Alzheimer's amyloid beta improves memory in lab animal brain tissue: Amyloid beta, neural lipid metabolism, cholesterol and synaptic plasticity

Alzheimer's amyloid beta improves memory in lab animal brain tissue: Amyloid beta, neural lipid metabolism, cholesterol and synaptic plasticity

This is Part 6 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5 | Part 6

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Amyloid beta, neural lipid metabolism, cholesterol and synaptic plasticity

In line with our early reasoning that Abeta is an apolipoprotein constituent of lipoproteins (and as such may have a diverse function in lipid metabolism) we studies the effects of the synthetic analog of amyloid beta protein, peptide Abeta1-40 (thought to be a major form of soluble Abeta [[24]]) on lipid synthesis in the hippocampal slices of rodents using metabolic labeling with C14-acetate, a radioactive lipid precursor [[56]]. Over the prolonged incubation with the label slices remained viable and actively synthesized phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and cholesterol. Abeta treatment increased the synthesis of PC, PE and cholesterol on 33, 67 and 46 % above the control values (100 %), respectively.

Abeta1-40 also modulated the synthesis of choline-containing phospholipids (cPLs, namely phosphatidylcholine and sphingomyelin), the major neural membrane component, an integral part of the brain cholinergic system, and a reservoir for lipid second messengers. We traced the synthesis of cPLs with radioactive choline in the presence of Abeta1-40 and found that Abeta increases the synthesis of cPLs to 47% above the controls (no Abeta). These data imply that the modulation of neural lipids by Abeta can be mediated via different metabolic pathways [].

Additional experimentation showed that Abeta also enhanced the uptake of tritiated [3H]cholesterol by slices, ~32.5% in 6 hrs above the control value (100 %, no Abeta). We used two kinds of controls. First, we stimulated slices with 50 mM potassium (that models basic neural synaptic function), followed by a biochemical analysis of lipid synthesis with a radioactive label. K+ evoked depolarization did not significantly change specified above lipid syntheses (contrary to lipid peroxidation modification that we report below), suggesting that membrane depolarization, modeling basal synaptic activity and neurotransmission, do not enhance hippocampal lipid syntheses as it occurs during the treatment of slices with Abeta peptide, and after long-lasting synaptic enhancement (LTP), as verified by autoradiography of hippocampal slices after the metabolic labeling with radioactive lipid precursor [14C] acetate and the induction of the LTP with a tetanic stimulus (100 Hz, 1 sec) in stratum radiatum (SR) recording pathway of the CA1 [[56, 58]].

Therefore, we set to test the role for Abeta in the synaptic plasticity in brain slices from adult male rat hippocampus under the condition that we characterized previously with regard to cholesterol and phospholipid synthesis [[56, 59]]. The prolonged maintenance of slices in a test tube for about twenty hours in our experimental setup preserved synaptic function (input/output curve, I/O, a basic measure of synaptic function, Figure 1, inset) but abrogated synaptic plasticity (measured as LTP, Figure 1, Panel A). Synthetic homolog of the Abeta (1-40 amino acids’ molecule length, representing the major form of soluble Abeta[[24]], Panel B) rescued LTP while cholesterol synthesis inhibition with a statin abolished LTP restoration by the peptide [[59]].

LTP models synaptic plasticity that underlies learning and memory, and depends on cholesterol and phospholipids supply via synthesis and lipoprotein transport as well as membrane lipid peroxidation (discussed at length of this article). The above effect of Abeta may represent its biological function of activity-dependent sensing membrane physical and chemical properties that is translated into membrane lipid homeostasis modulation to fine tune current synaptic action. Our observation implies an intriguing perspective that Abeta protein is a functional player in an activity-dependent cholesterol neurochemical pathways and contributes to the knowledge base on the important role for Abeta in synaptic structure-functional plasticity shown by others [[21, 43, 44, 45, 46, 60, 61, 62]].

Our findings also support early formulation of our hypothesis that the change in Abeta biochemistry in Alzheimer's disease and related disorders is a functional (but NOT pathologic) compensatory phenomenon aiming to counterbalance impaired cholesterol dynamics and associated neurotransmission and synaptic plasticity [[56, 59, 63, 64]]. Such cholesterol mediated failure of synaptic function and neural degeneration in our view represents the cause of the major sporadic form of Alzheimer's disease [[56, 59, 63, 64, also see Scheme 1 in the following lecture]].

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Amyloid beta restores memory in the model of hippocampal slices of lab animals



Figure 1. Effect of Alzheimer's Abeta1-40 on synaptic plasticity in CA1 area of adult rat hippocampus. A, Field excitatory postsynaptic potentials (fEPSPs) recorded from a single site in stratum radiatum of CA1 under the condition of the prolonged incubation of slices without the peptide Abeta1-40 (Control) or in the presence of the peptide (Abeta) are presented as normalized slopes versus time to yield LTP charts. Abeta1-40 peptide reversed the impairment of the LTP, a characteristic of synaptic plasticity, in slices subjected to 21+ hrs of maintenance ex-vivo, and made it statistically not different (P>0.05, nonparametric Mann-Whitney signed rank test, one-tailed) from the slices maintained for 6-8 hrs only [[56]]. Inset (I/O maximum) illustrates the maximum values of the input-stimulus/output-response (I/O) curves (indicative of basic synaptic function) that show no statistical differences (n=6, P>0.05, one-tailed) between slices maintained for a prolonged time with Abeta or without the peptide. D, Representative fEPSPs at the bottom right show that statin mevinolin (a cholesterol synthesis inhibitor) abolished LTP restoration by Abeta (for details and experimental protocol please see the text and the scheme in [[59]]). The presented waveforms are recorded during the baseline stimulation (1), immediately after the tetanic stimulus (2), as well as three (3) and twenty (4) minutes thereafter. Panel B illustrates amino acid sequence differences between rat and used in the study human Abeta1-40. “Stars” on the schematic hippocampal slice (Panel C) illustrate stimulating and recording electrodes positioning. The figure is reproduced by permission from the Neurobiology of Lipids, 1, 8 (2003), http://neurobiologyoflipids.org/content/1/8/ [[59]].

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References:

24. AR. Koudinov, NV. Koudinova, A. Kumar, R. Beavis, J. Ghiso. (1996) Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. Biochem. Biophys. Res. Commun. (1996) 223:592-597

43. FR. Kamenetz, T. Tomita, DR. Borchelt, SS. Sisodia, T. Iwatsubo, R. Malinow. Activity dependent secretion of beta-amyloid: roles of -amyloid in synaptic transmission. Soc. Neurosci. Abstr. (2000) 26: 491.

44. HA. Pearson, C. Peers. Physiological roles for amyloid beta peptides. J. Physiol. (2006) 15: 5–10.

45. JP. Steinbach, U. Muller, M. Leist, ZW. Li, P. Nicotera, A Aguzzi. Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. Cell Death Differ. (1998) 5:858–866.

46. S. Lesne, C. Ali, C. Gabriel, N Croci, ET. MacKenzie, CG. Glabe, M. Plotkine, C. Marchand-Verrecchia, D. Vivien, A. Buisson. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J. Neurosci. (2005) 25:9367–9377.

56. AR. Koudinov, NV. Koudinova. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. (2001) 15: 1858-1860. Available at: http://www.fasebj.org/cgi/content/abstract/00-0815fjev1. Also available as slide show at: http://neurobiologyoflipids.org/content/1/6/neurolipids112002-02.html#fr1

57. NV. Koudinova, AR. Koudinov. Amyloid beta protein attenuates the synthesis of phospholipids containing choline: another effector of neural membrane homeostasis? Soc. Neurosci. Abst. online. (2002) Program No.884.2. Available at: http://neurobiologyoflipids.org/content/1/5/

58. AR. Koudinov, NV. Koudinova. Cholesterols' role in synapse formation. Science (2002) 295: 2213.

59. AR. Koudinov, NV. Koudinova. Amyloid beta protein restores hippocampal long term potentiation: a central role for cholesterol? Neurobiol. Lipids (2003) 1: 8 Available at: http://neurobiologyoflipids.org/content/1/8/

60. J. Wu, R. Anwyl, MJ. Rowan. beta-amyloid-(1-40) increases long-term potentiation in rat hippocampus in vitro. Europ. J. Pharm. (1995) 284: R1-R3.

61. J. Wu, R. Anwyl, MJ. Rowan. beta-amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. NeuroReport (1995) 6: 2409-2413.

62. PE. Schulz. beta-peptides enhance the magnitude and probability of long term potentiation. Soc. Neurosci. Abstr. (1996) 22: 2111.

63. AR. Koudinov, NV. Koudinova. Brain cholesterol pathology is the cause of Alzheimer's disease. Clin Med Health Res (2001) clinmed/2001100005. Available at: http://clinmed.netprints.org/cgi/content/full/2001100005v1

64. AR. Koudinov, NV. Koudinova. Cholesterol, synaptic function and Alzheimer's disease. Pharmacopsychiatry (2003) S36: 107-12.


56. AR. Koudinov, NV. Koudinova. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. (2001) 15: 1858-1860. Available at fasebj.org , also available as a slide show at koudinov.info (to be reprinted at Alzheimer's Code):


Link to this publication: amyloid-beta-lipids-cholesterol-synapse

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Alzheimer Amyloid beta and its precursor molecule APP implicated in the function of peripheral synapses and the neuromuscular junction (NMJ) pathology

This is Part 5 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Alzheimer's Amyloid beta and its' precursor molecule APP implicated in the function of peripheral synapses and the neuromuscular junctions (NMJ) pathology

Further investigation is warranted to elucidate the normal role for amyloid beta protein (Abeta) and its’ precursor at peripheral synapses, neuromuscular junctions (NMJ) and NMJ pathologies (ex. inclusion-body myositis, IBM). Two basic observations include the study published more then a decade ago [[48]]. This was the first demonstration of APP and Abeta concentration postsynaptically at human neuro-muscular junctions, that led authors to conclude that “APP may have a role in normal junction biology and possibly in some diseases affecting NMJs”. Another study later showed that APP homolog in Drosophila (APPL) promotes synapse differentiation at the neuromuscular junction [[49]], leading the authors to propose a model “by which APPL, in conjunction with activity-dependent mechanisms, regulates synaptic structure and number”.

Recent comprehensive study performed analyses of neurotransmission in mature neuromuscular synapse of APP deficient mice. This research “found that APP deletion led to reduced paired-pulse facilitation [PPF, a measure of synaptic transmission and synaptic vesicles recycling efficacy] and increased depression of synaptic transmission with repetitive stimulation. Readily releasable pool size and total releasable vesicles were not affected, but probability of release was significantly increased. Strikingly, the amount of asynchronous release, a measure sensitive to presynaptic calcium concentration, was dramatically increased, and pharmacological studies revealed that it was attributed to aberrant activation of N- and L-type Ca(2+) channels.” Authors therefore proposed that APP modulates synaptic transmission at the NMJ by ensuring proper Ca(2+) channel function [[50]].

Another study [[51]] reported on an essential role of APP family of proteins in the development of neuromuscular synapses. “Mice deficient in APP and its homolog APP-like protein 2 (APLP2) exhibited aberrant apposition of presynaptic marker proteins with postsynaptic acetylcholine receptors and excessive nerve terminal sprouting. The number of synaptic vesicles at presynaptic terminals was dramatically reduced. [In agreement with the previous study by Yang L et al.[[Ref. 50]] ], these structural abnormalities were accompanied by defective neurotransmitter release and a high incidence of synaptic failure [[51]]. This is also in accord with the reduction of the synaptic vesicle density, active zone size, and docked vesicle number per active zone in submandibular ganglion synapses of mice lacking APP and APPLP2 demonstrated in lab animals with double gene deletions [[52]].

Another recent report demonstrated that APP is essential in regulating the presynaptic expression and activity of the high-affinity choline transporter (CHT), a molecule that mediates the rate-limiting step of cholinergic synaptic transmission in both the NMJ and central cholinergic neurons. Loss of APP was the cause of the aberrant localization of CHT at the neuromuscular synapses and reduced CHT activity at cholinergic projections. [[53]]

Interestingly, abnormal accumulation of APP and Abeta epitopes (as well as excessively phosphorylated tau in the form of paired helical filaments, PHF, see below) in vacuolated muscle fibers (VMF) is a characteristic feature of not just AD, but also the neuromuscular pathology such as IBM [[54, 55]]. Also important is the observation that in IBM there is an abnormal accumulation of a number of lipoprotein receptors (such as LDLR, VLDLR, LRP) and cholesterol within IBM vacuolated muscle fibers [[54]]. However, LDLR and VLDLR are also expressed at normal NMJ, suggesting “physiologic roles for them in transsynaptic signaling pathways and increased internalization of lipoproteins” at NMJ. Similarly, based on our physiological research with rat hippocampal slices, we earlier proposed that there is an activity-dependent demand for lipoprotein cholesterol and phospholipids at the central synapses [[56]]. Most important, the study by Jaworska-Wilczynska [[54]] confirms that there is a peripheral application of the functional crosstalk between Abeta, lipoproteins and cholesterol, that our own explanation of Abeta involvement in AD is about (see below).

References:

48. V. Askanas, WK. Engel, RB. Alvarez. Strong immunoreactivity of beta-amyloid precursor protein, including the beta-amyloid protein sequence, at human neuromuscular junctions. Neurosci. Lett. (1992) 143: 96-100.

49. L. Torroja, M. Packard, M. Gorczyca , K. White, V. Budnik. The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J. Neurosci. (1999) 19: 7793-7803.

50. L. Yang, B. Wang, C. Long, G. Wu, H. Zheng. Increased asynchronous release and aberrant calcium channel activation in amyloid precursor protein deficient neuromuscular synapses. Neuroscience (2007) 149(4):768-78.

51. P. Wang, G. Yang, DR. Mosier, P. Chang, T. Zaidi, YD. Gong, NM. Zhao, B. Dominguez, KF. Lee, WB. Gan, H. Zheng. Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J. Neurosci. (2005) 25(5):1219-25.

52. G. Yang, YD. Gong, K. Gong, WL. Jiang, E. Kwon, P. Wang, H. Zheng, XF. Zhang, WB. Gan, NM. Zhao. Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci. Lett. (2005) 384(1-2):66-71.

53. B. Wang, L. Yang, Z. Wang, H. Zheng. Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc. Natl. Acad. Sci. USA (2007) 104(35):14140-5.

54. M. Jaworska-Wilczynska, GM. Wilczynski, WK. Engel, DK. Strickland, KH. Weisgraber, V. Askanas. Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle. Neurology (2002) 58: 438-445.

55. AR. Koudinov, NV. Koudinova, U. Beisiegel. Cholesterol homeostasis failure at neuromuscular junctions and CNS synapses: a unifying cause of synaptic degeneration? Neurology online. (2002) Available at neurology.org

56. AR. Koudinov, NV. Koudinova. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. (2001) 15: 1858-1860. Available at fasebj.org , also available as a slide show at koudinov.info (to be reprinted at Alzheimer's Code):


Link to this publication: amyloid-beta-app-implicated-in-synapse

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What Alzheimer's disease code is? A semi-fiction novel of Alzheimer's disease research network of bandits from the United States University campuses

Question: What Alzheimer's disease code is?

Answer: Alzheimer's code is a semi-fiction novel of Alzheimer's disease research network of bandits from the United States University campuses and international Amyloid beta Biotech mafia members.

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Alzheimer's code is not-yet written semi-fiction mystery novel "The Alzheimer Code" by Alexei Koudinov (under his name Alex Kudinov-Sheffer). The idea of thi book come to Dr. Koudinov in summer 2006. The book scenario is not a fiction: it is a sad documentary of the contemporary very corrupted Alzheimer's disease research, leading scientists and academic Professors, Professional, Public and Governmental Institutions doing nothing to stop the preudoscience in-the-private interest.

Quoting original Alzheimer's code outline at early (archived) edition of Dr.Koudinov's Alzheimer's Club side bar:

"A semi-fiction documentary mystery novel "The Alzheimer Code" is under preparation. In this book the death of the President of the United States of America is followed by his preventive anti-amyloid vaccination against Alzheimer's disease. At the same time and for the same reason, in his agony of death Editor-in-Chief of London-based Nature science journal recalls he in fact witnessed the corruption of Alzheimer's pseudo-science, brought to the community by a keen student. This is a story of a corrupted Harvard University professor, a research center co-director and a godfather of the international network of science criminals. Be the first to know when Alzheimer Code is published..."

In fact, a reader does not need to wait for Alzheimer's code, as Dr. Koudinov Written evidence for United Kingdom Parliamentary inquiry on Science Publication and his "Open letter to President George W. Bush on conduct by scientists, STM journals, and Scientific Institutions", is a documentary summary of the facts behind the true story of Alzheimer's disease research mafia.

Additional original facts are scheduled to appear at www.alzheimercode.info, and will include original correspondence with the Wall Street journal Sharon Begley, Newsweek's Geofrey Cowley, Alzheimer's neurocientists, Editors of major Scientific Journals, Professional Organizations, Governmental Institutions and Funding bodies, and the observations of the conduct by scientists in major Alzheimer's laboratories and outside university campus.

Stay tuned, continue reading, as the story unfolds

Koudinov Letter to Forbes' Robert Langreth

Attention: Robert Langreth, Forbes, Senior Health Editor

This letter to you is also available at www.alzclub.org

Dear Forbes Editor,

I appreciate Forbes and Forbes series of articles on Alzheimer's and your and your commentators open minded view on the disease.

It's a pity there is no way at Forbes Blog to find a direct contact for articles' authors, as I am particularly interested to contact Robert Langreth of Treatments section, who authored several Blog articles on Alzheimer's clinical trial failure. Please forward this email to Mr. Robert Langreth!

I am Alzheimer's research who is talking on Alzheimer's amyloid beta protein as a normal and essential protein (see PDF of the article Alzheimer's amyloid beta is an essential synaptic protein, not neurotoxic junk for background reading and a preceeding short publication in Science magazine, my other selected reprints can be found here.

I also battle for disclosure of competing ineterests in Alzheimer's. I am a person behind three articles on Alzheimer's in the Wall Street Journal (2004, by Sharon Begley).

For background reading see my "Open letter to President George W. Bush on conduct by scientists, STM journals, and Scientific Institutions" (that should be now re-addressed to a new President of the US, I'll appreciate for your help in making such a letter public, as I am ready to re-address it, hope President Abama has more time on Ethics and Public health issues), and my written evidence to UK Parliamentary Committee on Science publishing "Editorial and Publisher Corruption"

It's a pity that you journalists are like on other Planet, not seeing what scientists like me are talking about for years, while this information is freely available on the Internet. Would you get such a deserved attention and talk on it in time, Eli Lilly would probably not enter just terminated Clinical Trial of a bad thought Alzheimer's drug.


Sincerely,

Alexei Koudinov, MD, PhD, DrSci

Amyloid beta and Amyloid Precursor Protein (APP) modulate the function of central synapses in brain

This is Part 4 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Amyloid beta and Amyloid Precursor Protein (APP) modulate the function of central synapses in brain

There are many articles reporting on amyloid beta role in modulating synaptic function [[reviewed in Ref. 17]]. In quoted above article by Malinow group of Cold Spring Harbor [[21, 43]] researchers found that evoked activity of neurons in hippocampal slices stimulated the production of Aβ. This happened primarily by an increased trafficking of APP towards beta secretase sites at the cell membrane. In addition of the increased Aβ formation, there could be an increase of the production of other APP derivates, such as AICD which could also modulate synaptic activity. It is well possible [[44]], that at “physiological expression levels of APP, this provided a negative feedback, since Abeta depresses synaptic activity. Without such depression, synaptic activity could become excessive, leading to excitotoxicity. Indeed, gamma secretase inhibition led to increased EPSC frequency [[21]], and kainate-induced seizures are potentiated in APP knockout mice [[45]]. Further to these studies, a recent report indicated that specific stimulation of NMDA receptors up-regulated APP, inhibited alpha-secretase activity and promoted amyloid beta production [[46]]. Collectively, these studies argue strongly that APP processing, and the presence of amyloid beta itself, are closely associated with synaptic activity and may serve to provide physiological control of activity, guarding against excessive glutamate release” [[44]].

Most recently it was show, that endogenous secreted APP-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory [[47]]. Specifically, “intrahippocampal infusion of antibodies targeted to endogenous sAPP alpha reduced long-term potentiation (LTP) in the dentate gyrus of adult rats by approximately 50%. Conversely, infusion of recombinant sAPP alpha dose-dependently increased LTP and facilitated in vitro tetanically evoked NMDA receptor-mediated currents. Pharmacological inhibition of alpha-secretase and other alpha-disintegrin-and-metalloproteases by TAPI-1 reduced both LTP and tetanus-evoked NMDA receptor-mediated currents in dentate granule cells. Both effects were prevented by co-application of exogenous recombinant sAPP alpha. Similarly, spatial memory was inhibited by intrahippocampal TAPI-1, an effect that was prevented by co-application of recombinant sAPP alpha” [[47]].

References:

17. AR. Koudinov, TT. Berezov. Alzheimers amyloid-beta (Abeta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiologica Exp. (2004) 64(1): 71-79.

21. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow. APP processing and synaptic function. Neuron (2003) 37:925-937


43. FR. Kamenetz, T. Tomita, DR. Borchelt, SS. Sisodia, T. Iwatsubo, R. Malinow. Activity dependent secretion of beta-amyloid: roles of beta-amyloid in synaptic transmission. Soc. Neurosci. Abstr. (2000) 26: 491.

44. HA. Pearson, C. Peers. Physiological roles for amyloid β peptides. J. Physiol. (2006) 15: 5–10.

45. JP. Steinbach, U. Muller, M. Leist, ZW. Li, P. Nicotera, A Aguzzi. Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. Cell Death Differ. (1998) 5:858–866.

46. S. Lesne, C. Ali, C. Gabriel, N Croci, ET. MacKenzie, CG. Glabe, M. Plotkine, C. Marchand-Verrecchia, D. Vivien, A. Buisson. NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. J. Neurosci. (2005) 25:9367–9377.

47. CJ. Taylor. Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol. Dis. (2008) (2):250-260.

Link to this publication: amyloid-beta-is-needed-for-synapse

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Lipoprotein-association of Alzheimer’s amyloid beta: a way to preserve phiological soluble state of a amphipathic apoAbeta molecule

This is Part 3 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

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Part 3 | Part 1 | Part 2

In line with the notion that Abeta is an apolipoprotein constituent of the HDL, we further showed that natural apoAbeta does not cross link with other apoliporoteins in normal CSF HDL (indicating a priority of apoAbeta-to-lipid interaction under normal condition) [[32]] and that an interaction of apoAbeta with apolipoproteins is a characteristic of Alzheimer’s CSF HDL samples [[25]]. In Alzheimer’s, therefore, there is a break of the lipoprotein structural integrity in a way that favors interaction of Abeta-to-Abeta(that creates oligomers [[33]] or apoAbeta-to-other apolipoprotein, shown for ApoE and ApoJ [[25]], and most recently for ApoA1 [[34]].

Of major support for the argument of the “mistaken identity” is the potent inhibition of neural toxicity of Abeta by lipoproteins [[34, 35, 36]], apoA1 and apoE, two major apolipoproteins and lipid binding proteins in the circulation and the brain, respectively [[34, 38]], and a risk factor for AD [[38]]. It is very unfortunate that these facts neither discussed nor experimentally addressed in key experimental [[12, 33]] and recent articles on oligomeric amyloid hypothesis [[13, 14]].

Additionally, there is a major experimental deficiency by oligomeric amyloid hypothesis proponents, and all others, who use “antibodies that can selectively target soluble oligomers of Abeta” [[1, 33]]. We do believe that these antibodies are poorly characterized and therefore may mistake natural lipoprotein-associated soluble apoAbeta (and other membrane-bound proteins) for lipid free Abeta oligomers. This is because micellar Abeta used for production of anti-oligomer antibodies [[33]] may well mimic the conformational motif of lipoprotein-bound apoAbeta and of other membrane-bound proteins [[39]].

Similarly, the experimental lack of the association of Abeta with lipoproteins (that potently arrests Ab neurotoxicity [[34,35,36,37]] questions physiological relevance of the study of the role for oligomers in synapse dysfunction and toxicity [[12,13,14]]. Moreover, it is well documented that “Abeta associat[ion] with membranes is dynamic and capable of adopting a number of conformations, each of which may have significance in understanding the progression of Alzheimer's disease.” [[29, 40]]. It is also shown that experimental Abeta neurotoxicity is modulated by the rate of peptide aggregation [[41]] and neuronal functional state [[42]]. Thus, potassium-induced membrane depolarization, a treatment modeling basic neuronal function, significantly reduced vulnerability to aggregated beta-amyloid peptides of cultured rat hippocampal neurons pretreated with high potassium [[42]]. Therefore, the lack of such a consideration is any experimental protocol on amyloid oligomers can generate a systemic error and lead to wrong conclusions (also see below).

References:


1. SR. Robinson, GM. Bishop, G. Munch. Alzheimer vaccine: amyloid  on trial. Bioessays (2003) 25:283-288.

12. DM. Walsh, I. Klyubin, JV. Fadeeva, WK. Cullen, R. Anwyl, MS. Wolfe, MJ. Rowan, DJ. Selkoe. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature (2002) 416:535-539.

13. Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R (2007) Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35(Pt 5), 1219-1223.

14. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1), 106-113.

25. AR. Koudinov, TT. Berezov, NV. Koudinova. The levels of soluble A in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. (2001) 314:115-118.


32. AR. Koudinov, TT. Berezov, NV. Koudinova. Alzheimer's amyloid beta protein association with high density lipoprotein in normal human cerebrospinal fluid: primary binding to lipid? Soc. Neurosci. (1997) 23:537.

33. R. Kayed, E. Head, JL. Thompson, TM. McIntire, SC. Milton, CW. Cotman, CG. Glabe. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (2003) 300:486-489.

34. Paula-Lima AC, Tricerri MA, Brito-Moreira J, Bomfim TR, Oliveira FF, Magdesian MH, Grinberg LT, Panizzutti R, Ferreira ST. Human apolipoprotein A-I binds amyloid-beta and prevents Abeta-induced neurotoxicity. Int. J. Biochem. Cell Biol. (2008 Dec 14) PMID 19130896

35. A. Cedazo-Minguez, M. Huttinger, RF. Cowburn. Beta-VLDL protects against Abeta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NeuroReport (2001) 12:201-206.

36. ZS. Farhangrazi, H. Ying, G. Bu, LL. Dugan, AM. Fagan, DW. Choi, DM. Holtzman. High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture. NeuroReport (1997) 8:1127-1130.

37. RP. Koldamova, IM. Lefterov, MI. Lefterova, JS. Lazo. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Abeta aggregation and toxicity. Biochemistry (2001) 40: 3553-3560.

38. JS. Whitson, MP. Mims, WJ. Strittmatter, T. Yamaki, JD. Morrisett, SH. Appel. Attenuation of the neurotoxic effect of Abeta amyloid peptide by apolipoprotein E. Biochem. Biophys. Res. Commun. (1994) 199(1):163-70.

39. B. Soreghan, C. Pike, R. Kayed, W. Tian, S. Milton, C. Cotman, CG. Glabe. The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties. Neuromolecular Med. (2002) 1:81-94

40. JA. Lemkul, DR. Bevan DR. A comparative molecular dynamics analysis of the amyloid beta-peptide in a lipid bilayer. Arch. Biochem. Biophys. (2008) 470(1):54-63.

41. LW. Hung, GD. Ciccotosto, E. Giannakis, DJ. Tew, K. Perez, CL. Masters, R. Cappai, JD. Wade, KJ. Barnham. Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity. J. Neurosci. (2008) 28(46):11950-8.

42. CJ. Pike, R. Balázs, CW. Cotman. Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization. J. Neurochem. (1996) 67(4):1774-7

Link to this publication: Alzheimer-amyloid-beta-lipoprotein

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Amyloid beta oligomers and lipoprotein apoAbeta: mistaken identity well possible, Part 2

This is Part 2 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

*****

Amyloid beta oligomers and lipoprotein apoAbeta: mistaken identity well possible

For a decade and a half we all know that Abeta is normally produced by cells and exists as normal soluble molecule and that it indeed is an important brain chemical with a diverse function [[reviewed in Ref.17]]. Even a key scientist of AD field, quoted above Dr. Selkoe acknowledged a number of years ago “that Abeta is produced physiologically and may have a normal function, but when it accumulates excessively in certain regions of the brain, it can oligomerize and attain new, potentially neurotoxic functions, as many labs worldwide -- including ours -- have shown. So, Abeta is normal, but it also appears to contribute to disease. Lowering its brain concentrations back to normal levels is one approach to treating and preventing AD. We are certainly not ignoring its physiological role.” [[18]]. Selkoe group was one of those who confirmed A association with the lipoproteins as a circulatory form of Abeta [[19]].

However, sadly and contrary to what Selkoe says, the physiological role for Abeta is largely ignored. We first hand experienced the opposition to deliver our public scientific concern on the validity of amyloid oligomers when attempting to contribute communication arising matter on the article published in Nature [[10, 12, 20]]. Our letter finally was published, but in a different journal, British Medical Journal [[15]]. A key date is March 26, 2003 when Neuron published an article that opened scientific discussion of synaptic function for Abeta and its precursor (APP) in the major neuroscience journal [[21]]. Interestingly, this research by the lab of an accomplished neuroscience leader was published three years after it was first reported at the 32nd Society for Neuroscience Annual Meeting 2000, enlightening the tight opposition by opponents for a public scientific presentation of the data on Abeta physiological function, and well supporting the conclusion of assisted by Dr. Koudinov widely recognized journalistic research by Sharon Beagley, major US-based science journalist (then a WSJ staff science writer) [[2,3,4,5,22]].

Our past study and research by others provided evidence that Abeta is a structure-functional apolipoprotein constituent (apoAbeta) of high density lipoproteins in both blood and cerebrospinal fluid [[23, 24, also see Refs. 17, 25 for detailed bibliography]]. Abeta is also secreted by hepatic cells [[26]] and by the astrocytes [[27]] as a part of lipoprotein complexes [[26, 27]]. Lipoproteins provide a proper thermodynamic environment for Abeta that shares with other apolipoproteins a unique structural property of amphipathicity [[28, 29]]. The amphipathicity explains an association of some apolipoproteins' hydrophobic parts with lipids of the outer layer of lipoprotein particles, and with apolar parts of other apolipoprotein molecules. Another characteristic of amphipathic molecules is the high tendency to self-associate which also takes place during protein oligomerization and amyloid fibril formation. Magnificent experimental evidence indicates that, out of the lipid environment, apolipoproteins are easily subjected to cross- and self- aggregation, oligo- and polymerization [[reviewed in Ref. 28]]. Moreover, some of them form amyloid fibrils and represent separate types of human amyloidosis, ex. apoA-I and serum amyloid A (AA). Interestingly, amyloid story of Alzheimer’ was introduced in 1984 by George Glenner [[30]], who studied different type amyloidoses. Should one carefully research his scientific contribution and legacy, he or she could be impressed by Dr. Glenner dedication and willingness to demonstrate Alzheimer’s is just another amyloid disease in line with other pathologies that he studied previously. Dr. Glenner died in 1995 at the age of 67, he suffered himself of systemic senile amyloidoses [[31]].

Well, Alzheimer’s story is not that simple as amyloid hypothesis proponents are trying to convince others. ...to be continued

References

17. AR. Koudinov, TT. Berezov. Alzheimers amyloid-beta (Abeta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiologica Exp. (2004) 64(1): 71-79. http://www.nencki.gov.pl/pdf/an/vol64/koudin.pdf

18. Correspondence with Dennis Selkoe. Alexei Koudinov web site (Aug. 2002-July 2004) Available at: http://koudinov.info/archive/selkoe.html

19. AL. Biere, B. Ostaszewski, ER. Stimson, BT. Hyman, JE. Maggio, DJ. Selkoe. Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. J. Biol. Chem. (1996) 271(51): 32916-22.

20. Correspondence with Nature Editorial office. (April 2002 – Dec. 2002) Available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinov2nature02.pdf

21. F. Kamenetz, T. Tomita, H. Hsieh, G. Seabrook, D. Borchelt, T. Iwatsubo, S. Sisodia, R. Malinow. APP processing and synaptic function. Neuron (2003) 37:925-937

22. Correspondence with Sharon Begley. Alzclub.org (2003) To be available at: http://www.alzclub.org

23. AR. Koudinov, E. Matsubara, B. Frangione, J. Ghiso. The Soluble form of Alzheimer's amyloid beta protein is complexed to high density lipoprotein 3 and very high density lipoprotein in normal human plasma plasma. Biochem. Biophys. Res. Commun. (1994) 205:1164-1171.

24. AR. Koudinov, NV. Koudinova, A. Kumar, R. Beavis, J. Ghiso. (1996) Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with high density lipoproteins. Biochem. Biophys. Res. Commun. (1996) 223:592-597

25. AR. Koudinov, TT. Berezov, NV. Koudinova. The levels of soluble A in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. (2001) 314:115-118.

26. AR. Koudinov, NV. Koudinova. Soluble amyloid beta protein is secreted by HepG2 cells as an apolipoprotein. Cell. Biol. Inter. (1997) 25:265-271.

27. MJ. Ladu, C Reardon, L Van Eldik, AM. Fagan, G Bu, DM. Holtzman. Lipoproteins in the central nervous system. Ann. NY Acad. Sci. (2000) 903: 167-175.

28. AR. Koudinov, TT. Berezov, A. Kumar, NV. Koudinova. (1998) Alzheimer's amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids. Clin. Chim. Acta (1998) 270: 75 –84.

29. AR. Koudinov, NV. Koudinova, TB. Berezov, YuD. Ivanov. HDL Phospholipid: a Natural Inhibitor of Alzheimer's Amyloid beta Fibrillogenesis? Clin. Chem. Lab. Med. (1999) 37: 993-4.

30. GG. Glenner, CW. Wong. (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. (1984) 120: 885-890.

31. W. Saxon. Dr. George G. Glenner, 67, Dies; Researched Alzheimer's Disease. New York Times. (14 July 1995). Available at: http://query.nytimes.com/gst/fullpage.html?res=990CE5DC1F30F937A25754C0A963958260

This AlzheimerCode publication URL

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

After amyloid hypothesis of Alhzeimer disease dementia, Part 1

This is Part 1 of the unabridged original manuscript, submitted by invitation in April 2009 to the theme issue of The Journal of Alzheimer's disease. Edited by the Journal edition was later published and is available upon request (will be published here at a later date)

Part 1 | Part 2 | Part 3 | Part 4 | Part 5

Alexei Koudinov, Elena Kezlya, Natalia Koudinova, Temirbolat Berezov Amyloid-beta, tau protein, and oxidative changes as a physiological compensatory mechanism to maintain CNS plasticity under Alzheimer's disease and other neurodegenerative conditions. Journal of Alzheimer’s Disease. 2009 18(2): 381-400. Unabridged Notedited Original Author Edition. Available at: http://alzheimercode.blogspot.com

*****

Amyloid hypothesis dominated the stage of Alzheimer’s disease research for over two decades but failed to explain the pathogenesis of Alzheimer’s disease (AD) or provide neurodegeneration cure. The original formulation of the hypothesis stated that at the origin of Alzheimer’s pathogenesis are the fibrillogenesis of amyloid beta protein (Abeta) and the formation of amyloid plaques that cause synaptic failure and clinical picture of memory loss. Interestingly, vast majority of Abeta experimentation was performed in vitro with the synthetic analogs of heterogeneous Abeta peptides (in terms of molecule length due to amino acid number variations). Also interesting is that despite of claimed abundance in AD brain, human Abeta was never purified in preparative quantities from Alzheimer’s brain sections. In 2002 failed experimental vaccine treatment of Alzheimer’s with antibodies against Abeta [[1]] caused severe brain inflammation in a significant number of patients, worthening of AD symptoms and patients’ death. This was the time of the first major public criticism of amyloid hypothesis and AD field. Two years later, Sharon Begley of the major international Wall Street Journal (WSJ) with the assistance of a number of premier scientists worldwide concluded in a series of the WSJ Science magazine [[2,3,4,5]] that over the years amyloid hypothesis has become dogma that retarded the development of the entire field for more then a decade. At the same time the hypothesis was challenged by a number of Alzheimer’s neuroscience research groups and finest science journalists worldwide [[2,3,4,5,6,7,8,9]]. Moreover, UK Parliament hearing [[10]] reported on the competing financial interest by a number of key players of AD field and science and professional establishment (such as American Academy of Neurology [[11]]), and uncovered the sad role of major STM journals (ex., Science, Nature, Neuron) in retarding the publication of alternative Alzheimer’s theories [[10]].

Yet, the pharmaceutical industry research is still dominated by amyloid hypothesis, primarily through the usage of mutant Abeta transgenic mice as a “gold standard” animal model for testing prospective Alzheimers therapies.

In reply on a challenge, amyloid proponents refurbished their big bucks backed argument. The latest edition of the amyloid theory states that the major AD culprit are amyloid beta oligomers [[12]]. They particularly say that “there is growing evidence that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Abeta (amyloid beta-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Abeta oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators.” [[13]]. In his latest review article, Dennis Selkoe of Harvard says that "during the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid beta-protein in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease." [[14]]. He adds, that “the reasons for elevated cortical Abeta levels in most patients with typical, late-onset AD are unknown, but… these could turn out to include augmented neuronal release of Abeta during some kinds of synaptic activity”. He thus allows physiological function for Abeta, but apparently is hesitant to discuss it publicly in greater details. “Elevated levels of soluble Abeta42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts, …can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats,” Selkoe concludes [[14]].

Lacking-since-inauguration is the possibility that Abeta oligomers are experimental artifacts [[12, 15]]. This is because missed is the pivotal consideration that as a lipoprotein structural component, Abeta molecule gets easy amyloidogenic oligomerization out of lipid environment. Association of Abeta with high density lipoproteins (HDL) in plasma and cerebrospinal fluid (CSF) was first demonstrated by us in early 1990s [[16]], confirmed by many groups since then, and is an apparent structural reason for Abeta involvement in lipid metabolism, as outlined below. ...To be continued

References:

1. SR. Robinson, GM. Bishop, G. Munch. Alzheimer vaccine: amyloid  on trial. Bioessays (2003) 25:283-288.

2. S. Begley. Is Alzheimer's Field Blocking Research Into Other Causes? The Wall Street Journal (9 April 2004) p.B.1
http://online.wsj.com/article/SB108145279348578177.html

3. S. Begley. Scientists World-Wide Battle a Narrow View Of Alzheimer's Cause.
The Wall Street Journal (16 April 2004) p.A.9
http://online.wsj.com/article/SB108206188684384119.html

4. S Begley. Fevered Debate Over Alzheimer's Origins Causes Deep Divisions. The Wall Street Journal (6 August 2004) p.B.1 http://neurobiologyoflipids.org/news/news2004.html#wsj060804

5. RW. Mahley, S Goldberg, RJ. Hodes. Does Bias Confound Alzheimer's Research? The Wall Street Journal (27 April 2004) p.A.19 http://neurobiologyoflipids.org/news/news2004.html#wsj

6. Bishop GM, Robinson SR, Smith MA, Perry G, Atwood CS. Call for Elan to publish Alzheimer's trial details. Nature. 2002 Apr 18;416(6882):672704047.

7. AR. Koudinov, MA. Smith, G. Perry, NV. Koudinova. Alzheimer's disease and amyloid beta protein. Science (25 June 2002) Available at: http://www.sciencemag.org/cgi/eletters/296/5575/1991

8. Correspondence with Geoffrey Cowley, Newsweek Health and Science reporter (2003) To be available at: http://alzheimercode.blogspot.com

9. Crowley D. (16 Nov 2003) Selkoe's sale of Elan shares referred to SEC. Sunday Times. Available at: http://www.timesonline.co.uk/article/0,,2095-895532,00.html

10. Koudinov AR. Part 1: Editorial and publisher corruption. Written evidence for inquiry on Scientific Publication by Science and Technology Committee, UK House of Commons. (2004) Available at: http://www.publications.parliament.uk/pa/cm200304/cmselect/cmsctech/399/399we125.htm Also available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinovwrittenevidence.pdf

11. Correspondence with Murray Sagsveen, General Counsel and Associate Executive Director, American Academy of Neurology (AAN). (Nov. 2002-March 2003) Available at: http://neurobiologyoflipids.org/editors/alexeikoudinov/pdfdocs/submittedletters/koudinov2aansagsveennov02march03.pdf

12. DM. Walsh, I. Klyubin, JV. Fadeeva, WK. Cullen, R. Anwyl, MS. Wolfe, MJ. Rowan, DJ. Selkoe. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature (2002) 416:535-539.

13. Rowan MJ, Klyubin I, Wang Q, Hu NW, Anwyl R (2007) Synaptic memory mechanisms: Alzheimer's disease amyloid beta-peptide-induced dysfunction. Biochem Soc Trans 35(Pt 5), 1219-1223.

14. Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192(1), 106-113.

15. AR. Koudinov, NV. Koudinova. Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or Beware: the dogma is revitalized. British Medical J. (2002) Available at: http://bmj.com/cgi/eletters/324/7338/656


16. NV. Koudinova, A. Kontush, TT. Berezov, AR. Koudinov. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiology Lipids (2003) 1:6. Available at: http://neurobiologyoflipids.org/content/1/6/

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