Detergent‐Insoluble EAAC1/EAAT3 Aberrantly Accumulates in Hippocampal Neurons of Alzheimer's Disease Patients

Abstract

Disturbed glutamate homeostasis may contribute to the pathological processes involved in Alzheimer's disease (AD). Once glutamate is released from synapses or from other intracellular sources, it is rapidly cleared by glutamate transporters. EAAC1 (also called EAAT3 or SLC1A1) is the primary glutamate transporter in forebrain neurons. In addition to transporting glutamate, EAAC1 plays other roles in regulating GABA synthesis, reducing oxidative stress in neurons, and is important in supporting neuron viability. Currently, little is known about EAAC1 in AD. To address whether EAAC1 is disturbed in AD, immunohistochemistry was performed on tissue from hippocampus and frontal cortex of AD and normal control subjects matched for age and gender. While EAAC1 immunostaining in cortex appeared comparable to controls, in the hippocampus, EAAC1 aberrantly accumulated in the cell bodies and proximal neuritic processes of CA2-CA3 pyramidal neurons in AD patients. Biochemical analyses showed that Triton X-100-insoluble EAAC1 was significantly increased in the hippocampus of AD patients compared to both controls and Parkinson's disease patients. These findings suggest that aberrant glutamate transporter expression is associated with AD-related neuropathology and that intracellular accumulation of detergent-insoluble EAAC1 is a feature of the complex biochemical lesions in AD that include altered protein solubility.

SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology

“…For example, altered brain levels or localization of EAAT3 were also reported in patients suffering from schizophrenia (Bauer et al., 2008) and Alzheimer’s disease (Duerson et al., 2009). Also, in mouse models of Huntington’s disease, both impaired SorCS2 function (Ma et al., 2017) and aberrant EAAT3 localization leading to increased oxidative stress (Li et al., 2010) were reported.…”

Parasynaptic NMDA Receptor Signaling Couples Neuronal Glutamate Transporter Function to AMPA Receptor Synaptic Distribution and Stability

“…These findings were supported by additional studies indicating that knockdown of EAAT3 resulted in both epilepsy and limbic hyperexcitability (Sepkuty et al, 2002; Mathews and Diamond, 2003). Furthermore, studies have demonstrated the accumulation of detergent-insoluble EAAT3 in the hippocampus of patients with Alzheimer’s disease (Duerson et al, 2009), a neurodegenerative disorder that has a marked decrease in AMPAR levels during its early onset and progression (Chang et al, 2006; Hsieh et al, 2006). In addition, altered expression levels of the EAAT3 mRNA transcript and protein levels are observed in post-mortem brain tissue from individuals with schizophrenia (McCullumsmith and Meador-Woodruff, 2002; Huerta et al, 2006; Lang et al, 2007), following seizure activity (Ross et al, 2011) and epilepsy (Mathern et al, 1999; Simantov et al, 1999; Crino et al, 2002; Proper et al, 2002; Rakhade and Loeb, 2008).…”

Expression of multiple glutamate transporter splice variants in the rodent testis

“…The reasons for this disparity are unclear but cannot represent methodological failure, as we are readily able to detect appropriate PCR products from brain tissues as shown in this study, and can similarly detect protein in the brain. 43 There may be several reasons for this disparity; thus, Jin et al 44 have previously described an alternate promoter for EAAC1, which yields a smaller EAAC1 protein. The involvement of multiple promoters in driving transcription of EAAC1 may occur in different tissue types and produce transcripts that display demonstrable heterogeneity at the 59 UTR.…”