Abstract
Presenilins, whose mutant forms are the most common cause of early onset familial Alzheimer's disease, are involved in two very distinct processes: (i) proteolytic activity as gamma-secretase acting on amyloid precursor protein to produce amyloid peptides and (ii) storage of Ca2+ in the endoplasmic reticulum (ER). In particular, absence of presenilin-1 (PS1) was claimed to potentiate capacitative calcium entry (CCE), i.e. the mechanism of replenishment of ER Ca2+ stores. However, until now, evidence in favor of the latter role has been obtained only in isolated or cultured cells and not on neurons in situ. Here, we studied the strength of the synapses between Schaffer's collaterals and CA1 neurons in hippocampal slices when they were submitted first to Ca(2+)-free medium containing thapsigargin and subsequently to normal artificial cerebrospinal fluid, a procedure known to trigger CCE. We demonstrate that Ca2+ influx via the CCE mechanism is sufficient to trigger robust long term potentiation of the synapses in hippocampal slices from transgenic mice with a postnatal, neuron-specific ablation of PS1, but remarkably not from wild-type mice. Our data establish for the first time in neurons confined in normal neuronal networks that PS1 acts on the refilling mechanism of ER Ca2+ stores.
Highlights
Mutations in presenilin-1 (PS1)1 and presenilin-2 (PS2) are the most common cause of early onset cases of familial Alzheimer’s disease [1,2,3]
Presenilins, whose mutant forms are the most common cause of early onset familial Alzheimer’s disease, are involved in two very distinct processes: (i) proteolytic activity as ␥-secretase acting on amyloid precursor protein to produce amyloid peptides and (ii) storage of Ca2؉ in the endoplasmic reticulum (ER)
calcium entry (CCE)-induced long term potentiation (LTP) in Hippocampus of PS1(nϪ/Ϫ) Mice— Classically, LTP is induced by tetanic stimulation, and it is well known that entry of calcium ions is an absolute requirement
Summary
Mutations in presenilin-1 (PS1) and presenilin-2 (PS2) are the most common cause of early onset cases of familial Alzheimer’s disease [1,2,3]. Presenilins are involved in calcium signaling in neurons and other cells (10 –13). Declining Ca2ϩ stores in the ER produce a signal, the molecular nature of which is still a matter of debate [16], to open store-operated Ca2ϩ channels (SOC) in the plasma membrane [17]. These activated channels serve to replenish the ER Ca2ϩ stores by the mechanism known as “capacitative calcium entry” (CCE) [18]. From experiments carried out on isolated or cultured cells, it has been proposed that presenilins exert different effects on the Ca2ϩ store system. We aimed to study the proposed role of PS1 in calcium signaling in neurons confined within normal neuronal networks, not by direct Ca2ϩ measurements but by an indirect mean, more appropriate to studies in slices from adult animals
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