title: 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.
authors.affiliation: Geriatric Research Education and Clinical Center, VA Medical Center, 1660 S. Columbian Way, Seattle, WA 98108, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Duerson
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Paramita
authors.initials: P
authors.lastname: Mookherjee
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: David V
authors.initials: DV
authors.lastname: Pow
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: David G
authors.initials: DG
authors.lastname: Cook
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D003902:Detergents / Q000494:pharmacology; D050580:Excitatory Amino Acid Transporter 3 / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D017830:Octoxynol / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism; D012995:Solubility
chemical_list: D003902:Detergents; D050580:Excitatory Amino Acid Transporter 3; C493400:SLC1A1 protein, human; D017830:Octoxynol