An increased excitation and inhibition onto CA1 pyramidal cells sets the path to Alzheimer’s disease

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.