Abstract
We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn2+ transport system due to a local increase in amyloid-β (Aβ) concentration. A single injection of Aβ (25 pmol) into the dentate gyrus affected dentate gyrus long-term potentiation (LTP) 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Aβ-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn2+ is involved in Aβ action. When Aβ was injected into the dentate gyrus, intracellular Zn2+ levels were increased only in the injected area in the dentate gyrus, suggesting that Aβ induces the influx of Zn2+ into cells in the injected area. When Aβ was added to hippocampal slices, Aβ did not increase intracellular Zn2+ levels in the dentate granule cell layer in ACSF without Zn2+, but in ACSF containing Zn2+. The increase in intracellular Zn2+ levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Aβ-mediated Zn2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn2+ may play a key role for transiently Aβ-induced cognition deficits.
Highlights
Memory function normally declines along with aging, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons [1]
The cognitive deficit and memory loss occurring before any prominent neuronal loss, which is observed in patients with mild cognitive impairment (MCI) or earlyphase Alzheimer’s disease, may be associated with Ab-induced synapse dysfunctions such as alterations in longterm potentiation (LTP) [11]
LTP was induced 1 h after injection of Ab into the dentate gyrus via an injection cannula attached to a recording electrode
Summary
Memory function normally declines along with aging, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons [1]. Some individuals go on to develop Alzheimer’s disease with progressive neurodegeneration [2,3,4]. Neuronal loss is not observed in animal models overexpressing amyloid-b (Ab) or infused with Ab, which develop early synaptic alterations but lack the extensive cell death [5, 6]. The cognitive deficit and memory loss occurring before any prominent neuronal loss, which is observed in patients with mild cognitive impairment (MCI) or earlyphase Alzheimer’s disease, may be associated with Ab-induced synapse dysfunctions such as alterations in LTP [11]
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