ESSENTIAL ROLE FOR CHOLESTEROL AND PHOSPHOLIPIDS IN NEURONAL AND SYNAPTIC PLASTICITY AND DYSFUNCTION
A.R. Koudinov1,2 , N.V. Koudinova2
1. Russian Academy of Medical Sciences, National Mental Health Research Center, Institute of Biomedical Chemistry, Timoshenko 38-27, Moscow 121359, Russian Federation
2. Weizmann Institute of Science, Department of Neurobiology and
Molecular Genetics, Rehovot 76100, Israel
There is no understanding of the role of cholesterol and phospholipids in the mechanisms of synaptic function and neurodegeneration. Here we report that cholesterol is essential for synaptic transmission and plasticity as investigated by a study of paired pulse facilitation (PPF) and long-term potentiation (LTP). Extracellular recording of field evoked postsynaptic potentials (fEPSP) showed significantly enhanced PPF of fEPSP slopes and an impairment of the LTP in CA1 subfield of adult rat ex-vivo hippocampal slices subjected to cyclodextrin- or normal human CSF-HDL-mediated cholesterol efflux. Immunofluorescence with antibodies against neurofilament and tau revealed that limited cholesterol and phospholipids depletion causes marked alteration of the normal hippocampal neuronal cytoskeleton, an increase in the number of tau-positive pyramidal and granule cells of the CA1 and the dentate gyrus, respectively, and the appearance of the PHF-phosphorylated tau in the mossy fibers. We further find that the LTP (and not a K+-evoked depolarization) causes an increase of [14C]acetate label incorporation into the hippocampal membrane lipids, suggesting the importance of neuronal lipid redistribution and synthesis for the plasticity-dependent neuronal membrane rearangements. Our current study and recent report on the classical b amyloid pathology and synaptic plasticity deficit in cholesterol-fed rats (Koudinov and Koudinova, Soc Neurosci Abst 26: 4526 ) also indicate that hippocampal cholesterol and phospholipids disregulation is a sufficient event to cause the major Alzheimer’s features of amyloid b deposition, abnormal neurities, a change in tau biology, and synaptic dysfunction.
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