Overactivation of NR2B‐containing NMDA receptors through entorhinal–hippocampal connection initiates accumulation of hyperphosphorylated tau in rat hippocampus after transient middle cerebral artery occlusion

Abstract

Middle cerebral artery occlusion (MCAO) induces secondary damages in the hippocampus that is remote from primary ischemic regions. Tau hyperphosphorylation is an important risk for neurodegenerative diseases. Increased tau phosphorylation has been identified in ischemic cortex, but little is known regarding the changes in the hippocampus. We showed that unilateral transient MCAO induced accumulation of hyperphosphorylated tau and concurrent dephosphorylation of glycogen synthase kinase-3b at Ser 9 in the ipsilateral hippocampus. These MCAO-induced changes were not reproduced when glutamatergic inputs from the entorhinal cortex to the hippocampus were transected; however, the changes were mimicked by intrahippocampal N-methyl-D-aspartate (NMDA) administration. Inhibition of NMDA receptor (NMDAR) subunit NR2B, but not NR2A activity in the hippocampus attenuated the accumulation of hyperphosphorylated tau and spatial cognitive impairment in MCAO rats. Together, our data suggest that overactivation of NR2B-containing NMDARs through entorhinal-hippocampal connection plays an important role in the accumulation of hyperphosphorylated tau in the hippocampus following MCAO. Glycogen synthase kinase-3b is an important protein kinase involved in NMDARs-mediated tau hyperphosphorylation. This study indicates that early inhibition of NR2B-containing NMDARs may represent a potential strategy to prevent or delay the occurrence of post-stroke dementia.

The Tau/A152T mutation, a risk factor for frontotemporal‐spectrum disorders, leads to NR 2B receptor‐mediated excitotoxicity

“…Consistent with this, several reports have suggested the involvement of the NR2B subunit in the mediation of seizures , and the reduction in Tau leads to seizure resistance in epilepsy models . Moreover, when rats were treated with transient middle cerebral artery occlusion to initiate an excitotoxic insult, NR2B‐containing NMDARs were overactivated, resulting in Tau hyperphosphorylation and aggregation .…”

Free d-aspartate triggers NMDA receptor-dependent cell death in primary cortical neurons and perturbs JNK activation, Tau phosphorylation, and protein SUMOylation in the cerebral cortex of mice lacking d-aspartate oxidase activity

“…Changes in Tau protein phosphorylation are associated with neuronal cell death (Canu et al, 1998;Mills et al, 1998) and Alzheimer's disease (Li et al, 2007). Previous studies revealed that Tau phosphorylation can be affected by NMDAR activation, oxidative stress, increased protein SUMOylation, and JNK phosphorylation (Alavi Naini and Soussi-Yanicostas, 2015;Allyson et al, 2010;De Montigny et al, 2013;Fleming and Johnson, 1995;Li et al, 2014;Luo et al, 2014;Ploia et al, 2011;Takahashi et al, 2008;Vogel et al, 2009;Xu et al, 2015;Yoshida et al, 2004;Zambrano et al, 2004). Interestingly, we found that altered JNK phosphorylation and protein SUMOylation are associated with extensive Tau hypophosphorylation at PHF1 and AT8 sites in the PFC and hippocampus of elderly Ddo −/− mice.…”

Synaptic signalling and its interface with neuropathologies: snapshots from the past, present and future

“…), and (v) excessive activation of specific NMDARs through an entorhinal‐hippocampal connection initiated the accumulation of hyperphosphorylated tau in the hippocampus, which subsequently induced a cognitive deficit (Xu et al . ). Finally, it worth recalling that many years ago Chen and Lipton () reviewed aspects of the open‐channel block, uncompetitive antagonism of NMDARs by memantine, which was then in Phase 3 clinical trial for the treatment moderate‐to‐severe AD.…”

“…Although, NMDAR-mediated glutamatergic signalling is involved in a wide range of neurological and psychiatric disorders, one commonality noted across all transmitter systems is a continuing trend to explore linkages to b-amyloid processing and AD. Many components of the b-amyloid system have been reported to interface with NMDARs: (i) co-expression of amyloid precursor protein (APP) in mammalian cells resulted in enhanced cell surface expression of NMDARs with no increase in total subunit expression (Cousins et al 2009), (ii) presenilins may regulate post-synaptic NMDAR function in part via a transsynaptic mechanism (Zhang et al 2010), (iii) NMDAR knock-down abolished soluble b-amyloid peptide oligomer binding to dendrites indicating that NMDARs are required for synaptic targeting of oligomers (Decker et al 2010), (iv) NMDARs activate an oxidative-degradative mechanism for oligomeric amyloid beta (Ab) 1-42 to induce reactive oxygen species production and stimulate arachidonic acid release (Shelat et al 2008), and (v) excessive activation of specific NMDARs through an entorhinal-hippocampal connection initiated the accumulation of hyperphosphorylated tau in the hippocampus, which subsequently induced a cognitive deficit (Xu et al 2015). Finally, it worth recalling that many years ago Chen and Lipton (2006) reviewed aspects of the openchannel block, uncompetitive antagonism of NMDARs by memantine, which was then in Phase 3 clinical trial for the treatment moderate-to-severe AD.…”