Essential role for cholesterol in synaptic plasticity and neuronal degeneration

There is no understanding of the role of cholesterol and phospholipids in t he mechanisms of synaptic function and neurodegeneration. Here we report th at cholesterol disbalance is critical for synaptic transmission and plastic ity as investigated by a study of paired pulse facilitation and long-term p otentiation (LTP). Extracellular recording of field-evoked postsynaptic pot entials showed enhanced PPF ratio and an impairment of LTP in CA1 subfield of adult rat ex-vivo hippocampal slices subjected to cyclodextrin- or norma l human CSF-HDL3-mediated cholesterol efflux. Immunofluorescence with antib odies against neurofilament and tau revealed that cholesterol and phospholi pids depletion causes alteration of normal hippocampal neurites and the app earance of PHF-tau in the mossy fibers. We further find that LTP and amyloi d beta protein increase [C-14] acetate label incorporation into newly synth esized hippocampal membrane lipids. Our results indicate the importance of neuronal cholesterol redistribution and synthesis for synaptic plasticity a nd neurodegeneration.