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Finding  Intelligent  Solutions 
to unlock Alzheimer's mystery


Modulation of Cholesterol Metabolism Initiates Alzheimer's Amyloid Deposition and Neuronal Dysfunction

LAY SUMMARY ARTICLE FOR SFN2000 SCIENTIFIC SESSION No.181.14

Natalia V. Koudinova & Alexei R. Koudinov

For continuous coverage, questions and to locate our related recent key FASEB J and Neurosci Lett articles please see: http://anzwers.org/free/neurology/

Our results provide evidence that brain cholesterol disbalance is a cause of Alzheimer’s-like brain amyloid and neuronal dysfunction. 

Almost everyone knows that one of the major pathological features of Alzheimer’s disease is brain amyloid. This dense insoluble aggregate called neuritic plaque is a tiny brain area full of different chemicals and localized between degenerating neurons. The major component of plaques is a small molecule called amyloid beta protein. Although the role of amyloid beta in Alzheimer’s disease is not clear, many scientists believe that it is a biological waste and the disease cause. This is despite the fact we learned in 1992 - at that time several research groups showed that there is a soluble form of amyloid beta. 

Soluble amyloid beta is present in blood, cerebrospinal fluid and in the brain of normal people and in Alzheimer’s patients. This implied that the production of amyloid beta served some important physiological function. Moreover, the way amyloid beta rises from its big amyloid precursor protein is similar in humans and insects. This fact of the nature conservatism means the vital necessity of amyloid beta for living organisms [this issue will be presented by us in detail at the History of Neuroscience  session (Session #: 20.12)].

Soluble amyloid beta protein is different from Alzheimer’s brain amyloid beta aggregates by physicochemical properties. 

Evidence described in our early papers indicates an association of soluble amyloid beta protein with a special group of normal blood and cerebrospinal fluid lipoproteins, high density lipoproteins, believed to be a protective factor in atherosclerotic vascular and heart diseases. Lipoproteins are lipid-protein particles that carry cholesterol, other lipids and many sticky proteins, called apolipoproteins. Association of amyloid beta with lipoproteins suggested a mechanism for protecting amyloid from aggregation in the brain of normal people. This is because amyloid beta could hide the sticky parts of its molecule between the lipids of  the lipoprotein complex. Moreover, this association implied that amyloid beta protein is involved in lipid metabolism, as are many other apolipoproteins. 

We tested this possibility and found that amyloid beta modulates cholesterol esterification in blood. This chemical reaction (catalyzed by a special enzyme) helps the body to redistribute cholesterol or get rid of it and is significantly decreased in blood and cerebrospinal fluid of Alzheimer’s and Down syndrome (sharing with Alzheimer’s disease brain amyloid deposition) patients. We further showed that amyloid beta protein modulates cholesterol synthesis in neurons in cell culture and in rat brain slices maintained live in vitro

These previous reports for the first time proposing amyloid beta protein as a player in the game of cholesterol turnover, were recently confirmed and extended by several other groups. They represent a very important background for our current study which will be presented on November 5, 2000 at the Society for Neuroscience Meeting in New Orleans, LA for the first time. 

These days there is an increasing number of papers implicating cholesterol in Alzheimer’s disease. In accord with the dogma, they mainly evaluate the effect of cholesterol on brain amyloid beta manufacturing and deposition. 

However, there has been no study that has examined the role of brain cholesterol in neuron function. The long term objective of our research is to understand an interaction of cholesterol and amyloid beta in memory formation and memory storage on the molecular level and in Alzheimer’s disease and Down syndrome. In an attempt to unravel this important issue we first were looking for a laboratory animal, which would have modified both brain cholesterol and amyloid beta metabolism. 

By modifying rat cholesterol status with the diet containing two percent cholesterol for several months we generated an animal model, expressing brain amyloid morphologically identical to neuritic plaque and vascular amyloid of Alzheimer’s disease brain specimens (verified by immunohistochemical analysis of brain sections for amyloid beta). 

We then prepared slices from the hippocampus, a special brain area essential for learning and memory storage and strongly expressing special receptors to handle neuronal uptake of lipoproteins carrying cholesterol. The very thin slices (less than half a millimeter) of the hippocampus, retaining the hippocampal integrity and neuronal architecture, were maintained live in vitro and subjected to a study of cholesterol synthesis. To this end we labeled slices with radioactive acetate, a simple precursor molecule which gets incorporated into all cellular lipids. 

After the labeling the lipids were extracted from the slices, separated by a special technique and quantitated by radioactivity counting. This methodology allowed us to trace the higher rate of cholesterol and phospholipid (two major lipid components of cell membrane) synthesis in rats fed with a cholesterol diet, and to conclude that brain cholesterol synthesis upregulation is a cause of Alzheimer’s-like brain amyloid. We analyzed many cholesterol-fed rats and control rats and an even greater number of hippocampal slices to ensure the statistical validity of the results. 

We also performed electrophysiological analyses of slices and found that cholesterol-fed rats lack hippocampal long term potentiation, an experimental amplification of synaptic transmission (see below), a cellular model of memory formation. 

The next step in this research is an elucidation of the detailed mechanism of the impaired synaptic function. 

In the brain, when the information (coded as a nerve impulse) is transmitted from one neuron to another, the first neuron output nerve ending releases special vesicles containing chemicals called neurotransmitters. The neurotransmitter molecules then bind to receptors on the surface of the input processes of the neuron-receiver. After the transient interaction with a receptor on the neuron-receiver, neurostransmitter molecules normally return back to the output nerve ending (from where they were released) in order to be ready for the next act of information transmission. This transient receptor interaction with neurotransmitters, occurring at the minute gap between neurons, called synapse, launches a number of chemical changes inside the neuron-receiver (called postsynaptic cell, in contrast to the releasing neurotransmitter presynaptic cell). These changes are the basis for the nerve signal processing, amplification, and for the formation of memory and memory storage. 

We will, therefore, elucidate the particular break in the chain of the events involved in neuron synaptic impairment under  cholesterol dynamics misregulation (see lay summary and slide show for SFN 2001 scientific presentation). Thus we will learn whether there is an abnormal receptor machinery function in the postsynaptic cells or if there is a defective neurotrasmitter release and recycling in the presynaptic neurons. We will also attempt to elucidate the role of amyloid beta in brain cholesterol redistribution under the synaptic function amplification and will examine TAU protein  pathology (another key feature of Alzheimer’s disease, characterized by the formation inside neurons the twisted strands of fiber, or neurofibrillary tangles, composed of pathologically modified TAU protein) under cholesterol modulation.

The results of our study will illuminate the still obscured basic mechanism of neuronal membrane rearrangements during synaptic amplification, and the role of cholesterol and amyloid beta in this process (see lay summary and slide show for SFN 2001 scientific presentation). 

Most importantly, our research should help us to unmask the story of the neuritic plaque and to interpret coded in it the still hidden pages of the Alzheimer’s mystery. This is why we are working hard to alleviate human suffering.

We joined the study of Alzheimer's disease in 1992. At that time it was shown that amyloid beta is a normal protein. We realized that the nature of amyloid deposits in Alzheimer’s disease, as well as its biological cause and consequences, could be approached through the study of the normal biology of amyloid beta. 

After graduation in 1992 as a medical doctor (from Russian State Medical University, Moscow, Russia) I was happy to accept an invitation to come to the laboratory of Professor Blas Frangione, an internationally recognized scientist in the field of Alzheimer’s disease and the recipient of the recently established Henry Wisniewski memorial award, in the Department of Pathology at New York University Medical Center, to complete my Ph.D. research project. After the Ph.D. thesis defense I continued working in Dr. Frangione's laboratory as a postdoctoral fellow. 

Since 1996 I joined the Institute of Biomedical Chemistry and the National Mental Health Research Center, Moscow, Russia, as a senior research scientist. Currently, I am a visiting scientist at the Department of Biological Regulation at the Weizmann Institute of Science, Rehovot, Israel. 

Our background research was recognised by Science magazine that named Natalia Koudinova a finalist in Pharmacia Biotech and Science Magazine Prize for Young Scientists Competition 1997.


For further details please see our year 2001 Annual Meeting teaching neuroscience sessions (also presented in the meeting press book) entitled “Brain cholesterol and neuronal function” (session #23.4) and "Neuronal cholesterol pathology is the cause of Alzheimer's disease" (session #23.3). Also, please see our scientific session “Essential role for cholesterol in synaptic plasticity and neuronal degeneration” and its press book summary article (session #752.5) and slide show
 

Text copyright © 2000, 2001 by Alexei Koudinov and Natalia Koudinova


Back to Drs.Koudinov SFN 2001/2000 Meeting Central

 


This article or any it part may be reproduced without our permission in case your report includes citation of the article source, our names and you let us know where your report will appear or has appeared.

To cite this article use:
N.V. Koudinova & A.R. Koudinov. (2000) Modulation of Cholesterol Metabolism Initiates Alzheimer's Amyloid Deposition and Neuronal Dysfunction. 30th Soc Neurosci Meeting Press book. part II, pp.87-89

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