likely to lead to far greater pleiotropic changes than mutations that support normal human development to late middle age (Honda et al., 2005). Instead, the random RNA errors accumulate with age-dependent oxidative damage (Nunomura et al., 1999; Nunomura et al., 2001). Marchesi’s theory is consistent with the latest understanding of age-related disease, i.e., the pleiotropic accumulation of multiple failures closely linked to the aging process and biological senescence. As such, treatments must address changing the subtle events linked to diet, exercise, brain activity, and inflammatory and oxidative processes that likely serve as the tipping point from physiology to pathology. References: Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, Hattier T, Harris PL, Siedlak SL, Fujioka H, Liu Q, Moreira PI, Miller FP, Nunomura A, Shimohama S, Perry G. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem. 2005 Jun 3;280(22):20978-86. Abstract Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug 1;60(8):759-67. Abstract Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999 Mar 15;19(6):1959-64. Abstract van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. Abstract View all comments by Rudy Castellani View all comments by Hyoung-gon Lee View all comments by Paula Moreira View all comments by Akihiko Nunomura View all comments by George Perry View all comments by Mark A. Smith View all comments by Xiongwei Zhu

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