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Glucosylceramide synthase decrease in frontal cortex of Alzheimer brain correlates with abnormal increase in endogenous ceramides: consequences to morphology and viability on enzyme suppression in cultured primary neurons.

Abstract：

:Abnormal increase in native long-chain ceramides (lcCer) in AD implicates roles in neuronal atrophy and cognitive dysfunction especially in view of divergent roles this second messenger plays in cell function. Since clearance is mediated by glucosylceramide synthase (GCS, EC 2.4.1.80) levels of the enzyme were compared for 18 samples of AD Brodmann area 9/10 frontal cortex with 11 age-matched controls. Western analysis for (ir)GCS showed a significant decrease in AD brain (p<0.01) consistent with the hypothesis that enzyme dysfunction contributes to neuronal decay. To examine kinetics and consequences to morphology, cerebellar granule cells were treated in vitro with d-threo-P4 (P4). This potent inhibitor of GCS induced a time- and concentration-dependent increase in lcCer parallel to loss of viability and dramatic changes in neuron/neurite morphology via caspase-independent pathways distinct from those of apoptosis or necrosis. Fluorescent labeling with NBD-sphingolipids or immunostaining with anti-synaptic or cytoskeletal markers showed unusual formation of globular swellings along neurites rich in synaptophysin that may resemble formation of dystrophic neurites in AD. Effects of the inhibitor were verified by changes in lcCer mass and turnover of (14)[C]-acetate and -galactose or NBD-labeled anabolic products. Addition of a panel of inhibitors of other pathways confirms GCS as the major route for clearance in the present model. Pretreatment with GM(1) whose turnover is compromised was protective and pointed to useful therapeutic applications by supplementing existing membrane stores prior to GSC dysfunction.

journal_name

Brain Res

journal_title

Brain research

authors

Marks N,Berg MJ,Saito M,Saito M

doi

10.1016/j.brainres.2007.10.066

subject

Has Abstract

pub_date

2008-01-29 00:00:00

pages

136-47

eissn

0006-8993

issn

1872-6240

pii

S0006-8993(07)02588-7

journal_volume

1191

pub_type

杂志文章

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Glucosylceramide synthase decrease in frontal cortex of Alzheimer brain correlates with abnormal increase in endogenous ceramides: consequences to morphology and viability on enzyme suppression in cultured primary neurons.