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. 2010 Sep 20;5(9):e12845.
doi: 10.1371/journal.pone.0012845.

Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease

Tao Ma  1 , Charles A Hoeffer, Estibaliz Capetillo-Zarate, Fangmin Yu, Helen Wong, Michael T Lin, Davide Tampellini, Eric Klann, Robert D Blitzer, Gunnar K Gouras
Affiliations

Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease

Tao Ma et al. PLoS One. .

Abstract

Background: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD).

Methodology/principal findings: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR.

Conclusions/significance: These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. mTOR signaling is impaired in an AD mouse model.
(A) Western blot of acute hippocampal slices from 3–4-month-old Tg2576 mice showed decreased levels of phospho-p70S6K (Thr389), phospho-4E-BP (Thr37/46) and PSD-95 compared to wild-type (WT) slices. n = 9. *p<0.05. (B) Western blot on cultured primary neurons at 12 DIV showed decreased levels of phospho-p70S6K, phospho-4E-BP and PSD-95 in Tg2576 compared WT neurons. n = 4. *p<0.05. (C and D) Immuno-fluorescence confocal microscopy for phospho-p70S6K in the CA1 region of hippocampal slices (C) and cultured primary neurons at 12 DIV (D) showed reduced immuno-staining in Tg2576 compared to WT mice. Representative images are shown from three experiments. Scale bar, 75 µm. (E) In contrast to 3 and 9 month-old mice, reduced phospho-p70S6K was no longer evident of brains from aged (21–month-old) Tg2576 compared to WT mice. n = 8 for 3-month-old; n = 4 for 9-month-old; n = 4 for 21–month-old. *p<0.05.
Figure 2
Figure 2. mTOR signaling dysfunction correlates with synaptic plasticity impairment in an AD mouse model.
(A) Treatment of slices with forskolin (FSK, 50 µM, 60 min) induced phosphorylation of p70S6K in WT (n = 10) but not Tg2576 mice (n = 11). Values of densitometry from drug-treated slices are normalized to their vehicle control. *p<0.05. (B) Treatment of slices with 3,5 dihydroxyphenylglycine (DHPG, 50 µM, 60 min) induced phosphorylation of p70S6K in WT (n = 9) but not Tg2576 mice (n = 6). Values of densitometry from drug-treated slices are normalized to their vehicle control. *p<0.05. (C) High frequency stimulation (HFS) induced normal LTP in slices from 3–4-month-old WT mice (open circles), but only decremental LTP in Tg2576 mice (triangles). Pretreatment of slices with rapamycin (Rapa, 1 µM, 30 min) blocked LTP induced in WT mice (dark gray circles). n = 4 for WT and Tg; n = 6 for Rapa treated WT. Rapamycin was present throughout the recording. Scale bar, 1 mV/20 ms. The inset traces show superimposed sample EPSPs recorded during the baseline period (black) and 60 min after HFS (red). (D) Treatment of slices with Rapa (1 µM, 120 min) reduced levels of PSD-95 in WT but not Tg2576 mice. n = 5. *p<0.05.
Figure 3
Figure 3. Up-regulation of the mTOR pathway via GSK3 inhibition rescues LTP impairment in Tg2576 mice.
(A) Compared to the LTP induced in hippocampal slices of WT mice (filled circles, n = 4), high frequency stimulation (HFS) induced normal LTP in slices from Tg2576 mice treated with LiCl (10 mM, open circles, n = 5), which was inhibited by 30 min of rapamycin (Rapa; 1 µM) pretreatment (gray triangles, n = 4). LiCl or rapamycin was present throughout the recording. (B) Similarly, treatment of slices from Tg2576 mice with kenpaullone (Ken, 5 µM, dark gray circles) prevented the impaired HFS induced LTP seen in untreated Tg2576 slices; the protection in LTP induction in Tg2576 slices by kenpaullone was inhibited by 30 min of rapamycin (1 µM) pretreatment (open circles). n = 3. Kenpaullone or rapamycin was present throughout the recording. (C) The decreased levels of phospho-p70S6K in hippocampal slices from Tg2576 compared to WT (control) mice was prevented by treatment with either Ken (5 µM) or LiCl (10 mM) for 60 min. n = 8. *p<0.05.
Figure 4
Figure 4. Inhibition of mTOR signaling and LTP by extracellular Aβ1-42 is prevented in FKBP12 cKO mice.
(A) Treatment of slices from WT mice with exogenous Aβ1-42 (100 nM, 60 min) reduced levels of phospho-p70S6K, phospho-4E-BP, and PSD-95 compared to untreated WT slices (controls). n = 4. *p<0.05. Representative Western blot from three experiments after direct loading of the Aβ1-42 preparation (far right of the panel) showed mostly Aβ1-42 monomers, and also significant amounts of dimers and trimers. (B) LTP induced by HFS in WT mice (controls; red, n = 8) was blocked by treatment with Aβ1-42 (100 nM, blue, n = 7). In contrast, LTP was sustained in the presence of Aβ1-42 (100 nM, green) in FKBP cKO mice (n = 8). Aβ1-42 was present throughout the recording. (C) Inhibitory effects of Aβ1-42 on phospho-p70S6K were blunted in FKBP12 cKO mice. n = 5. *p<0.05. Slices were treated with Aβ1-42 for 60 min. (D) Slices from both FKBP12 cKO and WT mice treated with Aβ1-42 (60 min) exhibited normal PPF compared to the WT control. The percent facilitation, determined by the ratio of the second fEPSP to the first fEPSP (interpulse interval  = 50 ms), together with representative fEPSP traces are shown. n = 5 for WT; n = 6 for WT treated with Aβ; n = 8 for FKBP12 cKO. Scale bar, 0.5 mV/25 ms.
Figure 5
Figure 5. Cellular co-localization of intraneuronal Aβ and components of the mTOR pathway in Tg2576 neurons.
(A and B) Immuno-fluorescence confocal microscopy of Aβ42 with either mTOR (A) or p70S6K (B) in Tg2576 neurons at 12 DIV. Note the punctate co-localization of intraneuronal Aβ42 with mTOR and p70S6K. Scale bar, 50 µm. (C) Aβ1-42 (100 nM, 60 min) treatment failed to induce inhibition of p70S6K phosphorylation and to reduce PSD-95 levels in slices from APP KO compared to WT (control) mice. n = 9. *p<0.05.
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