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. 2018 Sep 7;361(6406):eaan8821.
doi: 10.1126/science.aan8821.

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model

Se Hoon Choi  1 , Enjana Bylykbashi  1 , Zena K Chatila  1 , Star W Lee  2 , Benjamin Pulli  3 , Gregory D Clemenson  2 , Eunhee Kim  1 , Alexander Rompala  1 , Mary K Oram  1 , Caroline Asselin  1 , Jenna Aronson  1 , Can Zhang  1 , Sean J Miller  1 , Andrea Lesinski  1 , John W Chen  3 , Doo Yeon Kim  1 , Henriette van Praag  4 , Bruce M Spiegelman  5 , Fred H Gage  2 , Rudolph E Tanzi  6
Affiliations

Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model

Se Hoon Choi et al. Science. .

Abstract

Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer's disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

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Conflict of interest statement

Competing interest: We declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.. AHN activation alone does not change Aβ plaque levels.
(A) Stereotaxic injection of lentiviral vectors targets adult DG. Numbers (upper right) are approximate distances from bregma. Scale bar: 100 μm. (B) Experimental procedures timeline (C) Photomicrographs of DCX+ cells and 3D6+ Aβ plaques in the hippocampus of 5×FADCTL, 5×FADProAHN, 5×FAD+AHN(RUN), and 5×FADΨAHN(RUN) mice. Scale bar: 50 μm. (D) Distribution of AHN activation by P7C3 along with LV-Wnt3 or by exercise. Data points represent DCX+ cell count per mouse, as percentage of mean DCX+ cell count for 5×FADCTL mice by gender. In male 5×FADCTL, 5×FADProAHN, and 5×FADRUN mice, F(2,90) = 13.57, P < 0.01. In female, F(2,27) = 8.05, P < 0.01. (E) Quantitative analysis of Aβ burden volume in the hippocampus of 5×FADCTL, 5×FADProAHN, 5×FAD+AHN(RUN), and 5×FADψAHN(RUN) mice. Volume in arbitrary units (mean voxel count ± SEM; male, F(3,76) = 15.57, P < 0.01; female, F(2,19) = 7.659, P < 0.01). Female 5×FADΨAHN(RUN) mice were excluded due to low n.
Fig. 2.
Fig. 2.. Increasing AHN alone does not ameliorate cognitive function in 5×FAD mice, whereas exercise-induced AHN does.
(A) Schematic of DNMP in RAM task, consisted of sample and choice phase, and quantification of percent correct during choice phase (male, F(3,31) = 5.983, P < 0.01; female, F(2,19) = 3.887, P < 0.05). (B) Schematic of Y-maze task and spontaneous alternation behavior (male, F(3,31) = 3.935, P < 0.05; female, F(2,19) = 7.416, P < 0.01). Total arm entries were comparable among groups (fig. S4). (C) Schematic of RAM task and mean error number in training trials (left graph). 2-way ANOVA with repeated measures revealed significant effects for days (F(4,164) = 99.29, P < 0.01) and groups (F(3,41) = 5.129, P < 0.01) but not interaction (F(12,164) = 0.9894, P = 0.4613). Analysis of error number on each day by Fisher’s LSD post hoc tests revealed 5×FAD+AHN(RUN) differed significantly from both 5×FADCTL and 5×FADProAHN mice on days 2 and 3 (day 2, F(3,41) = 4.074, P < 0.05; day 3, F(3,41) = 3.499, P < 0.05). Right graph: mean error number in memory retention trial (F(3,41) = 5.675, P < 0.01).
Fig. 3.
Fig. 3.. Ablating AHN induces cell death in 5×FAD mice.
(A) Photomicrographs of DCX+ cells in the DG of 5-month-old WTSham, 5×FADSham, WTVeh, 5×FADVeh, WTIR, 5×FADIR, WTTMZ, and 5×FADTMZ mice. Scale bar: 100 μm. (B) Photomicrographs of DCX+ cells in the transduced DG of WT and 5×FAD mice by LV-GFP or LV-dnWnt. Mature granule neurons are stained for NeuN. Scale bar: 50 μm. (C) Quantification of DCX+ cells in male WTSham, WTIR, 5×FADSham, and 5×FADIR (F(3,32) = 197.9, P < 0.01; left), WTveh, WTTMZ, 5×FADveh, and 5×FADTMZ (F(3,46) = 23.96, P < 0.01; middle), and WTLV-GFP, WTLV-dnWnt, 5×FADLV-GFP, and 5×FADLV-dnWnt mice (F(3,45) = 35.21, P < 0.01; right). (D) Representative images of Casp3+ cells in 5×FADIR (left), 5×FADTMZ (middle), or 5×FADLV-dnWnt (right) mice. Insets represent digital magnification of arrow-indicated Casp3+ cells. Scale bars: 50 μm. (E) Quantification of Casp3+ cells in WTSham, WTIR, 5×FADSham, and 5×FADIR (F(3,32) = 72.38, P < 0.01; left), WTVeh, WTTMZ, 5×FADVeh, and 5×FADTMZ (F(3,46) = 11.26, P < 0.01; middle), and WTLV-GFP, WTLV-dnWnt, 5×FADLV-GFP, and 5×FADLV-dnWnt mice (F(3,45) = 11.98, P < 0.01; right). (F) Quantification of Casp3+ cells in 5×FADVeh, 5×FADTMZ (Mod KD), and 5×FADTMZ (High KD) (F(2,22) = 19.41, P < 0.01; left), and 5×FADLV-GFP, 5×FADLV-dnWnt (Mod KD), and 5×FADLV-dnWnt (High KD) mice (F(2,24) = 12.17, P < 0.01; right).
Fig. 4.
Fig. 4.. Ablating AHN induces granule cell and synaptic marker loss, and exacerbates cognitive impairment in 5×FAD mice.
(A) Representative images of Casp3+ cell colabeled with NeuN. Scale bar: 10 μm. (B) Quantification of granule cell number in WTSham, WTIR, 5×FADSham, and 5×FADIR (F(3,32) = 4.658, P < 0.01; left), WTVeh, WTTMZ (High KD), 5×FADVeh, and 5×FADTMZ (High KD) (F(3,33) = 6.041, P < 0.01; middle), and WTLV-GFP, WTLV-dnWnt (High KD), 5×FADLV-GFP, and 5×FADLV-dnWnt (High KD) mice (F(3,33) = 5.476, P < 0.01; right). (C) Hippocampal PSD95 levels (left: F(3,32) = 5.753, P < 0.01; middle: F(3,33) = 3.983, P < 0.05; right: F(3,33) = 4.639, P < 0.01). (D) Representative Golgi stains in 5×FADSham (upper) and 5×FADIR (lower) mice, and quantification of total dendritic length and neuron branch number in outer granule cell layer of 5×FADSham (n = 3) and 5×FADIR mice (n = 4). Scale bar: 100 μm. (E and F) Mean number of errors in training days of RAM task. In (E), left: WTSham, WTIR, 5×FADSham, and 5×FADIR mice; middle: WTveh, WTTMZ, 5×FADveh, and 5×FADTMZ mice; right: WTLV-GFP, WTLV-dnWnt, 5×FADLV-GFP, and 5×FADLV-dnWnt mice. In (F), left: 5×FADVeh, 5×FADtmz (Mod KD), and 5×FADtmz (High KD) mice; right: 5×FADLV-GFP, 5×FADLV-dnWnt (Mod KD), and 5×FADLV-dnWnt (High KD) mice.
Fig. 5.
Fig. 5.. Ablating AHN in male 5×FAD mice reduces hippocampal levels of TGF-β1, a protective cytokine.
(A) Hippocampal TGF-β1 levels in male 5×FADSham and 5×FADIR (left), 5×FADVeh and 5×FADTMZ (High KD) (middle), and 5×FADLV-GFP and 5×FADLV-dnWnt (High KD) mice (right). Levels as % of 5×FAD control group in each treatment. (B) Photomicrographs of 3D6+ Aβ plaques and NeuN+ cells (left), DCX+ cells (middle), and Casp3+ cell and NeuN+ cells (right) in the transduced DG of 5×FADIR mice by LV-TGF-β1. Scale bars: 50 μm (left, middle); 20 μm (right). (C) Hippocampal TGF-β1 levels in 5×FADIR/LV-RFP (n = 8) and 5×FADIR/LV-TGF-β1 (n = 8) (left), 5×FADTMZ/LV-RFP (n = 9) and 5×FADTMZ/LV-TGF-β1 (n = 12) (middle), and 5×FADLV-dnWnt/LV-RFP (n = 8) and 5×FADLV-dnWnt/LV-TGF-β1 (n = 9) (right) mice. Levels as % of 5×FAD control group in each treatment. 5×FADTMZ/LV-RFP and 5×FADLV-dnWnt/LV-RFP mice with moderate AHN knockdown were not included. (D) Quantification of Casp3+ cells in 5×FADIR/LV-RFP and 5×FADIR/LV-TGF-β1 (left), 5×FADTMZ/LV-RFP and 5×FADTMZ/LV-TGF-β1 (middle), and 5×FADLV-dnWnt/LV-RFP and 5×FADLV-dnWnt/LV-TGF-β1 (right) mice. (E) Representative images of Casp3+ cells (arrows) in GFP-labeled 3D-FAD cell cultures. Scale bar: 50 μm. (F) Quantification of Casp3+ cells in 3D-FAD cell cultures treated with vehicle (veh) or TGF-β1 (10 ng/ml). n = 3 per group. (G) Representative images of DAPI+ cells (blue) in ReN-FAD cell cultures treated with vehicle or TGF-β1. Scale bar: 50 μm. (H) Number of cells survived in 3D-FAD cultures treated with vehicle or TGF-β1. n = 3 per group.
Fig. 6.
Fig. 6.. Effects of ablating AHN in female 5×FAD mice.
(A) Quantification of DCX+ cells in female 5×FADCTL and 5×FAD−AHN mice. (B) Quantification of Casp3+ cells in female 5×FADCTL, 5×FAD−AHN (Mod KD), and 5×FAD−AHN (High KD) mice (F(2,20) = 4.803, P < 0.05). (C) Levels of hippocampal PSD95 (F(2,20) = 3.499, P < 0.05). Levels as % of 5×FADCTL group. (D) Mean error number in RAM task training trials. 2-way ANOVA with repeated measures revealed significant effects for days (F(4,80) = 24.19, P < 0.01) and groups (F(2,20) = 5.982, P < 0.01) but not interaction (F(8,80) = 0.4305, P = 0.8994). Analysis of error number on each day by Fisher’s LSD post hoc tests revealed 5×FAD−AHN (High KD) differed significantly from 5×FADCTL mice on days 3 and 5 (day 3, F(2,20) = 3.495, P < 0.05; day 5, F(2,20) = 3.419, P = 0.0428). (E) Spontaneous alternation in Y-maze (F(2,20) = 3.747, P < 0.05). Total arm entries comparable among groups (fig. S18G). (F) Hippocampal TGF-β1 levels. Levels as % of 5×FADCTL group. (G) Changes in TGF-β1 levels in the hippocampal homogenates of untreated male and female WT and 5×FAD mice with age (n = 7 per group). In 5-month-olds, *P < 0.05 between female 5×FAD and WT mice. In 10-month-olds, *P < 0.05 between male 5×FAD and WT mice; **P < 0.01 between female 5×FAD and WT mice.
Fig. 7.
Fig. 7.. AHN activation combined with increased BDNF levels ameliorates cognitive function in 5×FAD mice.
(A) Photomicrograph of lentiviral expression of LV-Wnt3 and LV-BDNF in the DG of 5×FADProAHN/LV-BDNF mice. Scale bar: 50 μm. (B) Hippocampal BDNF levels in 5×FADProAHN/LV-RFP, 5×FAD+AHN(RUN)/LV-RFP, and 5×FADProAHN/BDNF mice. (C) DCX+ cell quantification. (D) Quantitative analysis of Aβ burden volume (mean voxel count ± SEM). (E) Spontaneous alternation behavior in Y-maze task. Total arm entries comparable among groups (fig. S19). (F) Left: mean error number for each group (male 5×FADProAHN/LV-RFP, 5×FAD+AHN(RUN)/LV-RFP, and 5×FADProAHN/BDNF) in RAM task training days. Right: mean error number in memory retention trial. (G) Quantification of percent correct during choice phase of DNMP task among female 5×FADProAHN/LV-RFP, 5×FAD+AHN(RUN)/LV-RFP, and 5×FADProAHN/LV-BDNF mice. (H) Hippocampal BDNF levels in male 5×FADLV-RFP (n = 8) and 5×FADLV-BDNF (n = 12) mice. DCX+ cell number listed above graph. (I) Mean error number in RAM task training trials (left) and mean error number in memory retention trial (right). (J) Hippocampal BDNF levels in 5×FADProAHN/Veh, 5×FAD+AHN(RUN)/Veh, and 5×FADProAHN/AICAR mice. (K) Spontaneous alternation behavior in Y-maze task. Total arm entries comparable among groups (fig. S21B). (L) Mean error number in memory retention trial of RAM task. (M) Quantification of percent correct during choice phase of DNMP task among female 5×FADProAHN/Veh, 5×FAD+AHN(RUN)/Veh, and 5×FADProAHN/AICAR mice.
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