Memantine Differentially Regulates Tau Phosphorylation Induced by Chronic Restraint Stress of Varying Duration in Mice

Abstract

Exposure to chronic psychiatric stress has been linked to Alzheimer’s disease-related tau hyperphosphorylation and abnormalities in glutamate neurotransmission. However, the pathological relationship between glutamatergic dysfunction and tau phosphorylation in the cerebral cortex under chronic psychiatric stress is not fully understood. The present study investigated the effects of memantine (MEM, 5 and 10 mg/kg), an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on chronic restraint stress- (CRS-) induced tau phosphorylation in mice. CRS administered for 16 or 28 consecutive days (1 h daily) induced significant tau phosphorylation in the brain. MEM treatment suppressed the elevation of phosphorylated tau (P-tau) levels induced by 16-day CRS in a dose-dependent manner. P-tau reduction was accompanied by the attenuation of the upregulation of GSK3β and CDK5 expression and the downregulation of PP2A activity induced by CRS. Additionally, MEM reduced CRS-induced upregulation of NMDA receptor subunit levels (GluN2A, GluN2B) in the frontal cortex. However, MEM markedly enhanced tau phosphorylation in the frontal cortex and other cerebral cortical regions following 28 days of CRS. The stimulatory effect of MEM on CRS-induced tau phosphorylation was correlated with increased activities of AKT, JNK, and GSK3β, inactivation of PP2A, and downregulation of Pin1 and HSP70. Moreover, MEM did not effectively reverse the NMDA receptor upregulation induced by 28-day CRS and even increased GluN2B subunit levels. In contrast to the duration-dependent effects of MEM on P-tau levels, MEM produced an anxiolytic effect in both regimens as revealed by elevated plus maze testing. However, MEM did not affect the body weight reduction induced by CRS. Thus, MEM exerts distinctive effects on CRS-induced tau phosphorylation, which might be related to the expression of GluN2B. The differential effects of MEM on P-tau levels have crucial implications for its clinical application.

Behavioral and neurological improvement by Cydonia oblonga fruit extract in chronic immobilization stress rats

“…Similar to previous studies, the present study confirmed the anxiogenic, and the depressing effects induced by CIS (Ampuero et al, 2015; Chen, Li, Zhao, & Yang, 2008; Liu et al, 2019). In the OFT, a decrease in the time spent in the central zone is considered to reflect the fear of entering and exploring a novel environment and is associated with increased anxiety levels of the animal.…”

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

“…Accordingly, significant diminution of p-Tau [Ser396] was found after RL-208 administration. To our knowledge, memantine is also described as able to reduce tau phosphorylation [65][66][67], linking the RL-208 antagonist action on NMDAR again with the neuroprotectant effectivity in SAMP8.…”

Isorhynchophylline ameliorates stress-induced emotional disorder and cognitive impairment with modulation of NMDA receptors

“…Previous data showed that acute stress or corticosterone administration may cause hypofunction of NMDA receptors by inhibiting D-serine release, despite of increasing glutamate (Wang et al, 2021). Long-term hypofunction of NMDA receptor, on the condition of chronic stress, might cause compensatory NMDA receptor expression, as showed in published data (Liu et al, 2019;Lorigooini et al, 2020) Sketch map for the mechanisms of isorhynchophylline on CUMS induced emotional disorders and cognitive impairment.…”

“…Synaptic structure is the biological basis of learning and memory ( Luscher and Malenka, 2012 ), normal synaptic transmission requires presynaptic glutamate and D-serine to bind to NMDA receptors to maintain synaptic plasticity and cognitive function ( Hardingham and Bading, 2010 ). It’s reported that chronic stress induced glutamate elevation ( Garcia-Garcia et al, 2009 ; Hill et al, 2012 ; Willner, 2017 ) and NMDA receptors expression increasing ( Liu et al, 2019 ; Lorigooini et al, 2020 ) in hippocampal tissue, indicating hyperfunction of NMDA receptors. On the other hand, chronic stress induced D-serine deficit ( Wang et al, 2017 ), indicating hypofunction of NMDA receptors.…”