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Acta Neuropathologica

, Volume 136, Issue 4, pp 589–605 | Cite as

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons

  • Shahzad S. Khan
  • Michael LaCroix
  • Gabriel Boyle
  • Mathew A. Sherman
  • Jennifer L. Brown
  • Fatou Amar
  • Jacqeline Aldaco
  • Michael K. Lee
  • George S. Bloom
  • Sylvain E. LesnéEmail author
Original Paper

Abstract

α-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-β oligomers (AβOs), αSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re-entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for αSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of αSyn decreased extracellular AβOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates αSyn as an essential mediator of key phenotypes in AD and offers new functional insight into αSyn pathophysiology.

Keywords

Amyloid-β α-Synuclein Tau Alzheimer’s disease Spatial memory Neuronal cell cycle re-entry 

Abbreviations

AD

Alzheimer’s disease

CCR

Neuronal cell cycle re-entry

WT

Wild-type

APP

J20 APP transgenic mice

αSyn

TgI2.2 transgenic mice

αSyn-KO

SNCA-null mice

Notes

Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) to SEL (R01AG044342) and start-up funds from the University of Minnesota Foundation to SEL. We are indebted to the Strom and Moe families for their gift. The Bloom lab was supported by the Owens Family Foundation; the NIH (grant RF1 AG051085 to GSB and NIH pre-doctoral fellowship F31 NS09244401 to SSK); the Alzheimer’s Association (Zenith Fellowship ZEN-16-363266 to GSB); the Cure Alzheimer’s Fund; the University of Virginia’s President’s Fund for Excellence; Webb and Tate Wilson; and the Virginia Chapter of the Ladies Auxiliary of the Fraternal Order of Eagles.

Author contributions

SSK, ML, MAS, FA and SEL performed experiments; SEL, GSB and SSK conceived, designed and supervised experiments. MKL provided reagents and critical feedback. SSK, GSB and SEL wrote the manuscript; SEL and SSK prepared and organized the figures. GSB, ML and MKL contributed to critical discussions and edited the manuscript. All authors discussed the results and commented on this manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interests in relation to this manuscript. Correspondence and requests for materials should be addressed to S.E.L. (lesne002@umn.edu).

Supplementary material

401_2018_1886_MOESM1_ESM.tif (932 kb)
Suppl. Figure 1 Forebrain abundance of APP derivatives in APP/αSyn, APP and APP/αSyn-KO mice. (a, b) Representative Western blots (a) and quantitation (b) of full-length APP (fl-APP), carboxyl terminal fragment beta (CTFβ) and total APP CTFs detected in membrane (MB)-enriched fractions from 6-month-old APP/αSyn, APP and APP/αSyn-KO mice. Histograms show mean ± SD; One-way ANOVA [F(2,18) = 0.4849, P = 0.6310; F(2,18) = 1.7053, P = 0.2355 and F(2,18) = 1.4540, P = 0.2837 respectively] followed by Student’s t test, P < 0.05 vs. age-matched APP mice; n = 6–9 mice/group. (c) Representative confocal images of hippocampi labeled for αSyn (green; 4D6 antibody) and amyloid deposits (magenta, DW6 antibody) from 6-month-old APP/αSyn, APP and APP/αSyn-KO mice. Arrows indicate DW6-positive Aβ deposits. Note the absence of Lewy bodies in APP/αSyn mice. Scale bars = 200 μm (TIFF 931 kb)
401_2018_1886_MOESM2_ESM.tif (535 kb)
Suppl. Figure 2 Paths used by animals during the retention phase of the Barnes circular maze. (a) Representative path tracings for WT, APP, αSyn, APP/αSyn, APP/αSyn-KO and αSyn-KO mice during the probe trial. White and red diamonds indicate the starting and final position of the animals during the 180 s of the task. The target hole and quadrant are colored in plum and blue respectively (TIFF 535 kb)
401_2018_1886_MOESM3_ESM.tif (265 kb)
Suppl. Figure 3 Comparative behavioral analysis of 6-month-old WT, APP, αSyn and APP/αSyn mice. (a) Distance travelled during the learning phase of the spatial task. Two-way repeated-measures ANOVA revealed a significant effect of training (F(3,540) = 16.033, P < 0.0001), of the transgene (F(3,540) = 33.652, P < 0.0001), but no significant day*transgene interaction (F(9,540) = 1.465, P = 0.1594) for all 4 groups. APP and APP/αSyn mice ran more than WT mice on 3 out of the 4 training days (P < 0.05). APP/αSyn mice ran more than αSyn mice on all 4 training days (P < 0.05). (b) Average speed displayed by the mice during the learning phase of the task. Two-way repeated-measures ANOVA revealed a significant effect of transgene (F(3,540) = 12.544, P < 0.0001), no effect of training (F(3,540) = 0.469, P = 0.7040), and a significant day*transgene interaction (F(9,540) = 1.974, P = 0.0410) for all 4 groups. APP mice were faster than WT (P < 0.05) and αSyn (P < 0.05) mice on 3 out of the 4 training days. The data presented in (A) and (b) are consistent with the hyperactivity phenotype ascribed to APP animals ([10]). (c) Occurrence of freezing episodes during the learning phase of the spatial task. Two-way repeated-measures ANOVA revealed a significant effect of training (F(3,540) = 12.643, P < 0.0001), of the transgene (F(3,540) = 16.788, P < 0.0001), and a significant day*transgene interaction (F(9,540) = 2.748, P = 0.0040) for all 4 groups. APP and APP/αSyn mice froze more often than WT (P < 0.05) and αSyn (P < 0.05) mice during the last 2 days of the 4 training days, suggestive of enhanced anxiety. (d) Measure of path efficiency displayed by the mice during the learning phase of the task. Two-way repeated-measures ANOVA revealed a significant effect of transgene (F(3,540) = 5.783, P = 0.0007), of training (F(3,540) = 8.627, P < 0.0001), and a significant day*transgene interaction (F(9,540) = 2.188, P = 0.0220) for all 4 groups. APP and APP/αSyn mice displayed less efficient paths than WT (P < 0.05) and αSyn (P < 0.05) mice on two of the four training days (TIFF 265 kb)
401_2018_1886_MOESM4_ESM.tif (237 kb)
Suppl. Figure 4 Comparative behavioral analysis of 6-month-old WT, APP, αSyn-KO and APP/αSyn-KO mice. (a) Distance travelled during the learning phase of the spatial task. Two-way repeated-measures ANOVA revealed a significant effect of training (F(3,544) = 38.313, P < 0.0001), of the transgene (F(3,544) = 29.356, P < 0.0001), and a significant day*transgene interaction (F(9,544) = 3.261, P = 0.0007) for all 4 groups. Only APP mice ran more than WT mice throughout the four training days (P < 0.05). (b) Average speed displayed by the mice during the learning phase of the task. Two-way repeated-measures ANOVA revealed a significant effect of transgene (F(3,544) = 22.800, P < 0.0001), no effect of training (F(3,544) = 0.288, P = 0.8339), and no significant day*transgene interaction (F(9,544) = 1.812, P = 0.0634) for all 4 groups. APP mice were faster than WT mice on 3 out of the 4 training days (P < 0.05). APP/αSyn-KO were faster than αSyn-KO mice on 3 out the 4 training days (P < 0.05). (c) Occurrence of freezing episodes during the learning phase of the spatial task. Two-way repeated-measures ANOVA revealed a significant effect of training (F(3,544) = 45.449, P < 0.0001), of the transgene (F(3,544) = 11.363, P < 0.0001), and a significant day*transgene interaction (F(9,544) = 3.116, P = 0.0012) for all four groups. Only APP mice froze more often than WT mice during the last 2 days of the 4 training days (P < 0.05), suggestive of enhanced anxiety. (d) Measure of path efficiency displayed by the mice during the learning phase of the task. Two-way repeated-measures ANOVA revealed a significant effect of transgene (F(3,544) = 6.768, P = 0.0002), of training (F(3,544) = 36.67,8 P < 0.0001), but no significant day*transgene interaction (F(9,544) = 1.548, P = 0.1279) for all 4 groups. APP mice ran less efficient paths than WT mice on 2 of the 4 training days (P < 0.05) and APP/αSyn-KO mice ran less efficient paths than αSyn-KO mice on the last day of the training period (P < 0.05) (TIFF 236 kb)
401_2018_1886_MOESM5_ESM.tif (550 kb)
Suppl. Figure 5 Biochemical characterization of total αSyn under non-denaturing conditions across mouse genotypes. (a, b) Quantitation of 4D6 (a) and LB509 (b) dot blots of intracellular (IC) enriched fractions from 6-month-old APP/αSyn, APP, APP/αSyn-KO mice, αSyn, and αSyn-KO mice. Histograms show mean ± SD; One-way ANOVA [F(4,40) = 285.5325, P < 0.0001 and F(4,40) = 280.0677, P < 0.0001 respectively] followed by Student’s t test, *P < 0.05 vs. age-matched APP mice, *P = 0.0001 vs. αSyn,; Blots are representative of 3 experiments (n = 8 mice/age/genotype. (c) Co-immunoprecipitation of Aβ with αSyn in membrane extracts from the forebrain of APP mice. Aβ was detected with 6E10. Pre-aggregated synthetic human αSyn and Aβ1-42 were loaded as internal controls. Blot is representative of 3 experiments (n = 6 mice/age/genotype) (TIFF 550 kb)
401_2018_1886_MOESM6_ESM.tif (558 kb)
Suppl. Figure 6 Protein abundance of soluble αSyn species present in forebrain lysates across genotypes. (a, b) Representative images of 4D6 (a) and LB509 (b) Western blots of intracellular (IC) enriched brain fractions from 6-month-old APP/αSyn, APP, APP/αSyn-KO mice, αSyn, and αSyn-KO mice. (c, d) Quantitation of αSyn species in 4D6 (c) and LB509 (d) Western blots. Histograms show mean ± SD; One-way ANOVA [F (4,40) 14kDa−4D6  = 292.4196, P < 0.0001, F (4,40) 28kDa−4D6  = 869.6580, P < 0.0001, F (4,40) 35kDa−4D6  = 411.9445, P < 0.0001, F (4,40) 56kDa−4D6  = 595.8812, P < 0.0001 and F(4,40) 72kDa−4D6 = 412.4011, P < 0.0001 respectively] followed by Student’s t test or Student’s t test for LB509-positive αSyn, P < 0.05 vs. age-matched αSyn mice; Blot is representative of 3 experiments (n = 8 mice/age/genotype) (TIFF 557 kb)
401_2018_1886_MOESM7_ESM.tif (468 kb)
Suppl. Figure 7 Forebrain abundance of pre- and postsynaptic proteins in WT, APP, αSyn, αSyn-KO and APP/αSyn mice. (a, b) Representative Western blots (a) and quantitation (b) of the pre-synaptic markers SYP and Rab3A, and the postsynaptic marker, GluN2A, detected in membrane (MB)-enriched fractions from 6-month-old mice. Histograms show mean ± SD; One-way ANOVA [F(4,30) = 6.6070, P = 0.0023; F(4,30) = 11.3043, P < 0.0001; F(4,30) = 4.8234, P = 0.0051 and F(4,30) = 6.7021, P = 0.0008 respectively] followed by Student’s t test, P < 0.05 vs. age-matched APP mice; n = 6 mice/age/genotype (TIFF 468 kb)
401_2018_1886_MOESM8_ESM.tif (1.2 mb)
Suppl. Figure 8 Hippocampal tau pathology is bidirectionally altered by αSyn expression in APP mice. (a, b) Representative Western blots (a) and quantitation (b) of MC1- and CP13-tau detected in membrane (MB)-enriched fractions from 6-month-old mice. Histograms show mean ± SD; One-way ANOVA [F(5,30) = 17.3481, P = 0.0026 and F(5,30) = 19.7232, P < 0.0001 respectively] followed by Student’s t test, P < 0.05 vs. age-matched APP mice; n = 5 mice/age/genotype. (c, d) Representative confocal images of hippocampal neurons immunostained for Fyn (blue) and pS202-Tau (CP13, green) revealed an aberrant accumulation and differential missorting of soluble tau species in somatodendritic compartments of pyramidal neurons of 6-month-old APP/αSyn, APP, APP/αSyn-KO (c) and αSyn, αSyn-KO (d) mice. Scale bars = 50 μm. (e, f) Quantitation of MC1- (e) and CP13-tau (f) immunoreactivity in CA3 hippocampal fields. Histograms show mean ± SD; One-way ANOVA [F(2,18) = 36.2747, P < 0.0001 and F(2,18) = 34.4679, P < 0.0001 respectively] followed by Student’s t test, P < 0.05 vs. age-matched APP mice, P < 0.05 vs. age-matched APP/αSyn mice; n = 6 sections per animal; N = 6 animals/age/genotype (TIFF 1276 kb)
401_2018_1886_MOESM9_ESM.tif (1.6 mb)
Suppl. Figure 9 Bidirectional regulation of cell cycle re-entry by αSyn in APP mice and cultured neurons. (a) Representative confocal images of cyclin D1 (green), NeuN (magenta) and MAP2 (blue) from 6-month-old WT, αSyn and αSyn-KO mice. Images were captured from the prefrontal cortex. (b, c) Representative Western blots (b) and quantitation (c) of αSyn and βIII-tubulin detected in lysates from primary cortical neurons. Histograms show mean ± SD; One-way ANOVA [F(2,18) = 27.84, P < 0.0001] followed by Student’s t test, P < 0.05 vs. neurons expressing the scrambled shRNA; n = 8-9 dishes/group. (d, e) Representative Western blots (d) and quantitation (E) of Rab3A and NeuN detected in lysates from primary cortical neurons exposed to 1.5 μM AβO or vehicle for 24 h. Histograms show mean ± SD; t test, P < 0.05 vs. vehicle-treated neurons; n = 4 dishes/group (TIFF 1650 kb)
401_2018_1886_MOESM10_ESM.tif (794 kb)
Suppl. Figure 10 Tau pathology is bidirectionally altered by αSyn expression in cultured neurons exposed to AβOs. (a) Representative confocal images of primary cortical neurons immunostained for MAP2 (blue), conformationally altered tau (MC1, green) and αSyn (4D6, magenta) revealed an aberrant accumulation of soluble tau conformers in somatodendritic compartments of cultured neurons treated with 1.5 μM AβOs or vehicle for 24 h. Scale bars = 20 μm; n = 9 dishes/group (TIFF 793 kb)
401_2018_1886_MOESM11_ESM.tif (1.5 mb)
Suppl. Figure 11 Ablation of MAPT inhibits Cyclin D1 expression in cultured neurons exposed to AβOs. Representative wide-field confocal images of primary cortical neurons immunostained for MAP2 (blue) and Cyclin D1 (magenta) revealed the absence of immunoreactivity for Cyclin D1 in tau KO neurons. Only astrocytes (white arrowheads) readily expressed Cyclin D1 in these cultures. Dashed squares correspond to the fields of view shown in Fig. 7 (TIFF 1493 kb)
401_2018_1886_MOESM12_ESM.tif (478 kb)
Suppl. Figure 12 Proposed model of the role of alpha-synuclein in APP transgenic mice. In young APP mice, synaptic and cognitive deficits are caused by soluble Ab oligomers, including soluble non-fibrillar type-I (AβO-I, blue) and pre-fibrillar type II (AβO-II, purple). AβO-II are mostly sequestered in the vicinity of amyloid plaques formed of fibrillary Ab (fAβ), while AβO-I are more abundant away from deposits. Tau pathology (green) is subtle and restricted to local changes in dendrites and axons. Cyclin D1 (orange) expression is readily detectable in a large subset of neurons. In young APP/αSyn mice, amyloid burden is reduced thereby preventing the sequestration of AβO-II assemblies, which exacerbate tau pathology and cyclin D1 expression in neurons. These deleterious changes translate into greater cognitive impairment. In young APP/αSyn-KO mice, amyloid deposition is enhanced at the expanse of soluble AβOs resulting in reduced tau pathology, cyclin D1 expression and improved memory function (TIFF 478 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Shahzad S. Khan
    • 1
    • 2
  • Michael LaCroix
    • 3
    • 4
    • 5
    • 7
  • Gabriel Boyle
    • 3
    • 4
    • 5
  • Mathew A. Sherman
    • 3
    • 4
    • 5
  • Jennifer L. Brown
    • 3
    • 4
    • 5
  • Fatou Amar
    • 3
    • 4
    • 5
    • 8
  • Jacqeline Aldaco
    • 3
    • 4
    • 5
    • 9
  • Michael K. Lee
    • 3
    • 5
    • 6
  • George S. Bloom
    • 1
    • 2
  • Sylvain E. Lesné
    • 3
    • 4
    • 5
    Email author
  1. 1.Neuroscience Graduate ProgramThe University of VirginiaCharlottesvilleUSA
  2. 2.Departments of Biology, Cell Biology and NeuroscienceThe University of VirginiaCharlottesvilleUSA
  3. 3.Department of NeuroscienceThe University of MinnesotaMinneapolisUSA
  4. 4.N. Bud Grossman Center for Memory Research and CareThe University of MinnesotaMinneapolisUSA
  5. 5.Institute for Translational NeuroscienceThe University of MinnesotaMinneapolisUSA
  6. 6.Center for Neurodegenerative DiseaseThe University of MinnesotaMinneapolisUSA
  7. 7.University of Texas Southwestern Medical SchoolDallasUSA
  8. 8.Taub InstituteColumbia UniversityNew YorkUSA
  9. 9.University of HoustonHoustonUSA

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