TY - JOUR
T1 - Membrane cholesterol modulates β-amyloid-dependent Tau cleavage by inducing changes in the membrane content and localization of N-methyl-D-aspartic acid receptors
AU - Nicholson, Alexandra M.
AU - Methner, D. Nicole Riherd
AU - Ferreira, Adriana
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/1/14
Y1 - 2011/1/14
N2 - We have previously shown that β-amyloid (Aβ) treatment resulted in an age-dependent calpain activation leading to Tau cleavage into a neurotoxic 17-kDa fragment in a cellular model of Alzheimer disease. This detrimental cellular response was mediated by a developmentally regulated increase in membrane cholesterol levels. In this study, we assessed the molecular mechanisms by which cholesterol modulated Aβ-induced Tau cleavage in cultured hippocampal neurons. Our results indicated that these mechanisms did not involve the regulation of the binding of Aβ aggregates to the plasma membrane. On the other hand, experiments using N-methyl-D-aspartic acid receptor inhibitors suggested that these receptors played an essential role in cholesterol-mediated Aβ-dependent calpain activity and 17-kDa Tau production. Biochemical and immunocytochemical analyses demonstrated that decreasing membrane cholesterol levels in mature neurons resulted in a significant reduction of the NR1 subunit at the membrane as well as an increase in the number of large NR1, NR2A, and NR2B subunit clusters. Moreover, the majority of these larger N-methyl-D-aspartic acid receptor subunit immunoreactive spots was not juxtaposed to presynaptic sites in cholesterol-reduced neurons. These data suggested that changes at the synaptic level underlie the mechanism by which membrane cholesterol modulates developmental changes in the susceptibility of hippocampal neurons to Aβ-induced toxicity.
AB - We have previously shown that β-amyloid (Aβ) treatment resulted in an age-dependent calpain activation leading to Tau cleavage into a neurotoxic 17-kDa fragment in a cellular model of Alzheimer disease. This detrimental cellular response was mediated by a developmentally regulated increase in membrane cholesterol levels. In this study, we assessed the molecular mechanisms by which cholesterol modulated Aβ-induced Tau cleavage in cultured hippocampal neurons. Our results indicated that these mechanisms did not involve the regulation of the binding of Aβ aggregates to the plasma membrane. On the other hand, experiments using N-methyl-D-aspartic acid receptor inhibitors suggested that these receptors played an essential role in cholesterol-mediated Aβ-dependent calpain activity and 17-kDa Tau production. Biochemical and immunocytochemical analyses demonstrated that decreasing membrane cholesterol levels in mature neurons resulted in a significant reduction of the NR1 subunit at the membrane as well as an increase in the number of large NR1, NR2A, and NR2B subunit clusters. Moreover, the majority of these larger N-methyl-D-aspartic acid receptor subunit immunoreactive spots was not juxtaposed to presynaptic sites in cholesterol-reduced neurons. These data suggested that changes at the synaptic level underlie the mechanism by which membrane cholesterol modulates developmental changes in the susceptibility of hippocampal neurons to Aβ-induced toxicity.
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U2 - 10.1074/jbc.M110.154138
DO - 10.1074/jbc.M110.154138
M3 - Article
C2 - 21047784
AN - SCOPUS:78651381287
VL - 286
SP - 976
EP - 986
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 2
ER -