Alterations of some membrane transport proteins in Alzheimer's disease: role of amyloid β-peptide

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized clinically by progressive memory loss and decline in cognitive abilities and characterized pathologically by the presence of two types of abnormal deposits, i.e., senile plaques (SP) and neurofibrillary tangles (NFT), and by extensive synapse and neuronal loss. SP are composed of fibrillar amyloid β-peptide (Aβ) surrounded by dystrophic neurites. Recent studies suggest two prospective mechanisms for Aβ-associated membrane dysfunction and subsequent neurotoxicity. One suggests that Aβ oligomers can form heterogeneous ion-channels in the cell membrane leading to cellular degeneration, while the second suggests insertion of Aβ oligomers in membrane lipid bilayers could induce the dysfunction of ion-channels or pumps by binding to or inducing oxidative modification of membrane proteins . In this review, we discuss the effects of Aβ on membrane proteins that are involved in cholinergic and glutamatergic pathways, and some ion-channels.

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Rukhsana Sultana and D. Allan Butterfield

D. Allan Butterfield, PhD is the Alumni Association Endowed Professor of Biological Chemistry at the University of Kentucky. After earning his PhD in physical chemistry from Duke University, Professor Butterfield took a NIH Postdoctoral Fellowship in Neurosciences at Duke University School of Medicine. He joined the Department of Chemistry in 1975, rising to Full Professor in 1983. Professor Butterfield's NIH-funded research interests include oxidative stress-related mechanisms of neurodegeneration in Alzheimer's disease and the role of amyloid beta-peptide, as well as redox proteomics and its application in neurodegenerative disorders. He has published more than 400 refereed scientific papers and 4 books. He received the Presidential Award for Excellence in Science, Mathematics, and Engineering Mentoring from President Clinton in the White House, was awarded an Honorary Doctor of Science degree from the University of Maine, his undergraduate alma mater, and was selected for the Southern Chemist Award by the American Chemical Society. Professor Butterfield serves on review panels for the National Institutes of Health, on the Scientific Advisory Board for the Center for Neurobiology of the National University of Singapore, and as an Adjunct Professor of Aging at Edith Cowan University in Perth, Australia. Rukhsana Sultana, PhD currently is a Research Associate in the Department of Chemistry at University of Kentucky, Lexington, KY. She earned her PhD in Life Sciences (2002) from Hyderabad Central University, Hyderabad, India. Dr Sultana has over 10 years of research experience in the area of neurochemistry and alcoholism and has published 55 peer-reviewed publications in prestigious journals in addition to 4 book-chapters. Her research interests are in the area of oxidative stress with special emphasis on neurodegenerative diseases, neuroinflammation, cancer and nanotoxicology.

Introduction

Alzheimer's disease (AD) is an age-dependent, progressive dementing disorder that currently affects approximately five million Americans, and, in the absence of effective treatments to slow the onset of this disorder, the number of AD patients is predicted to reach 14–20 million in the next few decades due to the advancing age of the Baby Boomer bubble in the United States population. AD is the most common neurodegenerative disease characterized by progressive memory and cognitive dysfunction. Pathologically, AD brain is characterized by the presence of two types of abnormal deposits, i.e., senile plaques (SP) and neurofibrillary tangles (NFT), and by extensive synapse and neuronal loss.^1,2The major component of SP is a 39- to 42-residue peptide, called amyloid beta-peptide (Aβ), that is derived from proteolytic cleavage of an integral membrane protein known as amyloid precursor protein (APP). Aβ may have some important physiological functions, that has not yet been evaluated.³ However, Aβ has been shown to lead to oxidative damage to and death of neurons.^4–6 While Aβ aggregates to form fibrils, a number of studies suggest that small oligomers of Aβ are the actual toxic species of this peptide.^7–10

Lipid peroxidation is caused by Aβ and evidence of lipid peroxidation is extensive in AD brain.^4,6,11,12 Noting that lipid peroxidation is a free radical mediated process in which the radical by necessity must be located in the lipid bilayer near a reactive allylic hydrogen atoms on lipid acyl chains ⁴, Aβ inserts into the lipid bilayer as small oligomers. Recent reports suggest two prospective mechanisms for Aβ-associated membrane dysfunction and subsequent neurotoxicity. In one Aβ oligomers can insert in the membrane, forming an Aβ channel that can induce cellular degeneration by mediating specific ion conductance through the cellular membrane, dysregulation and/or destabilization of cellular ionic homeostasis and eventually leading to cell death (Fig. 1).^13–15In the second mechanism Aβ oligomers could induce oxidative dysfunction of ion-channels or pumps in the membrane (Fig. 1).^16–20

Fig. 1 The effects of Aβ on the membrane proteins : Aβ directly or indirectly affects functionality of many membrane proteins , alterations that are hypothesized to be correlated with the neurotoxicity and neuropathology associated with AD

As noted above, Aβ can intercalate into the membrane lipid bilayer, leading to protein , lipid , carbohydrate and nucleic acid damage by free radical processes. Evidence from AD brain and CSF to support this scenario includes, among others, elevated indices of oxidative stress, including protein carbonyls 3-nitrotyrosine (3-NT) [markers of protein oxidation], 4-hydroxy-2-nonenal (HNE) [marker of lipid peroxidation] and 8-hydroxy-2-deoxyguanosine [marker of DNA oxidation].^12,21–25 These oxidative stress modifications can induce dysfunctional proteins .²³ For example, HNE binds to proteins , including membrane proteins , by Michael addition leading to altered structure and function of the target protein .^11,12,26

In vitro and in vivo studies showed that Aβ can induce oxidative stress, consistent with the oxidative stress in an AD brain.^11,27–33The oxidative stress and neurotoxic effects of Aβ have been associated with the single methionine at residue 35 of Aβ1–42.³⁴ However, the pathogenic nature of amyloid oligomers and the mechanisms of the assembly process that cause the neurotoxicity leading to cell death are still unclear.

In this review, we discuss some of the membrane proteins that are involved in cholinergic or glutamatergic pathways in addition to some ion-channels with respect to effects of Aβ and potential mechanisms of AD pathogenesis.

Effect of Aβ on ion transport systems

Plasma membrane potassium channel

K⁺ channels regulate the concentration of K⁺ ions in neurons and other cells and thereby play important roles in generation of action potentials and maintaining the resting membrane potential. Any malfunction of the potassium channel may lead to impaired neurotransmission. K⁺ channel dysfunction has been reported in both central nervous system and peripheral tissues.³⁵

In AD brain, Ikeda and colleagues³⁶ reported abnormalities of the K⁺ channels in the hippocampus suggested by a decreased binding of ¹²⁵I-apamin, the bee venom that blocks small conductance Ca²⁺- and activated K⁺ channels responsible for hyperpolarization of neurons, in the subiculum and CA1 regions. In neurons from neonatal rats, Aβ was shown to inhibit voltage-dependent fast-inactivating K⁺ currents in hippocampal neurons.³⁷ In peripheral tissues, K⁺ channel dysfunction was initially identified in fibroblasts from patients with Alzheimer's disease where a 113-pS TEA-sensitive K⁺ channel was absent compared with normal human fibroblasts.³⁸This defect was mimicked in normal fibroblasts by the treatment with Aβ.¹⁷ In a number of in vitro studies including cultured fibroblasts and cholinergic septal cell lines, the addition of Aβ led to abnormal functioning of the potassium channel.³⁹ De Silva et al., (1998) showed functional abnormalities of K⁺ channels in fresh non-cultured cells from patients with AD.⁴⁰The alteration in the K⁺ channel activity may lead to increased levels of intracellularCa²⁺, resulting in altered neuronal excitability that may eventually lead to neuronal death.⁴¹ Both APP and presenilin 1 (PS1) have been suggested to contribute to the abnormalities of the potassium channel and thereby to the neurodegenerative process in AD.^42,43The alteration in the functions of the K⁺ channel protein may have indirect or secondary effects in neurodegeneration.

Calcium channels

Disruption of Ca²⁺ signaling is a key event underlying neuronal death in brain aging and Alzheimer's disease.^44–48 The increase in the calcium levels were shown to be either due to an increase in NMDA or GLU exposure⁴⁹ and voltage-gated calcium channels (VGCCs). VGCCs were reported to be affected in AD and its in vitro and in vivo models.^50–52Some AD patients treated with L-VGCCs (L type VGCCs) antagonists have shown improved learning and memory,⁵³consistent with the notion of involvement of these channels in neurodegenration associated with AD.

In addition to L-VGCCs, intracellular organelles such as ER might play a critical role in Ca²⁺ dysregulation during AD.^51,54,55Studies in fibroblasts from AD patients^56,57 or in cells bearing the human presenilin 1 (PS1) mutation showed evidence of abnormal Ca²⁺ release through IP₃R pathways.^58,59Some studies showed the involvement of both APP and PS1 mutation in the Ca²⁺ dysregulation.⁶⁰ The direct activation of the receptors or calcium channels contributing to the reported increase of intracellularCa²⁺ has been debated. Recent studies showed that Aβ oligomers could form calcium channels in synthetic bilayers thereby disrupting Ca²⁺ homeostasis.^14,61,62

Na⁺/K⁺-ATPase

Na⁺/K⁺-ATPase is a complex membrane enzyme that maintains a low intracellularNa⁺ concentration and a high intracellularK⁺ concentration as well as an intracellular negative electrical potential, by pumping Na⁺ out of and bringing K⁺ into the cell.⁶³Therefore, this pump plays an important role in regulating a number of cellular functions such as cell volume, excitability in nerve or muscle etc., and thereby protects neurons from damage resulting from excitotoxic stimuli. In addition, the Na⁺/K⁺- ATPase also brings about the active transport of sugars and amino acids in many animal tissues including the brain.

In AD brain Na⁺/K⁺-ATPase activity is decreased in AD that correlates with the specific reduction of the Na⁺/K⁺-ATPaseprotein level.⁶⁴Mark et al. (1995)⁶⁵ reported that acutely administered Aβ 1–40 or Aβ 25–35 significantly reduced Na⁺/K⁺-ATPase activity in cultured rat hippocampal neurons. Therefore, the decrease in Na⁺/K⁺-ATPase activity observed, at least in part, may result from the cytotoxic effects of Aβ proteins . Impaired Na⁺/K⁺-ATPase activity reportedly results in an increase in Na⁺ influx ([Na⁺]_i), membrane depolarization and Ca²⁺ influx through voltage-dependent Ca²⁺ channels.⁶⁵Thus, impaired Na⁺/K⁺-ATPase activity may also play an important role in the pathophysiology of neuronal excitotoxicity in AD. The reduction of Na⁺/K⁺-ATPase activities in AD brains may cause excessive excitatory responses in neurons resulting in neuronal death.

Acetylcholine receptor and cholinergic hypothesis

Cholinergic dysfunction is another neurochemical hallmark of AD, especially in the basal forebrain.^66–68 This observation led to the ‘cholinergic hypothesis’ of AD pathogenesis. Acetylcholine (ACh) is a central neurotransmitter that plays an important role in several cognitive functions such as learning and memory.^69,70Cholinergic neurons can modulate the activity of several other neuronal types, such as glutamatergic and GABAergic neurons.^71,72Consequently, perturbation of the cholinergic system can lead to dysfunction in other neurotransmitter systems, thereby having a deleterious outcome on brain function. In AD brain, cholinergic neurons in basal forebrain, which provide major inputs to the hippocampus and neocortex, are severely affected,^73–77 leading to decreased levels of ACh in these regions. This loss of ACh correlated with the reported memory and cognitive impairments in AD.⁷⁸A number of studies showed a decrease in choline acetyltransferase (ChAT) activity in AD cortex that correlated with the decreased levels of ChAT mRNA and the degree of dementia.^79–81Further, the expression of nicotinic ACh receptor (nAChR) subtypes, i.e., α7 and α4β2⁸² are reported to be highly expressed in AD affected brain regions, thereby suggesting a role of these receptors in the pathogenesis of AD. Moreover, muscarinic cholinergic receptors also are altered by Aβ ⁸³. A fraction of muscarinic cholinergic receptors are coupled to G-proteins that activate phospholipase C. This activation leads to release of IP₃ and Ca²⁺ from intracellular stores. When rat cortical neurons were treated with Aβ, carbachol-induced, the G-protein -coupled release of inosistol phosphates and Ca²⁺ release were attenuated. Antioxidants blocked the Aβ effects,⁸³consistent with the notion that Aβ disrupts muscarinc cholinergic receptors that may contribute to cholinergic deficits in AD. Concordant with the findings that Aβ leads to lipid peroxidation, forming HNE,^12,30HNE itself impairs signal transduction associated with muscarinic cholinergic and metabotropic glutamate receptors.⁸⁴

However, the relationship between cholinergic depletion, amyloidogenesis, and tau-phosphorylation is complex and not completely understood. It appears, however, that cholinergic depletion may increase the production of Aβ and exacerbate its neurotoxicity, including disruption of ACh synthesis and signal transduction events associated with cholinergic neurotransmission. Injection of Aβ1–42 in rat brain can induce oxidative stress and cholinergic impairment.⁸⁵Our group used redox proteomics to identify a number of oxidatively modified proteins in basal forebrain and hippocampus obtained from injection of Aβ1–42 into the rat basal forebrain, and some of the proteins that were identified to be oxidatively modified were also identified by proteomics to be oxidatively modified in AD brain.²⁷These results suggest a role of Aβ in the cholinergic dysfunction of AD.²⁷In addition, animal model studies suggested the disruption of nerve growth factor (NGF)-associated signaling may contribute to the loss of cholinergic neurons and subsequent memory loss.⁸⁶ However, it remains to be fully established if cholinergic neurodegeneration represents the pivotal functional determinant of the cognitive symptoms observed in AD. There is some literature available that suggest a possible relationships between cholinergic markers and other features of AD pathology.^87,88

The glutamatergic hypothesis (EAAT2)

The glutamatergic hypothesis of AD states that glutamate-related excitotoxic mechanisms involving the N-methyl-D-aspartate (NMDA) receptor lead to oxidative stress, neurodegeneration and cell death.^89–92Glutamate is the major excitatory neurotransmitter in the central nervous system. An increase in extracellularglutamate concentration leads to neuronal death through hyperactivation of NMDA receptors, with consequent influx of Ca²⁺, production of ROS, mitochondrial dysfunction, and cell death. Collectively, these processes are known as excitotoxicity.

The NMDA receptors are heteromeric complexes composed of the NR1 subunit combined with various types of NR2 subunits, e.g., NR2A, NR2B, NR2C, and NR2D.^93,94 A reduction of NR1/NR2B receptor expression levels with the progression of AD has been reported,⁹⁵suggesting an altered neuronal vulnerability to NMDA receptor activation in this disorder. Previous studies showed conflicting results regarding the levels of these various NMDA receptors in AD brain, and the binding sites for NMDA receptors have been shown to be either reduced⁹⁶ or stable. The mRNA levels are decreased in the AD brain.^95,97,98

In vitro studies using cultured cortical neurons showed that Aβ protein promoted endocytosis of NMDA receptors.⁹⁹In addition, in vitro studies from transgenic mice expressing the familial Swedish APP mutation showed lower cell surfaceNMDA receptor levels than control cells. These in vitro studies suggest that the decreased NMDA levels appear to be related to properties of Aβ.⁹⁹Some findings demonstrate that non-toxic amounts of secreted Aβ peptide reduce synaptic plasticity and glutamatergic transmission.^100,101Interestingly, presenilin 1 is found in a macromolecular complex with NR1 and NR2A,¹⁰²and hence a mutation of PS1 as observed in familial AD may be related to altered NMDA receptor functions. However, the exact role of NMDA receptor activation in AD pathogenesis is still not fully elucidated.

The NMDA receptor’s weak antagonist memantine (1-amino-3,5-dimethyladamantane) has been employed relatively recently for the treatment of severe AD.¹⁰³Most importantly, clinical trials have shown that memantine treatment leads to functional improvement in AD patients with severe dementia¹⁰⁴and is well tolerated.¹⁰⁵Since AD pathogenesis is a complex process that is not yet fully understood, and since complete inhibition of the NMDA receptor would interfere with synaptic remodeling and synaptic function, memantine is ideal as a NMDA receptor antangonist since it has a low affinity and a reasonably rapid off-rate.^106,107

The clearance of extracellularglutamate from the synaptic cleft is important to prevent the excitotoxicity, and this is primarily carried out by the glial glutamate transporter EAAT2. The loss of EAAT2 has been previously reported in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS),¹⁰⁸multiple sclerosis (MS),¹⁰⁹and AD.^12,110,111The loss of functional EAAT2 could lead to extracellular accumulation of excessive glutamate in the synapse that could result in excitotoxicity-mediated neurodegeneration. However, it is still not clear whether excitotoxicity is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. Previous studies showed the importance of regulating glutamate transport using mice lacking EAAT2 that develop progressive neurodegeneration and epilepsy as a result of aberrant glutamate homeostasis.^112,113

A significant increase in levels of glutamate in cortex and astrocytes of AD brain and decrease levels of EAAT2 protein in the affected areas of AD have been shown in a number of previous studies.^110,114A recent study reported marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both the gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients using gene chip arrays, real time PCR and immunohistochemistry.¹¹⁴ Subsequent studies in AD brain showed the aberrant neuronal expression of EAAT1 and EAAT2 are associated with tau accumulation.^115,116Further, glutamate transporter alterations in AD are associated with abnormal APP expression, functioning and/or processing of APP.¹¹⁰A decreased glutamate transporter activity and protein expression of glial specific glutamate transporters, EAAT1 and 2, were reported, which suggested that expression of mutant forms of APP disturbs astroglial transport of excitatory amino acids at the posttranscriptional level that lead to increased susceptibility to glutamate toxicity. In addition, GFAP-tau (glial fibrillary acidic protein -tau) transgenic mice also demonstrated a decrease in EAAT2 and glutamate uptake.¹¹⁷

Aβ decreases glutamate uptake.^118,119 The oxidative inhibition of the glutamate transporter protein in AD brain and by Aβ via the formation of a covalent HNE adduct has been reported in synaptosomes.¹²Oxidative modification of EAAT2 can promote excitoxicity cascades eventually leading to neurodegeneration. Other glutamate-related processes are abnormal in AD as well, e.g., glutamine synthetase^120,121 and glutamate reductase.^122–124These alterations could contribute to glutamate-mediated excitotoxic mechanisms.

HNE has been shown to modify and impair the function of ion-motive ATPases, the neuronal glucose transporter GLUT3 and the astrocyteglutamate transporter GLT-1.^29,30,125 Increased levels of HNE have been detected in association with degenerating neurons in tissue samples from patients with AD and even in the cerebrospinal fluid of AD patients.¹²⁶

Conclusions

The functional alterations of brain ion-channels, pumps, and membrane receptors in AD and the roles putatively played by Aβ in these alterations provide insights into the complicated mechanisms of neurodegeneration and may eventually permit the development of more specific drug therapies for neurologic disorders, including AD. Continued investigation of membrane-resident transport proteins in the brains of subjects with AD will undoubtedly lead to new therapeutic approaches to this devastating dementing disorder.

Acknowledgements

This work was supported in part by grants from the National Institutes of Health [AG-10836; AG-05119].

References

1. P. Giannakopoulos, P. R. Hof, E. Kovari, P. G. Vallet, F. R. Herrmann and C. Bouras, J. Neuropathol. Exp. Neurol., 1996, 55, 1210–1220.
2. D. J. Selkoe, Physiol. Rev., 2001, 81, 741–766.
3. H. A. Pearson and C. Peers, J. Physiol., 2006, 575, 5–10.
4. D. A. Butterfield and C. M. Lauderback, Free Radical Biol. Med., 2002, 32, 1050–1060.
5. D. A. Butterfield and E. R. Stadtman, Adv. Cell Aging Gerontol., 1997, 2, 161–191.
6. W. R. Markesbery and M. A. Lovell, Neurobiol. Aging, 1998, 19, 33–36.
7. K. H. Ashe, Biochem. Soc. Trans., 2005, 33, 591–594.
8. J. Drake, C. D. Link and D. A. Butterfield, Neurobiol. Aging, 2003, 24, 415–420.
9. W. L. Klein, W. B. Stine, Jr. and D. B. Teplow, Neurobiol. Aging, 2004, 25, 569–580.
10. D. M. Walsh, I. Klyubin, G. M. Shankar, M. Townsend, J. V. Fadeeva, V. Betts, M. B. Podlisny, J. P. Cleary, K. H. Ashe, M. J. Rowan and D. J. Selkoe, Biochem. Soc. Trans., 2005, 33, 1087–1090.
11. D. A. Butterfield, T. Reed, S. F. Newman and R. Sultana, Free Radical Biol. Med., 2007, 43, 658–677.
12. C. M. Lauderback, J. M. Hackett, F. F. Huang, J. N. Keller, L. I. Szweda, W. R. Markesbery and D. A. Butterfield, J. Neurochem., 2001, 78, 413–416.
13. R. Lal, H. Lin and A. P. Quist, Biochim. Biophys. Acta, 2007, 1768, 1966–1975.
14. N. Arispe, J. C. Diaz and O. Simakova, Biochim. Biophys. Acta, 2007, 1768, 1952–1965.
15. H. Jang, J. Zheng and R. Nussinov, Biophys. J., 2007.
16. N. Arispe, E. Rojas and H. B. Pollard, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 567–571.
17. R. Etcheberrigaray, E. Ito, C. S. Kim and D. L. Alkon, Science, 1994, 264, 276–279.
18. Y. Verdier and B. Penke, Curr. Protein Pept. Sci., 2004, 5, 19–31.
19. H. Y. Wang, D. H. Lee, M. R. D'Andrea, P. A. Peterson, R. P. Shank and A. B. Reitz, J. Biol. Chem., 2000, 275, 5626–5632.
20. B. Corry, Mol. Biosyst., 2006, 2, 527–535.
21. A. Castegna, V. Thongboonkerd, J. B. Klein, B. Lynn, W. R. Markesbery and D. A. Butterfield, J. Neurochem., 2003, 85, 1394–1401.
22. R. Sultana, H. F. Poon, J. Cai, W. M. Pierce, M. Merchant, J. B. Klein, W. R. Markesbery and D. A. Butterfield, Neurobiol. Dis., 2006, 22, 76–87.
23. M. Y. Aksenov, M. V. Aksenova, D. A. Butterfield, J. W. Geddes and W. R. Markesbery, Neuroscience, 2001, 103, 373–383.
24. K. Hensley, N. Hall, R. Subramaniam, P. Cole, M. Harris, M. Aksenov, M. Aksenova, S. P. Gabbita, J. F. Wu, J. M. Carney, M. Lovell, W. R. Markesbery and D. A. Butterfield, J. Neurochem., 1995, 65, 2146–2156.
25. M. A. Smith, S. Taneda, P. L. Richey, S. Miyata, S. D. Yan, D. Stern, L. M. Sayre, V. M. Monnier and G. Perry, Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 5710–5714.
26. R. Sultana and D. A. Butterfield, Neurochem. Res., 2004, 29, 2215–2220.
27. D. Boyd-Kimball, R. Sultana, H. F. Poon, B. C. Lynn, F. Casamenti, G. Pepeu, J. B. Klein and D. A. Butterfield, Neuroscience, 2005, 132, 313–324.
28. D. A. Butterfield, K. Hensley, M. Harris, M. Mattson and J. Carney, Biochem. Biophys. Res. Commun., 1994, 200, 710–715.
29. J. N. Keller, Z. Pang, J. W. Geddes, J. G. Begley, A. Germeyer, G. Waeg and M. P. Mattson, J. Neurochem., 1997, 69, 273–284.
30. R. J. Mark, M. A. Lovell, W. R. Markesbery, K. Uchida and M. P. Mattson, J. Neurochem., 1997, 68, 255–264.
31. M. P. Mattson and W. A. Pedersen, Int. J. Dev. Neurosci., 1998, 16, 737–753.
32. H. Mohmmad Abdul, G. L. Wenk, M. Gramling, B. Hauss-Wegrzyniak and D. A. Butterfield, Neurosci. Lett., 2004, 368, 148–150.
33. S. M. Yatin, M. Aksenov and D. A. Butterfield, Neurochem. Res., 1999, 24, 427–435.
34. D. A. Butterfield and D. Boyd-Kimball, Biochim. Biophys. Acta, 2005, 1703, 149–156.
35. M. A. Ariano, C. Cepeda, C. R. Calvert, J. Flores-Hernandez, E. Hernandez-Echeagaray, G. J. Klapstein, S. H. Chandler, N. Aronin, M. DiFiglia and M. S. Levine, J. Neurophysiol., 2005, 93, 2565–2574.
36. M. Ikeda, D. Dewar and J. McCulloch, Brain Res., 1991, 567, 51–56.
37. T. A. Good, D. O. Smith and R. M. Murphy, Biophys. J., 1996, 70, 296–304.
38. R. Etcheberrigaray, E. Ito, K. Oka, B. Tofel-Grehl, G. E. Gibson and D. L. Alkon, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 8209–8213.
39. L. V. Colom, M. E. Diaz, D. R. Beers, A. Neely, W. J. Xie and S. H. Appel, J. Neurochem., 1998, 70, 1925–1934.
40. H. A. de Silva, J. K. Aronson, D. G. Grahame-Smith, K. A. Jobst and A. D. Smith, Lancet, 1998, 352, 1590–1593.
41. T. A. Good and R. M. Murphy, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 15130–15135.
42. K. Furukawa, S. W. Barger, E. M. Blalock and M. P. Mattson, Nature, 1996, 379, 74–78.
43. S. A. Malin, W. X. Guo, G. Jafari, A. M. Goate and J. M. Nerbonne, Neurobiol. Dis., 1998, 4, 398–409.
44. M. P. Mattson and S. L. Chan, Cell. Calcium, 2003, 34, 385–397.
45. F. M. LaFerla, Nat. Rev. Neurosci., 2002, 3, 862–872.
46. O. Thibault, J. C. Gant and P. W. Landfield, Aging Cell, 2007, 6, 307–317.
47. O. Thibault and P. W. Landfield, Science, 1996, 272, 1017–1020.
48. G. E. Gibson and C. Peterson, Neurobiol. Aging, 1987, 8, 329–343.
49. M. P. Mattson, Neurosci. Biobehav. Rev., 1997, 21, 193–206.
50. J. A. Bobich, Q. Zheng and A. Campbell, J. Alzheimers. Dis., 2004, 6, 243–255.
51. D. G. Cook, X. Li, S. D. Cherry and A. R. Cantrell, J. Neurophysiol., 2005, 94, 4421–4429.
52. J. H. Weiss, C. J. Pike and C. W. Cotman, J. Neurochem., 1994, 62, 372–375.
53. F. Forette, M. L. Seux, J. A. Staessen, L. Thijs, M. R. Babarskiene, S. Babeanu, A. Bossini, R. Fagard, B. Gil-Extremera, T. Laks, Z. Kobalava, C. Sarti, J. Tuomilehto, H. Vanhanen, J. Webster, Y. Yodfat and W. H. Birkenhäger, Arch. Intern. Med., 2002, 162, 2046–2052.
54. H. Tu, O. Nelson, A. Bezprozvanny, Z. Wang, S. F. Lee, Y. H. Hao, L. Serneels, B. De Strooper,, G. Yu and I. Bezprozvanny, Cell, 2006, 126, 981–993.
55. E. C. Toescu and A. Verkhratsky, Cell. Calcium, 2003, 34, 311–323.
56. A. Palotas, J. Kalman, G. Laskay, A. Juhasz, Z. Janka and B. Penke, Neurochem. Res., 2001, 26, 817–820.
57. G. Gibson, R. Martins, J. Blass and S. Gandy, Life Sci., 1996, 59, 477–489.
58. G. E. Gibson, M. Vestling, H. Zhang, S. Szolosi, D. Alkon, L. Lannfelt, S. Gandy and R. F. Cowburn, Neurobiol. Aging, 1997, 18, 573–580.
59. G. E. Stutzmann, Neuroscientist, 2005, 11, 110–115.
60. N. J. Haughey, A. Nath, S. L. Chan, A. C. Borchard, M. S. Rao and M. P. Mattson, J. Neurochem., 2002, 83, 1509–1524.
61. M. Kawahara and Y. Kuroda, Brain Res. Bull., 2000, 53, 389–397.
62. A. Demuro, E. Mina, R. Kayed, S. C. Milton, I. Parker and C. G. Glabe, J. Biol. Chem., 2005, 280, 17294–17300.
63. J. D. Horisberger, V. Lemas, J. P. Kraehenbuhl and B. C. Rossier, Annu. Rev. Physiol., 1991, 53, 565–584.
64. G. Liguri, N. Taddei, P. Nassi, S. Latorraca, C. Nediani and S. Sorbi, Neurosci. Lett., 1990, 112, 338–342.
65. R. J. Mark, K. Hensley, D. A. Butterfield and M. P. Mattson, J. Neurosci., 1995, 15, 6239–6249.
66. P. Behl, C. Bocti, R. H. Swartz, F. Gao, D. J. Sahlas, K. L. Lanctot, D. L. Streiner and S. E. Black, Arch. Neurol., 2007, 64, 266–272.
67. P. Davies and A. J. Maloney, Lancet, 1976, 2, 1403.
68. P. J. Whitehouse, D. L. Price, A. W. Clark, J. T. Coyle and M. R. DeLong, Ann. Neurol., 1981, 10, 122–126.
69. J. L. Muir, Pharmacol., Biochem. Behav., 1997, 56, 687–696.
70. L. Ricceri, L. Minghetti, A. Moles, P. Popoli, A. Confaloni, R. De Simone, P. Piscopo, M. L. Scattoni, M. Di Luca and G. Calamandrei, Exp. Neurol., 2004, 189, 162–172.
71. C. J. Frazier, A. V. Buhler, J. L. Weiner and T. V. Dunwiddie, J. Neurosci., 1998, 18, 8228–8235.
72. H. R. Santos, H. S. Ribeiro, P. Setti-Perdigao, E. X. Albuquerque and N. G. Castro, J. Pharmacol. Exp. Ther., 2006, 319, 376–385.
73. J. T. Coyle, D. L. Price and M. R. DeLong, Science, 1983, 219, 1184–1190.
74. C. K. Wu, L. Thal, D. Pizzo, L. Hansen, E. Masliah and C. Geula, Exp. Neurol., 2005, 195, 484–496.
75. S. Kar, S. P. Slowikowski, D. Westaway and H. T. Mount, J. Psychiatry. Neurosci., 2004, 29, 427–441.
76. K. Herholz, S. Weisenbach, G. Zundorf, O. Lenz, H. Schroder, B. Bauer, E. Kalbe and W. D. Heiss, Neuroimage, 2004, 21, 136–143.
77. E. J. Mufson, S. D. Ginsberg, M. D. Ikonomovic and S. T. DeKosky, J. Chem. Neuroanat., 2003, 26, 233–242.
78. D. S. Auld, T. J. Kornecook, S. Bastianetto and R. Quirion, Prog. Neurobiol., 2002, 68, 209–245.
79. W. A. Pedersen, M. A. Kloczewiak and J. K. Blusztajn, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 8068–8071.
80. E. Hellstrom-Lindahl, M. Mousavi, X. Zhang, R. Ravid and A. Nordberg, Mol. Brain. Res., 1999, 66, 94–103.
81. A. Wevers, L. Monteggia, S. Nowacki, W. Bloch, U. Schutz, J. Lindstrom, E. F. Pereira, H. Eisenberg, E. Giacobini, R. A. de Vos, E. N. Steur, A. Maelicke, E. X. Albuquerque and H. Schröder, Eur. J. Neurosci., 1999, 11, 2551–2565.
82. A. Wevers and H. Schroder, J. Alzheimers Dis., 1999, 1, 207–219.
83. J. F. Kelly, K. Furukawa, S. W. Barger, M. R. Rengen, R. J. Mark, E. M. Blanc, G. S. Roth and M. P. Mattson, Proc. Natl. Acad. Sci. U. S. A., 1996, 93, 6753–6758.
84. E. M. Blanc, J. F. Kelly, R. J. Mark, G. Waeg and M. P. Mattson, J. Neurochem., 1997, 69, 570–580.
85. M. G. Giovannini, C. Scali, C. Prosperi, A. Bellucci, M. G. Vannucchi, S. Rosi, G. Pepeu and F. Casamenti, Neurobiol. Dis., 2002, 11, 257–274.
86. S. Capsoni and A. Cattaneo, Cell. Mol. Neurobiol., 2006, 26, 619–633.
87. F. J. Gil-Bea, M. Garcia-Alloza, J. Dominguez, B. Marcos and M. J. Ramirez, Neurosci. Lett., 2005, 375, 37–41.
88. L. Frolich, J. Neural Transm., 2002, 109, 1003–1013.
89. D. A. Butterfield and C. B. Pocernich, CNS Drugs, 2003, 17, 641–652.
90. F. G. De Felice, P. T. Velasco, M. P. Lambert, K. Viola, S. J. Fernandez, S. T. Ferreira and W. L. Klein, J. Biol. Chem., 2007, 282, 11590–11601.
91. M. P. Mattson and W. Duan, J. Neurosci. Res., 1999, 58, 152–166.
92. E. K. Michaelis, Prog. Neurobiol., 1998, 54, 369–415.
93. A. L. Buller and D. T. Monaghan, Eur. J. Pharmacol., 1997, 320, 87–94.
94. S. Cull-Candy, S. Brickley and M. Farrant, Curr. Opin. Neurobiol., 2001, 11, 327–335.
95. A. J. Mishizen-Eberz, R. A. Rissman, T. L. Carter, M. D. Ikonomovic, B. B. Wolfe and D. M. Armstrong, Neurobiol. Dis., 2004, 15, 80–92.
96. M. R. Hynd, H. L. Scott and P. R. Dodd, J. Neurochem., 2004, 89, 240–247.
97. M. R. Hynd, H. L. Scott and P. R. Dodd, J. Neurochem., 2001, 78, 175–182.
98. H. Bi and C. I. Sze, J. Neurol. Sci., 2002, 200, 11–18.
99. E. M. Snyder, Y. Nong, C. G. Almeida, S. Paul, T. Moran, E. Y. Choi, A. C. Nairn, M.W. Salter, P. J. Lombroso, G. K. Gouras and P. Greengard, Nat. Neurosci., 2005, 8, 1051–1058.
100. M. K. Sun and D. L. Alkon, J. Neurophysiol., 2002, 87, 2441–2449.
101. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia and R. Malinow, Neuron, 2003, 37, 925–937.
102. C. A. Saura, S. Y. Choi, V. Beglopoulos, S. Malkani, D. Zhang, B. S. Shankaranarayana Rao, S. Chattarji and R. J. Kelleher, Neuron, 2004, 42, 23–36.
103. E. Scarpini, P. Scheltens and H. Feldman, Lancet Neurol., 2003, 2, 539–547.
104. T. Heinen-Kammerer, H. Rulhoff, S. Nelles and R. Rychlik, Clin. Drug Investig., 2006, 26, 303–314.
105. B. Winblad and N. Poritis, Int. J. Geriatr. Psychiatry, 1999, 14, 135–146.
106. S. A. Lipton, Curr. Alzheimer Res., 2005, 2, 155–165.
107. S. A. Lipton, Z. Gu and T. Nakamura, Int. Rev. Neurobiol., 2007, 82, 1–27.
108. J. D. Rothstein, L. J. Martin and R. W. Kuncl, N. Engl. J. Med., 1992, 326, 1464–1468.
109. P. Werner, D. Pitt and C. S. Raine, Ann. Neurol., 2001, 50, 169–180.
110. S. Li, M. Mallory, M. Alford, S. Tanaka and E. Masliah, J. Neuropathol. Exp. Neurol., 1997, 56, 901–911.
111. E. Masliah, M. Alford, M. Mallory, E. Rockenstein, D. Moechars and F. Van Leuven, Exp. Neurol., 2000, 163, 381–387.
112. J. D. Rothstein, M. Dykes-Hoberg, C. A. Pardo, L. A. Bristol, L. Jin, R. W. Kuncl, Y. Kanai, M. A. Hediger, Y. Wang, J. P. Schielke and D. F. Welty, Neuron, 1996, 16, 675–686.
113. K. Tanaka, K. Watase, T. Manabe, K. Yamada, M. Watanabe, K. Takahashi, H. Iwama, T. Nishikawa, T. Nishikawa, N. Ichihara, T. Kikuchi, S. Okuyama, N. Kawashima, S. Hori, M. Takimoto and K. Wada, Science, 1997, 276, 1699–1702.
114. C. P. Jacob, E. Koutsilieri, J. Bartl, E. Neuen-Jacob, T. Arzberger, N. Zander, R. Ravid, W. Roggendorf, P. Riederer and E. Grünblatt, J. Alzheimers. Dis., 2007, 11, 97–116.
115. D. R. Thai, Brain Pathol., 2002, 12, 405–411.
116. H. L. Scott, D. V. Pow, A. E. Tannenberg and P. R. Dodd, J. Neurosci., 2002, 22, RC206.
117. D. V. Dabir, M. B. Robinson, E. Swanson, B. Zhang, J. Q. Trojanowski, V. M. Lee and M. S. Forman, J. Neurosci., 2006, 26, 644–654.
118. D. V. Pow, T. Naidoo, B. E. Lingwood, G. N. Healy, S. M. Williams, R. K. Sullivan, S. O'Driscoll and P. B. Colditz, Dev. Brain Res., 2004, 153, 1–11.
119. C. M. Lauderback, M. E. Harris-White, Y. Wang, N. W. Pedigo, Jr., J. M. Carney and D. A. Butterfield, Life Sci., 1999, 65, 1977–1981.
120. A. Castegna, M. Aksenov, M. Aksenova, V. Thongboonkerd, J. B. Klein, W. M. Pierce, R. Booze, W. R. Markesbery and D. A. Butterfield, Free Radical Biol. Med., 2002, 33, 562–571.
121. D. A. Butterfield, K. Hensley, P. Cole, R. Subramaniam, M. Aksenov, M. Aksenova, P.M. Bummer, B.E. Haley and J. M. Carney, J. Neurochem., 1997, 68, 2451–2457.
122. K. Iwatsuji, S. Nakamura and M. Kameyama, Gerontology, 1989, 35, 218–224.
123. G. E. Gibson, K. F. Sheu and J. P. Blass, J. Neural Transm., 1998, 105, 855–870.
124. G. Burbaeva, I. S. Boksha, E. B. Tereshkina, O. K. Savushkina, L. I. Starodubtseva and M. S. Turishcheva, Neurochem. Res., 2005, 30, 1443–1451.
125. E. M. Blanc, M. Toborek, R. J. Mark, B. Hennig and M. P. Mattson, J. Neurochem., 1997, 68, 1870–1881.
126. M. A. Lovell, W. D. Ehmann, M. P. Mattson and W. R. Markesbery, Neurobiol. Aging, 1997, 18, 457–461.

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