Aberrant detergent-insoluble excitatory amino acid transporter 2 accumulates in alzheimer disease

Alzheimer disease (AD) is characterized by deposition of amyloid-β, tau, and other specific proteins that accumulate in the brain in detergent-insoluble complexes. Alzheimer disease also involves glutamatergic neurotransmitter system disturbances. Excitatory amino acid transporter 2 (EAAT2) is the dominant glutamate transporter in cerebral cortex and hippocampus. We investigated whether accumulation of detergent-insoluble EAAT2 is related to cognitive impairment and neuropathologic changes in AD by quantifying detergent-insoluble EAAT2 levels in hippocampus and frontal cortex of cognitively normal patients, patients with clinical dementia rating of 0.5 (mildly impaired), and AD patients. Parkinson disease patients served as neurodegenerative disease controls. We found that Triton X-100-insoluble EAAT2 levels were significantly increased in patients withAD compared with controls, whereas Triton X-100-insoluble EAAT2 levels inpatients with clinical dementia rating of 0.5 were intermediately elevatedbetween control and AD subjects. Detergentinsolubility of presenilin-1, a structurally similar protein, did not differ among the groups, thus arguing that EAAT2 detergent insolubility was not causedby nonspecific cellular injury. These findings demonstrate that detergent-insoluble EAAT2 accumulation is a progressive biochemical lesion that correlates with cognitive impairment and neuropathologic changes in AD. These findings lend further support to the idea that dysregulationof the glutamatergic system may play a significant role in AD pathogenesis.