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. 2020 Jul 3:8:541.
doi: 10.3389/fcell.2020.00541. eCollection 2020.

Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice

Sara Cocco  1 , Marco Rinaudo  1 , Salvatore Fusco  1   2 , Valentina Longo  1 , Katia Gironi  1 , Pietro Renna  1 , Giuseppe Aceto  1 , Alessia Mastrodonato  1 , Domenica Donatella Li Puma  1   2 , Maria Vittoria Podda  1   2 , Claudio Grassi  1   2
Affiliations

Plasma BDNF Levels Following Transcranial Direct Current Stimulation Allow Prediction of Synaptic Plasticity and Memory Deficits in 3×Tg-AD Mice

Sara Cocco et al. Front Cell Dev Biol. .

Abstract

Early diagnosis of Alzheimer's disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREB Ser133 and pCaMKII Thr286 , which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.

Keywords: Alzheimer’s disease; BDNF; blood biomarkers; neuroplasticity; personalized medicine; tDCS.

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Figures

FIGURE 1
FIGURE 1
Age-dependent pathological memory and synaptic plasticity changes in 3×Tg-AD mice. (A–D) 3-month-old 3×Tg-AD mice did not differ from age-matched WT mice in: (A) the preference toward the novel object in the NOR test (n = 9 mice for each group; P = 0.40, one-way ANOVA); (B) the latency to platform in the training phase of the MWM test (n = 9 mice for each group; P = 0.73, two-way RM ANOVA) and (C) the time spent in the target quadrant during the probe test performed on day 5 of MWM (P = 0.66, one-way ANOVA); (D) the magnitude of LTP at hippocampal CA3-CA1 synapses (n = 9 slices from 5 3×Tg-AD-3M mice; n = 9 slices from 6 WT-3M mice; P = 0.89, one-way ANOVA). Time course shows LTP at CA3-CA1 synapses induced by HFS (4 trains of 50 stimuli at 100 Hz for 500 ms repeated every 20 s) delivered at time 0 (arrow). Results are expressed as percentages of baseline fEPSP slope (= 100%). Insets show representative fEPSPs at baseline (gray line) and during the last 5 min of LTP recording (black line). Bar graphs compare LTP observed during the last 5 min of recording. (E–H) Compared to aged-matched WT mice, 7-month-old 3×Tg-AD mice showed significant decreases in: (E) preference index in the NOR test (P < 0.001); (F) latency to platform in the training phase of the MWM test (n = 8 mice for each group; P = 0.009, two-way RM ANOVA) and (G) time spent in the target quadrant during the probe test of MWM (P = 0.032, one-way ANOVA); (H) LTP (n = 10 slices from 5 3×Tg-AD-7M mice; n = 10 slices from 5 WT-7M mice, P = 0.0001, one-way ANOVA). Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; n.s., not significant.
FIGURE 2
FIGURE 2
Effect of tDCS on memory in 3×Tg-AD-3M and WT-3M mice. (A–C) Memory was enhanced by tDCS in 3-month-old WT but not in 3×Tg-AD-3M mice, as shown by: (A) preference toward the novel object in NOR test (n = 9 sham-WT-3M mice vs. n = 10 tDCS-WT-3M mice, P = 0.001; n = 9 sham-3×Tg-AD-3M mice vs. n = 8 tDCS-3×Tg-AD-3M mice, P = 0.42, one-way ANOVA); (B) latency to reach the platform in the training phase of the MWM test (n = 10 sham-WT-3M mice and n = 9 tDCS-WT-3M mice, P < 0.001; n = 9 sham-3×Tg-AD-3M mice and n = 9 tDCS-3×Tg-AD-3M mice, P < 0.001, two-way RM ANOVA across training days) and (C) time spent in the target quadrant during probe test (sham-WT-3M mice vs. tDCS-WT-3M mice, P = 0.029; sham-3×Tg-AD-3M mice vs. tDCS-3×Tg-AD-3M mice; P = 0.24, one-way ANOVA). Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; n.s., not significant.
FIGURE 3
FIGURE 3
tDCS differentially impacts hippocampal LTP in 3×Tg-AD-3M and WT mice. (A,B) Time course of LTP at CA3-CA1 synapses induced by HFS delivered at time 0 (arrow). Results are expressed as percentages of baseline fEPSP slope (= 100%). Insets show representative fEPSPs at baseline (gray line) and during the last 5 min of LTP recording (black line). Bar graphs compare LTP observed during the last 5 min of recording. (A) Slices obtained from tDCS-WT-3M mice (n = 12 slices from 7 mice) showed enhanced LTP compared to sham-WT-3M mice (n = 12 slices from 9 mice, P = 0.007, one-way ANOVA). (B) tDCS failed to enhance LTP in 3×Tg-AD-3M mice (n = 10 slices from 5 tDCS mice; n = 12 slices from 5 sham mice, P = 0.71; one-way ANOVA). Data are expressed as mean ± SEM; **P < 0.01; n.s., not significant.
FIGURE 4
FIGURE 4
Molecular changes in 3×Tg-AD-3M and WT-3M mice following tDCS. Representative immunoblots revealed increased pCREBSer133 (A) and pCaMKIIThr286 (B) following tDCS in WT-3M mice but not in 3×Tg-AD-3M mice. Bar graphs in the lower panel show results of densitometric analyses on all samples (n = 3 mice for each group; pCREBSer133, P = 0.003 tDCS-WT-3M vs. sham-WT-3M; P = 0.77 tDCS-3×Tg-AD-3M vs. sham-3×Tg-AD-3M; pCaMKIIThr286, P = 0.045 tDCS-WT-3M vs. sham-WT-3M; P = 0.58 tDCS-3×Tg-AD-3M vs. sham-3×Tg-AD-3M two-way ANOVA, Bonferroni post hoc) normalized to both the corresponding total protein levels and GAPDH. (C) Plasma BDNF levels were measured before (pre) and 1 week after (1 w post) tDCS. BDNF was increased by tDCS in WT mice (P = 0.031, one-way RM ANOVA) but not in 3×Tg-AD-3M mice (P = 0.12, Friedman RM ANOVA on Ranks) (n = 4 mice for each group). Data are expressed as mean ± SEM. *P < 0.05; **P < 0.01; n.s., not significant.
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