Impaired neuroplasticity due to abnormal accumulation of Aβ has been proposed as a key factor in the cognitive decline with AD pathogenesis, even preceding plaque formation or neurodegeneration 
. Developing a mechanistic understanding of the ability of soluble Aβ to interfere with synaptic plasticity, and in particular the stable, translation-dependent forms of plasticity that are thought to mediate LTM, could yield important insights into the pathophysiology of AD. mTOR-mediated protein synthesis is important for long-lasting forms of synaptic plasticity and memory 
. In the present study, we demonstrate that mTOR signaling in the hippocampus is impaired in a transgenic mouse model of AD, an effect that is mimicked by treating hippocampi of normal mice with soluble Aβ1-42. Importantly, pharmacological or genetic up-regulation of mTOR signaling restored LTP in slices from Tg2576 mice and prevented Aβ-induced impairment in LTP. These findings provide novel insights into the mechanism of Aβ-related synaptic dysfunction underlying memory impairment in AD.
In agreement with the data with FKBP12 cKO mice, GSK3 inhibitors also rescued the Aβ-related LTP failure. Originally identified as a regulator of glycogen metabolism, GSK3 is a multifunctional serine/threonine kinase that has many potential substrates. It has been reported that GSK3 can inhibit mTOR through phosphorylation of TSC2 
. Furthermore, GSK3 is highly expressed in hippocampus and is implicated in synaptic plasticity 
. In fact, GSK3 dysfunction has been proposed as an important underlying molecular mechanism for AD pathogenesis and accordingly has stimulated interest in the development of therapeutically useful GSK3 antagonists 
. In our study, the rescue of LTP by GSK3 inhibitors was sensitive to rapamycin, consistent with GSK3 acting to regulate mTOR signaling.
Inhibition of mTOR signaling was reported in the brains of another AD transgenic mouse model 
. On the other hand, mTOR signaling was reported to be up-regulated in postmortem human AD brains, particularly in tangle bearing neurons 
. We confirmed isolated phospho-p70S6K increases in AD vulnerable neurons of human AD brain, which was particularly prominent in tangle-bearing neurons (Supplementary Figure S3
). Of note, we observed reductions in phospho-p70S6K only at early but not at later ages in brains of Tg2576 mice. It is possible that up-regulation of mTOR noted in human AD 
and 3xAD-Tg mice 
develops later secondary to another process, such as tau alterations, cell cycle re-entry and/or inflammation; for example, the latter is known to stimulate mTOR signaling 
. In addition, although it is well established that acute inhibition of mTOR impairs synaptic plasticity, it was recently reported that chronic treatment with rapamycin improved behavior of AD transgenic mice 
, although effects were mild. Acute compared to chronic treatment may be critical in explaining the differences among studies. Of note, there are two mTOR complexes, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). The mTORC1 complex plays a critical role in synaptic plasticity. In contrast, nothing is currently known about the role of mTORC2 in synaptic plasticity 
. Prolonged but not acute treatment with rapamycin has been reported to lead to interference with mTORC2 
, which has functions that are independent of mTORC1 
. In light of these studies, we hypothesize that there is a complex relationship between aging, Aβ, and dysregulation of the mTOR pathway in AD.
Of note, there are many other examples of similarly contradictory-appearing data with respect to signaling in other common age-related diseases. For example, a study reporting down-regulation of mTOR signaling in huntingtin-accumulating neurons in a mouse model of Huntington's disease at the same time showed that treating the mice with rapamycin was protective 
. In another age-related disease, adult onset diabetes, defective insulin signaling through the insulin-PI3K-Akt pathway, which is upstream of mTOR, is well-established, although inhibition of this same pathway is known to extend lifespan in yeast and C. elegans models 
. Of note, similar conflicting data also exist on the insulin-PI3K-Akt pathway in AD models. On one hand, Aβ was shown to impair insulin-PI3K-AKT signaling 
and insulin treatment was reported to improve cognitive function in patients with early AD 
, while on the other hand, AD transgenic mice with reduced insulin signaling were reported to be protected against cognitive decline 
Although the precise molecular mechanism whereby Aβ alters the mTOR pathway is not known, our finding that Aβ42 co-localizes with mTOR and p70S6K within neurites of APP mutant transgenic mice places it in the right location to dysregulate mTOR signaling. Recent evidence supports that extracellular Aβ acts via APP processing and potentially also intraneuronal Aβ42 
, and therefore we examined whether extracellular Aβ1-42 down-regulated mTOR in APP knockout neurons. Remarkably, the effect of exogenous Aβ on mTOR signaling was blocked in APP knockout neurons, further supporting an emerging complex link between extracellular and intracellular Aβ.
Given the pivotal role of mTOR in maintaining cellular and organismal homeostasis by controlling multiple fundamental biological processes, perturbing the balance in mTOR signaling might be key to better understanding the Aβ-related impairment in signaling involved in the synaptic dysfunction that characterizes AD.