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Updated 26 November 2005
Brain Cholesterol Pathology is the Cause of Alzheimer's Disease
By Alexei R. Koudinov and Natalia V. Koudinova, Neurobiology of Lipids, Russian Academy of Medical Sciences—Posted 19 August 2002
We propose that cholesterol homeostasis biological misregulation itself has a key role for synaptic plasticity impairment,
neuronal degeneration and is the primary cause for several Alzheimer's hallmarks not limited to brain amyloid. Moreover,
Alzheimer's changes in neurochemistry of amyloid b, tau, neuronal cytoskeleton, and oxidative stress reactions represent
physiological transitory mechanisms aiming to compensate impaired brain cholesterol dynamics and/or associated neurotransmission
and synaptic plasticity failure.
To see the full text of our article in Clinical Medicine and Health Research NetPrints (27 November 2001),
download the PDF or go to this link.
Hypothesis Update—Posted 22 September 2003
Amyloid b protein restores hippocampal long term potentiation: a central role for cholesterol? An update on "Brain cholesterol pathology is the cause of Alzheimer's disease."
By Alexei R. Koudinov and Natalia V. Koudinova, Neurobiology of Lipids, Russian Academy of Medical Sciences
The basic formulation of our hypothesis (see above) proposed that Alzheimer's changes in neurochemistry of amyloid b, tau, neuronal cytoskeleton, and oxidative stress reactions represent physiological transitory mechanisms aiming to compensate impaired brain cholesterol dynamics and/or associated neurotransmission and synaptic plasticity failure.
We now show that amyloid b protein restores hippocampal long term potentiation, and that this effect could be mediated by Ab's facilitatory role in neural/brain dynamics of cholesterol, an essential molecule for brain function, plasticity and neurodegeneration.
Detailed discussion is in open access as the Neurobiology of Lipids article:
Koudinov A and Koudinova N. Amyloid b protein restores hippocampal long term potentiation: a central role for cholesterol? Neurobiology of Lipids 1, 8 (2003). Published online September 15, 2003. Article.
Hypothesis Update—Posted 20 October 2004
Cholesterol homeostasis failure: a unifying cause of synaptic degeneration
By Alexei R. Koudinov and Natalia V. Koudinova, Neurobiology of Lipids, Russian Academy of Medical Sciences
We and others previously showed that fine tuning of neural cholesterol dynamics is essential for basic synapse function, plasticity and behavior (1-4). Significant experimental evidence indicates that cholinergic function, ionotropic and metabotropic receptor machinery, excessive tau phosphorylation, the change of amyloid beta (Abeta or Aβ) biochemistry, neural oxidative stress reactions, and other features of neurodegeneration also depend on fine tuning of brain cholesterol homeostasis. This evidence implies that cholesterol homeostasis break is the unifying primary cause of sporadic and familial Alzheimers disease (AD), neuromuscular diseases (particularly inclusion-body myositis), Niemann-Pick's type C disease and Down syndrome. Furthermore, the interaction of cholesterol and amyloid beta and APP biochemistry explans why rare genetic cases of AD (associated with mutations in amyloid beta protein precursor and presenilin (PS) genes) are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and Aβ generation.
The reciprocal effect of Aβ on cholesterol synthesis, cellular uptake, efflux, esterification, and its relation to the restoration of synaptic plasticity may represent one of the not comprehend physiological functions of Aβ. This is because the central event for cholesterol-mediated (or any other type) synapse degeneration is an impairment of neurotransmission and synaptic function/plasticity, which triggers a set of similar physiological compensatory mechanisms to restore broken function. Primary cause of a disease defines the specificity of a chemical neurotransmission break (ex. dopaminergic system in Parkinson's), and the fine tuning of compensatory mechanisms, yielding the unique pattern of neurodegenerative markers overlap in different diseases. The proposed scenario implies that battling secondary degenerative markers (such as amyloid or tau) sadly has no ability to effectively cure CNS degeneration.
Source
Koudinova NV, Berezov TT, Koudinov AR. Cholesterol homeostasis failure: a unifying cause of synaptic degeneration. Soc Neurosci 34th Annual Meeting Presentation. Program No. 30.7 (Sat-Wed, Oct. 23-27, 2004, 10:00 AM - 11:00 AM, 3:00 PM - 4:00 PM, Poster JJJ23). Abstract; Original
SFN poster Slide show [.ppt]; Slide
show lecture article [.pdf}
References
1. Koudinov AR. Dietary cholesterol impairs behavior of lab rats with naive genotype: evidence for the sufficiency of the environmental brain cholesterol modulation to cause sporadic Alzheimer's neurodegeneration phenotype. Soc Neurosci Abstr. Program No. 730.8 (2003). Abstract
2. Koudinov AR, Koudinova NV. Cholesterol, synaptic function and Alzheimer's disease. Pharmacopsych. 36, S107-112 (2003). Free full text of the preprint:
Further Reading
34th Society for Neuroscience annual meeting neurobiology of lipids sessions. Neurobiol. Lipids Vol.3, 5 (2004), Published online 13 September 2004.
33rd Society for Neuroscience annual meeting neurobiology of lipids sessions . Neurobiol. Lipids Vol.2, 3 (2003), Published online 1 October 2003.
Hypothesis Update—Posted 26 November 2005
At a Crossroad of Amyloid-β Functional Pathways: Homeostasis of cholesterol and lipid peroxidation are integrated components of neural membrane neuroplasticity mechanisms and neurodegeneration
by Alexei Koudinov and Natalia Koudinova
Cholesterol dynamics failure is the primary pathogenic cause in a number of diseases, such as Alzheimer's (AD), Down syndrome, neuromuscular disorders, and Niemann-Pick type C (NPC) disease [1,2,3]. Other neurodegenerative diseases may have another primary pathological break (e.g., the break of the forebrain dopamine system in Parkinson disease). In any type of neurodegeneration, however, the brain operates its standard set of compensatory mechanisms, causing the overlap of morphologic changes, and explaining the unity of markers across the spectrum of neurodegenerative disorders [1,2,3]. We previously showed that fine tuning of neural cholesterol dynamics is essential for synapse function, plasticity, behavior, and suggested that in familial cases of Alzheimer disease, mutations in amyloid precursor protein (APP) and presenilin (PS) genes are translated into the disorder via membrane cholesterol sensitivity of APP processing by secretases and amyloid-β protein generation [4,5].
This was recently confirmed by others [6]. We also reported that impaired long-term potentiation (LTP) in Alzheimer transgenic mouse models depends on human antioxidant enzyme Cu/Zn-SOD, not APP expression, and that oxidative mechanisms (such as hydrogen peroxide treatment) and lipid peroxidation (LPO) modulate synaptic plasticity [7,8]. Thus, we showed that LPO induction with a promoter AAPH slowly decreased baseline evoked postsynaptic potentials (extracellular EPSP) in naive rat hippocampal slices, and tetanus-induced tLTP values. The effect was not abolished by the AAPH washout, and caused no ability to express tLTP after the treatment. In contrast, vitamin E (classical LPO blocker) did not affect normal maintenance of the tLTP and itself produced slow onset potentiation at a non-potentiated pathway. Therefore, cholesterol homeostasis and LPO are essential for neuronal membrane structure-functional plasticity/integrity, membrane ability to fine-tune activity-dependent synaptic strength, and associated enzyme/receptor function. This is maintained by the integration of cholesterol synthesis, intracellular and intramembrane redistribution, cellular lipoprotein uptake and efflux of cholesterol (regulated by amyloid-β (Aβ) and APP metabolism), and membrane fluidity and oxidative stress modulation by LPO and Aβ, respectively [9-15]. In such a scenario, Aβ (as well as APP and its processing pathways) remains a pivotal molecule of Alzheimer pathogenesis, acting as a functional component regulating neural membrane integrity by modulating cholesterol dynamics and oxidative mechanisms.
References:
1. Koudinov AR, Koudinova NV. Cholesterol homeostasis failure as a unifying cause of synaptic degeneration. J Neurol Sci. 2005 Mar 15; 229-230:233-40. Abstract
2. Koudinova NV, Berezov TT, Koudinov AR. Cholesterol homeostasis failure: a unifying cause of synaptic degeneration. Society for Neuroscience Meeting 2004. Program No. 23.8 (2004). Abstract
3. Koudinov AR, Koudinova NV. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 2001 Aug;15(10):1858-60. 14731; Koudinov AR, Koudinova NV. Cholesterol's role in synapse formation. Science. 2002 Mar 22;295(5563):2213. Abstract
4. Koudinova NV, Koudinov AR. APP and amyloid beta protein are integrated sensor-effector system for neural cholesterol and membrane dynamics regulation. Society for Neuroscience Meeting 2003. Program No. 30.7 (2003). Abstract
5. Koudinov AR, Koudinova NV. Amyloid beta protein restores hippocampal long term potentiation: a central role for cholesterol? Neurobiol. Lipids. 2003 Sept; 1:8. Abstract
6. Grimm MOW, Grimm HS, Patzold AJ, Zinser EG, Halonen R, Duering M, Tschape JA, De Strooper B, Muller U, Shen J, Hartmann T. Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nature Cell Biology (9 October 2005) ePub ahead of print. Abstract
7. Koudinov AR, Berezov TT. Is oxidative stress a physiologic modulator for neural plasticity? 34th Society for Neuroscience Meeting 2004. Program No.556.8 (2004) Abstract
8. Koudinov AR, Beresov TT. Lipid peroxidation modulates synaptic plasticity and implicates compensatory nature of oxidative mechanisms in neurodegeneration. 35th Society for Neuroscience Meeting 2005. Program No.903.11 (2005). Abstract
9. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol. Lipids Vol.1, 6 (2003). Abstract
10. Koudinov AR, Berezov TT. Cholesterol, statins, and Alzheimer disease. PLoS Med. 2005 Mar;2(3):e81. Abstract
11. Kontush A. Apolipoprotein Abeta: black sheep in a good family. Brain Pathol. (Oct 2004) 14(4):433-47. Abstract
12. Lee HG, Castellani RJ, Zhu X, Perry G, Smith MA. Amyloid-beta in Alzheimer's disease: the horse or the cart? Pathogenic or protective? Int J Exp Pathol. (June 2005) ;86(3):133-8. Abstract
13. Koudinov AR, Berezov TT. Alzheimer's amyloid-beta (A beta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiol Exp (Wars). 2004;64(1):71-9 2.0 Abstract
14. Alzheimer's disease and amyloid cascade hypothesis: not easy connection. Society for Neuroscience Meeting 2004.Program No.91.5 (2004). Abstract
15. Koudinova NV. Alzheimer's amyloid beta oligomers and lipoprotein apoAbeta: mistaken identity is possible. Bioessays. (Oct 2003) 25(10):1024. Abstract
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