Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Abstract

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.

Astrocytes: News about Brain Health and Diseases

“…In other conditions, the uptake of Aβ within astrocytes results in digestion and, thus, in the control of its level [ 93 ]. An important event in AD is the progressive deletion of excitatory amino acid transporter 2 (EAAT2), a major glutamate transporter abundant in astrocytes but present also in neurons [ 94 ]. The lack of the same transporter in the two types of cells yields different defects: in astrocytes, an early defect of short-term memory, special reference learning, and also long-term memory; in neurons, of only long-term memory [ 94 ].…”

“…An important event in AD is the progressive deletion of excitatory amino acid transporter 2 (EAAT2), a major glutamate transporter abundant in astrocytes but present also in neurons [ 94 ]. The lack of the same transporter in the two types of cells yields different defects: in astrocytes, an early defect of short-term memory, special reference learning, and also long-term memory; in neurons, of only long-term memory [ 94 ]. Neurons and astrocytes have been known for years to exchange extracellular vesicles [ 95 ].…”

“…The majority of the recent astrocyte data regarding AD were obtained by studies of mouse brain models [ 84 , 85 , 87 , 89 , 94 ]. Additional data were obtained from mouse astrocyte lines, in some cases, duplicated with human lines or cultures [ 78 , 88 , 92 ].…”

The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc

“…Reprinted with permission from John Wiley and Sons (Newcomer et al, 1995a). strongly implicated GLT-1 in the pathogenesis of Alzheimer's disease (Sharma et al, 2019;Zott et al, 2019) emphasizing the importance of understanding the fine regulation of the concentrations of glutamate and other glutamate agonists in and around synapses.…”

“…Although GLT-1 for over a decade after its discovery was assumed to be expressed exclusively in astrocytes ( Rimmele and Rosenberg, 2016 ), it was ultimately shown to be the primary glutamate transporter expressed in axon terminals ( Chen et al, 2004 ; Petr et al, 2015 ) where it serves an important metabolic function in providing glutamate as a substrate for synaptic mitochondria ( McNair et al, 2020 ). Recent work has strongly implicated GLT-1 in the pathogenesis of Alzheimer’s disease ( Sharma et al, 2019 ; Zott et al, 2019 ) emphasizing the importance of understanding the fine regulation of the concentrations of glutamate and other glutamate agonists in and around synapses.…”