Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons.
Microtubule-associated protein 2 (MAP2) is a neuron-specific cytoskeletal protein enriched in dendrites and cell bodies. MAP2 regulates microtubule stability in a phosphorylation-dependent manner, which has been implicated in dendrite outgrowth and branching. We have previously reported that cholesterol deficiency causes tau phosphorylation and microtubule depolymerization in axons (Fan et al. 2001). To investigate whether cholesterol also modulates microtubule stability in dendrites by modulating MAP2 phosphorylation, we examined the effect of compactin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and TU-2078 (TU), a squalene epoxidase inhibitor, on these parameters using cultured neurons. We have found that cholesterol deficiency induced by compactin and TU, inhibited dendrite outgrowth, but not of axons, and attenuated axonal branching. Dephosphorylation of MAP2 and microtubule depolymerization accompanied these alterations. The amount of protein phosphatase 2 A (PP2A) and its activity in association with microtubules were decreased, while those unbound to microtubules were increased. The synthesized ceramide levels and the total ceramide content were increased in these cholesterol-deficient neurons. These alterations caused by compactin were prevented by concurrent treatment of cultured neurons with beta-migrating very-low-density lipoproteins (beta-VLDL) or cholesterol. Taken together, we propose that cholesterol-deficiency causes a selective inhibition of dendrite outgrowth due to the decreased stability of microtubules as a result of inhibition of MAP2 phosphorylation.
Fan
Qi-Wen
QW
Department of Dementia Research, National Institute for Longevity Sciences, Aichi, Japan.
Yu
Wei
W
Gong
Jian-Sheng
JS
Zou
Kun
K
Sawamura
Naoya
N
Senda
Takao
T
Yanagisawa
Katsuhiko
K
Michikawa
Makoto
M
D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000172:deficiency / Q000502:physiology*; D003712:Dendrites / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D017207:Rats, Sprague-Dawley
D002518:Ceramides; D008869:Microtubule-Associated Proteins; D002784:Cholesterol; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2