Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

Individuals at risk of developing Alzheimer’s disease (AD) often exhibit hippocampal hyperexcitability. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse may underlie this hyperexcitability. Here, we used a tau mouse model of AD (rTg(TauP301L)4510) to examine the effects of tau pathology on hippocampal glutamate regulation. We found a 40% increase in hippocampal vGLUT, which packages glutamate into vesicles, and has previously been shown to influence glutamate release, and a 40% decrease in hippocampal GLT-1, the major glutamate transporter responsible for removing glutamate from the extracellular space. To determine whether these alterations affected glutamate regulation in vivo, we measured tonic glutamate levels, potassium-evoked glutamate release, and glutamate uptake/clearance in the dentate gyrus (DG), CA3, and CA1 regions of the hippocampus. P301L tau expression resulted in a 4- and 7-fold increase in potassium-evoked glutamate release in the DG and CA3, respectively, and significantly decreased glutamate clearance in all 3 regions. Both release and clearance correlated with memory performance in the hippocampal-dependent Barnes maze task. Alterations in mice expressing P301L were observed at a time when tau pathology was subtle and before readily detectable neuron loss. These data suggest novel mechanisms by which tau may mediate hyperexcitability.

In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.

Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer’s disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer’s disease.

A 75-year-old man with chronic (30-year) unexplained paroxysmal hypoxemia presented with postural hypoxemia and desaturation consistent with a clinical manifestation of platypnea-orthodeoxia syndrome. His history included a lack of significant past pulmonary disease, yet with intermittent need for oxygen supplementation. On admission he was found to have an interatrial shunt through a patent foramen ovale. Device closure by percutaneous catheterization led to sustained resolution of symptoms. Platypnea-orthodeoxia syndrome is a rare but important consideration in the differential diagnosis of hypoxemia, as it represents a potentially curable cause of hypoxemia, with missed diagnosis leading to possible patient morbidity if untreated. Even more importantly, an astute and careful history and physical examination are integral to the diagnosis of this rare but likely under-recognized syndrome.