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)
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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, 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]].
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]].
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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