Abstract
Synapses are critical targets of Alzheimer's disease (AD), a highly prevalent neurodegenerative disease associated with accumulation of extracellular amyloid-β peptides. Although amyloidosis and aggregation of the 42-amino acid amyloid-β (Aβ (42) ) have long been considered pathogenic triggers for AD, clinical evidence linking high levels of Aβ (42) with normal cognition challenges this hypothesis. To resolve this conundrum on the role of Aβ (42) in regulating synaptic activity, we used an adeno-associated viral vector approach that triggers extracellular accumulation of Aβ (42) and spatial memory impairment. We show that Aβ (42) leads to an early increase in excitatory and proximal inhibitory synaptic transmission onto hippocampal CA1 pyramidal cells, and an increased expression of the glutamate transporter GLT-1 in these cells. Aβ (42) accumulation does not cause early cognitive deficits unless accompanied by an increased neuronal GLT-1 expression, suggesting this transporter is a critical mediator of Aβ (42) 's effects. These findings unveil key molecular and cellular mechanisms implicated with AD pathogenesis.