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  • Title: Cholesterol, synaptic function and Alzheimer's disease.
    Author: Koudinov AR, Koudinova NV.
    Journal: Pharmacopsychiatry; 2003 Sep; 36 Suppl 2():S107-12. PubMed ID: 14574623.
    Abstract:
    We experimentally modeled neuronal cholesterol imbalance by creating an acute biochemical increase in cholesterol turnover in rat hippocampal slices. This kind of experimental set-up impairs the redistribution of cholesterol from one cell to another via lipoprotein transport. While increasing cholesterol removal or immediately afterwards, we evoked and recorded two brain waveforms, paired pulse facilitation (PPF) and long-term potentiation (LTP), which indicate neurotransmission and synaptic plasticity, respectively. We found that the lack of cholesterol supply to neurons impaired both PPF and LTP. From additional immunofluorescent analysis of the slices, we could demonstrate that the cholesterol imbalance also caused neurodegeneration of hippocampal neural cell processes and the appearance of tau protein pathology in the mossy fibers. We also analyzed rats fed a cholesterol diet and discovered that they had increased hippocampal cholesterol biosynthesis and impaired LTP. Cholesterol-fed rats were also characterized by Alzheimer's-like brain amyloid that we did not observe in the model of acute cholesterol imbalance. Our data and research by others suggest that biological cholesterol homeostasis dysregulation itself plays a key role in synaptic plasticity impairment and neuronal degeneration, and is the primary cause for several Alzheimer's disease hallmarks not limited to brain amyloids. Moreover, changes in the neurochemistry of amyloid beta, tau, neuronal cytoskeleton, and oxidative stress reactions due to Alzheimer's likely represent physiological transitory mechanisms that aim to compensate impaired brain cholesterol dynamics and/or associated neurotransmission and synaptic plasticity failure. Part of this article was published as netprint and is available under the URL http://clinmed.netprints.org/cgi/content/full/2001100005v1.
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