Abstract
Glucocorticoid, a major risk factor of Alzheimer’s disease (AD), is widely known to promote microtubule dysfunction recognized as the early pathological feature that culminates in memory deficits. However, the exact glucocorticoid receptor (GR)-mediated mechanism of how glucocorticoid triggers microtubule destabilization and following intracellular transport deficits remains elusive. Therefore, we investigated the effect of glucocorticoid on microtubule instability and cognitive impairment using male ICR mice and human neuroblastoma SH-SY5Y cells. The mice group that was exposed to corticosteroid, the major glucocorticoid form of rodents, showed reduced trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) 1/2 and mitochondria, which are necessary for memory establishment, into the synapse due to microtubule destabilization. In SH-SY5Y cells, cortisol, the major glucocorticoid form of humans, also decreased microtubule stability represented by reduced acetylated α-tubulin to tyrosinated α-tubulin ratio (A/T ratio), depending on the mitochondria GR-mediated pathway. Cortisol translocated the Hsp70-bound GR into mitochondria which thereafter promoted GR-Bcl-2 interaction. Increased ER-mitochondria connectivity via GR-Bcl-2 coupling led to mitochondrial Ca2+ influx, which triggered mTOR activation. Subsequent autophagy inhibition by mTOR phosphorylation increased SCG10 protein levels via reducing ubiquitination of SCG10, eventually inducing microtubule destabilization. Thus, failure of trafficking AMPAR1/2 and mitochondria into the cell terminus occurred by kinesin-1 detachment from microtubules, which is responsible for transporting organelles towards periphery. However, the mice exposed to pretreatment of microtubule stabilizer paclitaxel showed the restored translocation of AMPAR1/2 or mitochondria into synapses and improved memory function compared to corticosterone-treated mice. In conclusion, glucocorticoid enhances ER-mitochondria coupling which evokes elevated SCG10 and microtubule destabilization dependent on mitochondrial GR. This eventually leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery.
Highlights
Microtubule takes a pivotal role acting as major highway for intracellular trafficking of necessary components such as proteins or organelles
Microtubule dynamics can be controlled by the intrinsic GTPase activity of tubulins and various post-translational modification (PTM) that occur on Cterminal tails, interacting with motor proteins and microtubule-associated proteins
The perinuclear clumping of mitochondria was observed in mice with corticosterone (Fig. 1d), which is the representative phenomenon for microtubule dysfunction
Summary
Microtubule takes a pivotal role acting as major highway for intracellular trafficking of necessary components such as proteins or organelles. Maintaining homeostasis in microtubule networks in neuronal cells is important for strengthening synaptic connection and regulating axonal transport. It is not surprising that microtubule dysfunction and following synaptic transport deficits are commonly observed in Official journal of the Cell Death Differentiation Association. Microtubule networks are important for consolidating memory via promoting AMPAR translocation into synapse. Stable acetylated α-tubulin is responsible for transporting mitochondria into neuronal cell periphery to provide energy for synaptic homeostasis and memory formation[4]. Microtubule dysfunction precedes memory impairment since neuronal cells failed to import AMPAR and mitochondria into synapses, both of which are necessary to trigger long term potentiation and eventual memory formation. Even though microtubule dysfunction represents a downstream of neurodegenerative cascades, the mechanism concerning pathogenesis of microtubule destabilization and memory impairment needs further investigation for discovering potential therapeutics of AD
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