Longitudinal imaging reveals subhippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice

Abstract

Tauopathies are neurodegenerative disorders characterized by abnormal intracellular aggregates of tau protein, and include Alzheimer’s disease, corticobasal degeneration, frontotemporal dementia, and traumatic brain injury. Glutamate metabolism is altered in neurodegenerative disorders manifesting in higher or lower concentrations of glutamate, its transporters or receptors. Previously, glutamate chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) demonstrated that glutamate levels are reduced in regions of synapse loss in the hippocampus of a mouse model of late-stage tauopathy. We performed a longitudinal GluCEST imaging experiment paired with a cross-sectional study of histologic markers of tauopathy to determine whether 1) early GluCEST changes are associated with synapse loss before volume loss occurs in the hippocampus, and whether 2) subhippocampal dynamics in GluCEST are associated with histopathologic events related to glutamate alterations in tauopathy. Live imaging of the hippocampus in three serial slices was performed without exogenous contrast agents, and subregions were segmented based on a k-means cluster model. Subregions of the hippocampus were analyzed (cornu ammonis CA1, CA3, dentate gyrus, and ventricle) in order to associate local MRI-observable changes in glutamate with histological measures of glial cell proliferation (GFAP), synapse density (synaptophysin, VGlut1) and glutamate receptor (NMDA-NR1) levels. Early differences in GluCEST between healthy and tauopathy mice were measured in the CA1 and DG subregions (30% reduction, p≤0.001). Synapse density was also significantly reduced in every subregion of the hippocampus in tauopathy mice by 6 months. Volume was not significantly reduced in any subregion until 13 months. Further, a gradient in glutamate levels was observed in vivo along hippocampal axes that became polarized as tauopathy progressed. Dynamics in hippocampal glutamate levels throughout lifetime were most closely correlated with combined changes in synaptophysin and GFAP, indicating that GluCEST imaging may be a surrogate marker of glutamate concentration in glial cells and at the synaptic level.

Reproducibility of 2DGluCEST in healthy human volunteers at 7 T

“…An advantage of this imaging method is that the glutamate measurements are devoid of any glutamine contamination. The GluCEST technique has been implemented in studies of mouse models of Alzheimer's disease, which demonstrated the sensitivity of the method to detect decreased concentrations of glutamate in diseased mice compared with healthy, age‐matched controls . In the mouse model of Parkinson's disease, increased GluCEST was measured from the striatum compared with the healthy controls .…”

“…4,5 For example, elevated glutamate likely contributes to "excitotoxic" neuronal cell loss in Alzheimer's disease through overstimulation of glutamatergic receptors. [6][7][8][9] Decreased glutamate is observed in animal model of Alzheimer's disease and in patients with advanced pathology, [10][11][12][13] particularly within the hippocampus, and is positively correlated with the progressive loss of glutamate transporter proteins in brain regions associated with memory and cognitive function. 14,15 Although altered glutamate levels are implicated in the pathogenesis of neurological and neuropsychiatric diseases, glutamate has also been shown to decrease with age in the neurotypical brain.…”

“…The GluCEST technique has been implemented in studies of mouse models of Alzheimer's disease, which demonstrated the sensitivity of the method to detect decreased concentrations of glutamate in diseased mice compared with healthy, age-matched controls. 10,27,28 In the mouse model of Parkinson's disease, increased GluCEST was measured from the striatum compared with the healthy controls. 26,29 This method was also used in studying the Huntington's disease mouse model in which the decreased GluCEST was measured in the striatal region of the brain.…”

Nuclear Tau modulates VGluT1 expression: a new function for Tau

“…Nevertheless, although these observations suggest a role of Tau in the nuclear compartment, this field is still largely unexplored and it is not known whether nuclear Tau could have a role in modulating gene expression or some aspects of chromatin function that might be relevant for the pathophysiology of tauopathies. Here, we provide the first demonstration that the nuclear pool of Tau modulates the expression of the vesicular glutamate transporter VGluT1, which is known to be strongly upregulated in early phases of tauopathies [25,26]. Moreover, we show that increasing the soluble pool of Tau favours its nuclear translocation and increases the expression of VGluT1.…”

“…To investigate whether nuclear Tau might have a role in modulating gene expression, we checked the expression of disease-related genes in Tau-overexpressing cells. A growing body of evidence suggests that glutamate release is altered during the progression of tauopathies, causing an early synaptic hyperexcitability in the asymptomatic phase mediated by Tau [11,25,26].…”