Cholesterol reduction impairs exocytosis of synaptic vesicles

Author(s): Linetti A, Fratangeli A, Taverna E, Valnegri P, Francolini  M, et al.


Cholesterol and sphingolipids are abundant in neuronal membranes, where they help the organisation of the membrane microdomains involved in major roles such as axonal and dendritic growth, and synapse and spine stability. The aim of this study was to analyse their roles in presynaptic physiology. We first confirmed the presence of proteins of the exocytic machinery (SNARES and Ca(v)2.1 channels) in the lipid microdomains of cultured neurons, and then incubated the neurons with fumonisin B (an inhibitor of sphingolipid synthesis), or with mevastatin or zaragozic acid (two compounds that affect the synthesis of cholesterol by inhibiting HMG-CoA reductase or squalene synthase). The results demonstrate that fumonisin B and zaragozic acid efficiently decrease sphingolipid and cholesterol levels without greatly affecting the viability of neurons or the expression of synaptic proteins. Electron microscopy showed that the morphology and number of synaptic vesicles in the presynaptic boutons of cholesterol-depleted neurons were similar to those observed in control neurons. Zaragozic acid (but not fumonisin B) treatment impaired synaptic vesicle uptake of the lipophilic dye FM1-43 and an antibody directed against the luminal epitope of synaptotagmin-1, effects that depended on the reduction in cholesterol because they were reversed by cholesterol reloading. The time-lapse confocal imaging of neurons transfected with ecliptic SynaptopHluorin showed that cholesterol depletion affects the post-depolarisation increase in fluorescence intensity. Taken together, these findings show that reduced cholesterol levels impair synaptic vesicle exocytosis in cultured neurons.

Similar Articles

Alzheimer's  disease: the challenge of the second century

Author(s): Holtzman DM, Morris JC, Goate AM

Epidemiology of  Alzheimer disease

Author(s): Reitz C, Brayne C, Mayeux R

Trafficking regulation of proteins in Alzheimer's disease

Author(s): Jiang S, Li Y, Zhang X, Bu G, Xu H, et al.

Trafficking and proteolytic processing of APP

Author(s): Haass C, Kaether C, Thinakaran G, Sisodia S

Efficient inhibition of the Alzheimer's disease  beta-secretase by membrane targeting

Author(s): Rajendran L, Schneider A, Schlechtingen G, Weidlich S,  Ries J, et al.

Crystal structure of an active form of BACE1, an enzyme responsible for  amyloid beta protein production

Author(s): Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, et al. 

Aβ-degrading enzymes: potential for treatment of Alzheimer disease

Author(s): Miners JS, Barua N, Kehoe PG, Gill S, Love S

Nonsteroidal anti-inflammatory drugs repress beta-secretase gene  promoter activity by the activation of PPARgamma

Author(s): Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E,  et al.

Critical time window of neuronal cholesterol  synthesis during neurite outgrowth

Author(s): Fünfschilling U, Jockusch WJ, Sivakumar N, Möbius W,  Corthals K, et al.

Cholesterol  homeostasis in neurons and glial cells

Author(s): Vance JE, Hayashi H, Karten B

Lipoproteins and their receptors in the central nervous system

Author(s): Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH