This paper is clealry of importance because of the prominent neurodegeneration induced by complement inhibition. It would be interesting to know what type of degeneration was seen, whether it involves cytoskeletal pathology, cell cycle abnormalities, and whether specific populations of neurons proximal or distal to plaques were affected.

View all comments by Inez Vincent

The paper by Lemere and colleagues provides further evidence for the role that the complement system plays in inflammation generally, and in Aβ phagocytosis particularly. The group developed a double transgenic APP and complement C3-deficient mouse model (APP;C3-/-). The researchers then found, as one might expect, increased Aβ deposition in 17-month-old, but not 8- and 12-month-old mice, and a shift in microglial phenotype. Their results are in accord with previous results of Wyss-Coray et al. (Wyss-Coray et al., 2002), who used the slightly different strategy of developing transgenic mice overexpressing the soluble complement receptor-related protein y (sCrry) to inhibit complement. Based on such data, one might suppose that complement activation, as an important facilitator of Aβ clearance, should be stimulated to provide benefit in AD. Such stimulation can be provided by vaccination with Aβ. For transgenic mice, this is indeed the case: vaccination with Aβ produces a dramatic reduction in the Aβ load.

But there are crucial...  Read more

The paper by Lemere and colleagues provides further evidence for the role that the complement system plays in inflammation generally, and in Aβ phagocytosis particularly. The group developed a double transgenic APP and complement C3-deficient mouse model (APP;C3-/-). The researchers then found, as one might expect, increased Aβ deposition in 17-month-old, but not 8- and 12-month-old mice, and a shift in microglial phenotype. Their results are in accord with previous results of Wyss-Coray et al. (Wyss-Coray et al., 2002), who used the slightly different strategy of developing transgenic mice overexpressing the soluble complement receptor-related protein y (sCrry) to inhibit complement. Based on such data, one might suppose that complement activation, as an important facilitator of Aβ clearance, should be stimulated to provide benefit in AD. Such stimulation can be provided by vaccination with Aβ. For transgenic mice, this is indeed the case: vaccination with Aβ produces a dramatic reduction in the Aβ load.

But there are crucial differences between these transgenic models and AD. Human Aβ powerfully activates human complement (Rogers et al., 1992) but not mouse complement. This is due to weaker binding of mouse C1q to human Aβ (Webster et al., 1999). The differences are manifested in weaker complement activation overall in transgenic mice. Mouse Aβ deposits are opsonized, but the membrane attack complex is not assembled (Schwab et al., 2004). In human AD, opsonization of Aβ plaques occurs alongside assembly of the membrane attack complex. These events can be visualized damaging nerve fibers in and around senile plaques (McGeer et al., 1989; Akiyama et al., 2000). Thus, complement, though beneficial in AD mouse models, is a potent neurotoxic agent in AD. As a result, vaccination with Aβ in AD can be expected to stimulate more complement activation and to enhance the damaging effects of the membrane attack complex. That was observed in the clinical trial of Wyeth/Elan’s AN1792 vaccine. The trial was canceled, but many more vaccination strategies have since been developed. These can be expected to produce the same kinds of side effects unless the consequences of enhanced assembly of the membrane attack complex can be overcome (McGeer and McGeer, 2003).

View all comments by P.L. McGeer

This is a very timely and important paper that supports a more sophisticated view of the role of inflammation in amyloid deposition. Ten years ago, most in the Alzheimer research community believed that inflammation was part of the pathogenic mechanism in AD. However, increasingly, literature from the APP mice argues that the classical, M1 form of inflammation with IL-1 and TNFα expression can motivate microglia/macrophages to clear amyloid plaques. Studies ranging from LPS injections to complement inhibition (as in Maier et al.) to IL-1 overexpression demonstrate Aβ reductions associated with microglial activation (DiCarlo et al., 2001; Shaftel et al., 2007). Instead, it appears that it is the alternative, or M2 activation state of microglia, that is associated with toxicity. A key proponent of this perspective has been Carol Colton, who demonstrated increased expression of type 2 markers in AD and APP mouse brains, and enhanced toxicity when iNOS, a traditional M1 protein, was knocked out in APP mice (Colton et al., 2006a; Colton et al., 2006b). It appears that anti-Aβ...  Read more

This is a very timely and important paper that supports a more sophisticated view of the role of inflammation in amyloid deposition. Ten years ago, most in the Alzheimer research community believed that inflammation was part of the pathogenic mechanism in AD. However, increasingly, literature from the APP mice argues that the classical, M1 form of inflammation with IL-1 and TNFα expression can motivate microglia/macrophages to clear amyloid plaques. Studies ranging from LPS injections to complement inhibition (as in Maier et al.) to IL-1 overexpression demonstrate Aβ reductions associated with microglial activation (DiCarlo et al., 2001; Shaftel et al., 2007). Instead, it appears that it is the alternative, or M2 activation state of microglia, that is associated with toxicity. A key proponent of this perspective has been Carol Colton, who demonstrated increased expression of type 2 markers in AD and APP mouse brains, and enhanced toxicity when iNOS, a traditional M1 protein, was knocked out in APP mice (Colton et al., 2006a; Colton et al., 2006b). It appears that anti-Aβ immunotherapy can shift the microglial activation state from the M1 phenotype to the M2 phenotype, possibly explaining some of its actions.

Although most data supporting a beneficial role for microglial activation come from mouse models of amyloid deposition, the recent failure of the ADAPT trial of AD prevention with NSAIDs can also be consistent with this perspective (ADAPT Research Group et al., 2007). One of the key links in the argument for inflammation being pathogenic in AD is the reduced rate of dementia in those using NSAIDs. The assumption is this reflects protection due to use of the drug. However, it may equally be the case that the drug use signals individuals who are prone to inflammation. If this were true, drug use may identify these folks, but if anything, to the extent they entered brain, the NSAIDs might thwart the protective effects of the proinflammatory trait. When administered randomly, rather than by self-selection, ADAPT found that NSAIDs increased the risk of AD (in those who did not already have the disease).

Another intriguing feature of this manuscript is the appearance of neuron loss. APP mice have generally been regarded as having modest neuron loss at best. However, using more sophisticated methods, and genetic manipulations in mice, amyloid-dependent neuron toxicity is emerging in this and other models (O'Neil et al., 2007; Wilcock et al., 2008).

The real question is the extent to which this will translate to the human circumstance. AD is more than simply amyloid deposition, and the role of inflammation in the other pathologies associated with the disease will be important to determine. For this reason, the tauopathy mice that have pronounced neuronal loss will be important new models in which to evaluate these same manipulations for their potential role in preventing or exacerbating the tauopathy and neurotoxicity.

References:
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP (2006a) Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 3:27:27. Abstract

Colton CA, Vitek MP, Wink DA, Xu Q, Cantillana V, Previti ML, Van Nostrand WE, Weinberg JB, Dawson H (2006b) NO synthase 2 (NOS2) deletion promotes multiple pathologies in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 103:12867-12872. Abstract

DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D (2001) Intrahippocampal LPS injections reduce Aá load in APP+PS1 transgenic mice. Neurobiol Aging 22:1007-1012. Abstract

ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M (2007) Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68:1800-1808. Abstract

O'Neil JN, Mouton PR, Tizabi Y, Ottinger MA, Lei DL, Ingram DK, Manaye KF (2007) Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice. J Chem Neuroanat 34:102-107. Abstract

Shaftel SS, Kyrkanides S, Olschowka JA, Miller JN, Johnson RE, O'Banion MK (2007) Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J Clin Invest 117:1595-1604. Abstract

Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA (2008) 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 28:1537-1545. Abstract

View all comments by Dave Morgan

It would be nice to see Andrea Tenner weigh in on this discussion. She has created a mouse with "humanized" C1q. Contrary to expectations, that study indicated there are no important differences in how Aβ interacts with C1q in humans and rodents (Li et al., 2008). She also showed that addition of C1q to cultured neurons could protect against Aβ toxicity (Pisalyaput and Tenner, 2008). The latter, if I may say so, complements the papers discussed above.

References:
Li M, Ager RR, Fraser DA, Tjokro NO, Tenner AJ. 2008. Development of a humanized C1q A chain knock-in mouse: Assessment of antibody independent ss-amyloid induced complement activation. Mol Immunol. 45:3244-52. Abstract

Pisalyaput K, Tenner AJ. 2008. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 104:696-707. Abstract

View all comments by Steve Barger

The paper by Maier, Lemere, and colleagues (2008) provides an extension of previous findings by Wyss-Coray, Masliah, and coworkers (2002) showing that inhibiting the complement cascade in aged AD model mice (in the former case by knocking out C3; in the latter by expressing the complement inhibitor, soluble complement receptor-related protein y) promotes cerebral amyloidosis, as judged by Aβ plaque load and biochemical analysis of insoluble Aβ. Maier and colleagues further noted a trend toward increased Aβ levels in blood plasma from cross-bred (APP;C3-/-) mice, reduced NeuN-positivity in crossed mouse hippocampal pyramidal neurons, and an increase in more “anti-inflammatory” microglia. These results add to the emerging complex picture of brain inflammation in the context of AD-like pathology, and offer additional insight into the beneficial role of the complement cascade in these transgenic AD model mice.

This interesting work by Maier et al. raises a number of questions regarding the interplay between innate immune cells (i.e., microglia and macrophages) and AD-like...  Read more

The paper by Maier, Lemere, and colleagues (2008) provides an extension of previous findings by Wyss-Coray, Masliah, and coworkers (2002) showing that inhibiting the complement cascade in aged AD model mice (in the former case by knocking out C3; in the latter by expressing the complement inhibitor, soluble complement receptor-related protein y) promotes cerebral amyloidosis, as judged by Aβ plaque load and biochemical analysis of insoluble Aβ. Maier and colleagues further noted a trend toward increased Aβ levels in blood plasma from cross-bred (APP;C3-/-) mice, reduced NeuN-positivity in crossed mouse hippocampal pyramidal neurons, and an increase in more “anti-inflammatory” microglia. These results add to the emerging complex picture of brain inflammation in the context of AD-like pathology, and offer additional insight into the beneficial role of the complement cascade in these transgenic AD model mice.

This interesting work by Maier et al. raises a number of questions regarding the interplay between innate immune cells (i.e., microglia and macrophages) and AD-like pathology. It is somewhat unfortunate that multiplex immunofluorescence and/or FACS analysis could not be performed on the CD45-positive microglia/macrophages that the authors show to be increased in brains of their crossed mice. Due to poor antigenicity of paraffin-embedded brain tissue, the authors instead performed Western blots for F4/80 Ag and macrosialin (CD68), and found a trend toward reduction of these proteins in crossed mice. However, it is unclear whether these reductions correspond to the same CD45-positive microglial population or another population of CNS-resident microglia or pericytes, or perhaps invading monocytes/macrophages. Did the authors note vascular cuffing in these crossed mice or otherwise detect presence of blood-borne macrophages?

While the biological role of F4/80 Ag (a member of the epidermal growth factor transmembrane 7 family) remains unclear (a controversial role has been proposed in promoting T cell tolerance; see van den Berg and Kraal, 2005), macrosialin’s location in late endosomes of innate immune cells, together with its belonging to the LAMP/scavenger receptor family, suggests that it plays a role in phagocytosis (Wong et al., 2005). This agrees well with the findings of Maier and colleagues, if we assume that microglia are at least partially efficient at phagocytosing/clearing Aβ in mouse models of the disease, and that CD68 plays a role in promoting microglial Aβ uptake/clearance. The authors also show significant reduction in iNOS and TNFα, and a significant increase in IL-4 in these crossed mice (IL-10 trended toward increased in crossed mice as well). Based on these alterations in innate immune molecules, the authors conclude that microglial/macrophage activation is shifted toward a more alternate (anti-inflammatory or M2) form. I’m just not sure that we know enough yet about the immunology of these rather enigmatic innate immune cells to begin to classify them into distinct, well-defined, biologically meaningful subgroups. We have previously suggested that microglia/macrophage “activation” is better defined in terms of a continuum of responses, ranging from pro-inflammatory/anti-phagocytic to anti-inflammatory/pro-phagocytic, including intermediate phenotypes that have properties of both ends of the spectrum (Town et al., 2005). Of course, such taxonomy is further complicated by multiple functionally distinct subpopulations of microglia/macrophages, defined by markers such as CD11b and Ly-6C (à la Geissmann and colleagues, 2003).

I wanted to comment on a few points raised by Dave Morgan regarding LPS administration to AD model mice and also the ADAPT trial. It is interesting to note that an acute (single intra-hippocampal injection) of LPS increased reactive microglia (as defined by MHC II immunoreactivity) in AD model mice and promoted reduction of Aβ deposits (DiCarlo et al., 2001). However, in AD model mice a chronic treatment regimen with LPS (weekly for 12 weeks) actually increased both microgliosis (by F4/80 Ag) and astrocytosis (by GFAP) and resulted in increases in cerebral Aβ1-40 and Aβ1-42, intraneuronal Aβ, and F4/80 Ag-positive microglia surrounding neurons containing Aβ deposits (Sheng et al., 2003). It is unclear how AD patients would react to intrathecal/intracranial injections of LPS, but certainly, given the aseptic meningoencephalitis that occurred in just over 5 percent of AD patients given the AN1792 vaccine, the safety of such an approach would need to be thoroughly evaluated in non-human primates before consideration in humans.

It deserves mentioning that the ADAPT trial was prematurely halted in late 2004 for a number of reasons, including an investigation launched by the public watchdog group “Public Citizen” and the “coxib” (Vioxx [naproxen]) cardiovascular side effects scare, which has made interpretation of this incomplete RCT complex (because treatment was suspended just after a few years following initiation; ADAPT Research Group, 2007). Interestingly, a recent epidemiologic study has carefully investigated “confounding by indication” (here, the idea that the inverse risk relationship between NSAIDs and AD was owed to arthritis, a presumed surrogate for NSAID use), and the authors found that, even after correcting for arthritis incidence, the inverse NSAID-AD risk relationship holds up (Szekely et al., 2008).

Finally, I wanted to mention our recent work targeting TGFβ signaling on peripheral macrophages in an AD mouse model, where we found dramatic (>90 percent by some methods) reduction of cerebral amyloidosis accompanied by 1) increased infiltration of blood-borne macrophage-like cells, 2) increased CD45, CD68, CD11b, and CD11c immunoreactivity (but cells were mostly negative for Ly-6C), and 3) reduced TNFα and increased IL-10 brain levels (Town et al., 2008). Our results suggest that it is possible to target a subpopulation of macrophages to productively clear Aβ deposits without provoking potentially damaging brain inflammation. Of course, we will have to wait and see if/when this therapeutic modality makes it to human clinical trials before we know whether we can “have our cake and eat it, too.”

In summary, Maier and colleagues should be credited for contributing to our understanding of the potentially protective role of C3 in AD-like pathology. As we learn more about the biological roles that these various “activated” microglial products play, we will be better equipped to target the correct phenotype for eventual AD therapy.

References:
ADAPT Research Group, Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Abstract

van den Berg TK and Kraal G. A function for the macrophage F4/80 molecule in tolerance induction. Trends Immunol. 2005 26(10):506-509. Abstract

DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D (2001) Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol Aging 22:1007-1012. Abstract

Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003 Jul;19(1):71-82. Abstract

Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA. Complement C3 Deficiency Leads to Accelerated Amyloid Beta Plaque Deposition and Neurodegeneration and Modulation of the Microglia/Macrophage Phenotype in Amyloid Precursor Protein Transgenic Mice. J. Neurosci. 18 June 2008;28(25):6333-6341. Abstract

Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE. Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis. 2003 Oct;14(1):133-45. Abstract

Szekely CA, Green RC, Breitner JC, Østbye T, Beiser AS, Corrada MM, Dodge HH, Ganguli M, Kawas CH, Kuller LH, Psaty BM, Resnick SM, Wolf PA, Zonderman AB, Welsh-Bohmer KA, Zandi PP. No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. Neurology. 2008 Jun 10;70(24):2291-8. Abstract

Town T, Nikolic V, Tan J. The microglial "activation" continuum: from innate to adaptive responses. Journal of Neuroinflammation. 2005;2:24. Abstract

Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008 Jun;14(6):681-7. Abstract

Wong AM, Patel NV, Patel NK, Wei M, Morgan TE, de Beer MC, de Villiers WJ, Finch CE. Macrosialin increases during normal brain aging are attenuated by caloric restriction. Neurosci Lett. 2005 Dec 23;390(2):76-80. Abstract

Wyss-Coray T, Yan F, Hsiu-Ti Lin A, Lambris JD, Alexander JJ, Quigg RJ, Masliah E. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10837-42. Abstract

View all comments by Terrence Town

The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.

Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating β- and γ-secretases...  Read more

The findings of Massaad and colleagues will advance our basic understanding of the neuroprotective role of mitochondrially targeted antioxidants in Alzheimer disease (AD) pathogenesis. Their findings suggest that mitochondrial superoxide dismutase 2 (SOD2) decreases hippocampal superoxide radicals, ameliorates learning/memory deficits, and decreases amyloid-β (Aβ) plaques in double transgenic mice that overexpress SOD2 and mutant human amyloid precursor protein. Interestingly, they also found a decreased ratio of Aβ1-42 to 1-40 in double transgenic mice. These findings further support the mitochondrial oxidative damage hypothesis of AD, and may have important implications for mitochondrially targeted antioxidant therapeutics in AD.

Increasing evidence suggests that mitochondrial abnormalities are involved in the development and progression of AD (reviewed in Reddy, 2009). Further, it has been proposed that mitochondrially generated free radicals and oxidative damage are involved in abnormal processing of APP and in generating Aβ peptide by activating β- and γ-secretases (Reddy, 2006; Reddy and Beal, 2008). There is some evidence to support this hypothesis (Tamagno et al., 2008; Jin et al., 2008). Further, recently several groups (Crouch et al., 2005; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hanson Petersen et al., 2008) found that Aβ peptide is localized to mitochondrial membranes and the mitochondrial matrix, and that mitochondrially localized Aβ peptide interacts with mitochondrial proteins, induces free radical production, decreases cytochrome oxidase activity, inhibits ATP production, and damages AD neurons. In addition, recent structural studies revealed that Aβ fragments mitochondria, suggesting that mitochondrial structural abnormalities (caused by Aβ) may be critical for mitochondrial dysfunction in AD (Wang et al., 2009; Mao et al., 2009). Overall, these studies suggest that Aβ and mitochondrial dysfunction play a big role in AD pathogenesis.

To determine the role of overexpressed SOD2 in AD pathogenesis, Massaad et al. crossed SOD2 transgenic mice with Tg2576 mice and studied cognitive deficits, Aβ1-42 and 1-40 levels, and Aβ deposits in Tg2576 mice and double mutant mice (SOD2xTg2576 mice). They found decreased Aβ deposits and reduced cognitive deficits in double transgenic mice relative to Tg2576 mice, suggesting that mitochondrial superoxide dismutase improves cognitive functions in AD. However, it is still unclear 1) how overexpressed mitochondrial superoxide dismutase alters the ratio of Aβ1-42 to 1-40; and 2) how overexpressed mitochondrial superoxide dismutase improves learning and memory functions in double mutant mice. Further research is needed to find answers to these questions, and the answers may have some important implications to AD patients.

Overall, findings of the study by Massaad and colleagues, together with previous studies (Hirai et al., 2001; Swerdlow et al., 1997; Reddy et al., 2004; Manczak et al., 2004; Caspersen et al., 2005; Manczak et al., 2006; Devi et al., 2006; Hansson Petersen et al., 2008; Wang et al., 2009), improve our understanding of mitochondrial oxidative damage in AD pathogenesis. Given the limited success of recent clinical trials using natural antioxidants in AD patients, findings from this new study may have some important implications for the development of mitochondrially targeted therapeutics for AD patients.

References:
Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005 Dec;19(14):2040-1. Abstract

Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006 Aug 30;26(35):9057-68. Abstract

Hansson Petersen CA, Alikhani N, Behbahani H, Wiehager B, Pavlov PF, Alafuzoff I, Leinonen V, Ito A, Winblad B, Glaser E, Ankarcrona M. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13145-50. Epub 2008 Aug 29. Abstract

Hirai K, Aliev G, Nunomura A, Fujioka H, Russel RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Peterson RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer's disease. J Neurosci. 2001 May 1;21(9):3017-23. Abstract

Jin SM, Cho HJ, Jung ES, Shim MY, Mook-Jung I. DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress. Cell Death Differ. 2008 Sep;15(9):1375-84. Epub 2008 Apr 18. Abstract

Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of Abeta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet. 2006 May 1;15(9):1437-49. Abstract

Manczak M, Park B, Jung Y, Reddy PH. Differential expression of oxidative phosphorylation genes in patients with Alzheimer's disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5(2):147-62. Abstract

Mao P, Manczak M, Shree D and Reddy PH. Abnormal mitochondrial structural and functional changes caused by amyloid beta in Alzheimer’s disease. Paper presented at the International Conference on Alzheimer’s disease held Vienna, Austria July 11-16, 2009.

Reddy PH. Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. J Neurochem. 2006 Jan;96(1):1-13. Abstract

Reddy PH. Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer's disease.Exp Neurol. 2009 Aug;218(2):286-92. Abstract

Reddy PH Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. Trends Mol Med. 2008 Feb;14(2):45-53. Abstract

Reddy PH, McWeeney S, Park BS, Manczak M, Gutala RV, Partovi D, Jung Y,

Yau V, Searles R, Mori M Quinn J. Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease. Hum Mol Genet. 2004 Jun 15;13(12):1225-40. Abstract

Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett JP Jr., Davis RE, Parker WD Jr. Cybrids in Alzheimer's disease: a cellular model of the disease? Neurology. 1997;49:918-925. Abstract

Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M. Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein.J Neurochem. 2008 Feb;104(3):683-95. Abstract

Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X. Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci. 2009 Jul 15;29(28):9090-103. Abstract

View all comments by P. Hemachandra Reddy