GluN2B-NMDA Receptors in Alzheimers Disease: What Do they Got to Do with AD?

Abstract

Alzheimer's disease (AD) is one of the most devastating and debilitating diseases affecting the aging population. Dementia is the most widely known deficit in AD patients, typically starts with loss of recent memory (minutes to hours), and progresses to loss of long-held memories and unable to recognize their loved ones. People with AD eventually lose their ability to take care of themselves. As a consequence the cost of care is huge, and it also takes a tremendous emotional toll on the family of AD patients. Two hallmarks of AD are senile plaques and neurofibrillary tangles, which are composed of amyloid β (Αβ) and tau, respectively. Despite extensive search for effective treatment over the past decades, available drugs have limited efficacy without affecting the course of AD. For example, cholinesterase inhibitors (such as Aricept) enhance the function of cholinergic functions by elevating the concentration of acetylcholine and improve memory functions moderately [1]. Memantine, a NMDA subtype glutamate receptor blocker, is used in treating moderate to severe AD patients, although its mechanism is still in debate [2]. Significant efforts have been devoted to curb the production of Aβ or enhance its clearance, with the aim to reduce the plaque accumulation in the brain. Antibodies that bind Aβ to increase their removal have received a lot of attention. Although recent clinical trial results have been largely negative and disappointing [3], the recent exciting preliminary clinical trial results from Biogen has somewhat revived the hope in this approach. NMDARs play critical roles in synaptic plasticity, memory functions and the refinement of neuronal connections during development [4]. It is well established that excessive activation of NMDARs can lead to neuronal death, generally defined as excitotoxicity. How NMDARs can mediate the above two apparently opposite functions has been a recent debate. There are two camps: one hypothesizes that NMDAR subunit composition determines whether NMDARs is beneficial or malicious (i.e., containing GluN2B leads to excitotoxicity while containing GluN2A is beneficial) [5], the other camp claims that it is their subcellular locations determines which action occurs (i.e., NMDARs at extrasynaptic regions mediate excitotoxicity while synaptic NMDARs are essential for physiological functions) [6]. It needs to be mentioned that extrasynaptic NMDARs (which are outside a synapse) can be activated only by glutamate spilled out of a synapse or by ambient glutamate present in the extracellular space. The majority of excitatory synapses on excitatory neurons in the neocortex and hippocampus are located on dendritic spines. Spine loss is highly correlated with the reduction in cognitive function in AD patients [7]. There is a large literature implicates that GluN2B-NMDARs play a critical role in neurodegeneration and in Aβ-induced synaptic dysfunction and synapse loss in AD, while inhibiting GluN2B-NMDARs with selective antagonists appears to prevent or reverse some of the deficits [4,8]. Antagonists to GluN2B-NMDARs may have therapeutic values by providing neuroprotection and may improve cognitive function in AD patients. Besides Aβ, Tau has been shown to be required for localizing fyn tyrosine kinase to dendritic spines, where it phosphorylates GluN2B-NMDARs and results in enhanced association between GluN2B-NMDAR with PSD-95 and subsequent downstream neurotoxic effects. Disrupting the interaction between GluN2B and PSD-95 in vivo improved memory functions and reduced premature