Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers.
Synaptic pathology is associated with protein accumulation events, and is thought by many to be the best correlate of cognitive impairment in normal aging and different types of dementia including Alzheimer's disease. Numerous studies point to the disruption of microtubule-based transport mechanisms as a contributor to synaptic degeneration. Reported reductions in a microtubule stability marker, acetylated alpha-tubulin, suggest that disrupted transport occurs in Alzheimer's disease neurons, and such a reduction is known to be associated with transport failure and synaptic compromise in a hippocampal slice model of protein accumulation. The slice model exhibits accumulated proteins in response to chloroquine-mediated lysosomal dysfunction, resulting in corresponding decreases in acetylated tubulin and pre- and postsynaptic markers (synaptophysin and glutamate receptors). To test whether the protein deposition-induced loss of synaptic proteins is due to disruption of microtubule integrity, a potent microtubule-stabilizing agent, the taxol derivative TX67 (10-succinyl paclitaxel), was applied to the hippocampal slice cultures. In the absence of lysosomal stress, TX67 (100-300 nM) provided microtubule stabilization as indicated by markedly increased levels of acetylated tubulin. When TX67 was applied to the slices during the chloroquine treatment period, pre- and postsynaptic markers were maintained at control levels. In addition, a correlation was evident across slice samples between levels of acetylated tubulin and glutamate receptor subunit GluR1. These data indicate that disruption of microtubule integrity accounts for protein deposition-induced synaptic decline. They also suggest that microtubule-stabilizing drugs can be used to slow or halt the progressive synaptic deterioration linked to Alzheimer-type pathogenesis.
Butler
David
D
Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269-3092, USA.
Bendiske
Jennifer
J
Michaelis
Mary L
ML
Karanian
David A
DA
Bahr
Ben A
BA
D000107:Acetylation / Q000187:drug effects; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D009924:Organ Culture Techniques; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism*; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology*
C520232:10-succinyl paclitaxel; D000199:Actins; D017470:Receptors, Glutamate; D016708:Synaptophysin; D050257:Tubulin Modulators; D002738:Chloroquine; D017239:Paclitaxel