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Lateralized brunt of sleep deprivation on white matter injury in a rat model of Alzheimer’s disease

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Abstract

Sleep disturbance is a recognized risk factor for Alzheimer’s disease (AD), but the underlying micro-pathological evidence remains limited. To bridge this gap, we established an amyloid-β oligomers (AβO)-induced rat model of AD and subjected it to intermittent sleep deprivation (SD). Diffusion tensor imaging (DTI) and transmission electron microscopy were employed to assess white matter (WM) integrity and ultrastructural changes in myelin sheaths. Our findings demonstrated that SD exacerbated AβO-induced cognitive decline. Furthermore, we found SD aggravated AβO-induced asymmetrical impairments in WM, presenting with reductions in tract integrity observed in commissural fibers and association fasciculi, particularly the right anterior commissure, right corpus callosum, and left cingulum. Ultrastructural changes in myelin sheaths within the hippocampus and corpus callosum further confirmed a lateralized effect. Moreover, SD worsened AβO-induced lateralized disruption of the brain structural network, with impairments in critical nodes of the left hemisphere strongly correlated with cognitive dysfunction. This work represents the first identification of a lateralized impact of SD on the mesoscopic network and cognitive deficits in an AD rat model. These findings could deepen our understanding of the complex interplay between sleep disturbance and AD pathology, providing valuable insights into the early progression of the disease, as well as the development of neuroimaging biomarkers for screening early AD patients with self-reported sleep disturbances. Enhanced understanding of these mechanisms may pave the way for targeted interventions to alleviate cognitive decline and improve the quality of life for individuals at risk of or affected by AD.

Graphical Abstract

a AβO injection and sleep deprivation were conducted on adult rats. b Sleep deprivation and AβO-induced neurotoxicity aggravated cognitive disability with a synergistic effect. c Sleep deprivation and AβO-induced neurotoxicity reduced the integrity of specific association fasciculi and commissural fibers with ultrastructural demyelination. d On the basis of white matter integrity destruction, the structural connection was disrupted. The exacerbated topological properties with lateralized effects were correlated with cognitive decline.

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Source data are provided as Table S7 and S10

Fig. 7

Source data are provided as Table S8, S9, and S11

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Data availability

All data associated with this study are present in the paper or the Supplementary Materials. Any additional information that supports the findings reported in this study is available by contacting the corresponding author upon reasonable request.

Abbreviations

Aβ :

Amyloid-β oligomer injection group

AβO :

Amyloid-β oligomer

AD :

Alzheimer’s disease

ADC :

Apparent diffusion coefficient

AxD :

Axial diffusivity

CC :

Corpus callosum

CG :

Cingulate gyrus

Con :

Control

Cp :

Clustering coefficient

DR :

Discrimination ratio

DTI :

Diffusion tensor imaging

Eg :

Global efficiency

Eloc :

Local efficiency

Ent :

Entorhinal cortex

FA :

Fractional anisotropy

HIP :

Hippocampus

L :

Left

Lp :

Length of shortest path

mPFC :

Medial prefrontal cortex

MCI :

Mild cognitive impairment

MR :

Magnetic resonance

R :

Right

RD :

Radial diffusivity

ROI :

Regions of interest

SD :

Sleep deprivation or sleep deprivation group

SA :

Sleep deprivation combined with amyloid-β oligomer injection group

SWN :

Small world network

SCD :

Subjective cognitive decline

T-Lobe :

Temporal lobe

VBM :

Voxel-based morphometry

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This study was supported by grants from the Scientific Research Key Program of the Beijing Municipal Commission of Education (KZ202110025032), the National Natural Science Foundation of China (81771370, 82071514), the National Key Research and Development Program of China (2020YFC2005300, 2022YFC2503900) and the Scientific Research Common Program of Beijing Municipal Commission of Education (KM201810025004, KM202110025029).

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Authors and Affiliations

  1. Department of Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Xin Mao, Ding Han, Wensheng Guo, Wanning Zhang, Hongqi Wang, Guitao Zhang, Hui Li, Yizhi Song, Yan Wu & Lirong Chang

  2. Department of Neuropsychiatry and Behavioral Neurology and Clinical Psychology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Ning Zhang

  3. Electron Microscope Room of Central Laboratory, Capital Medical University, Beijing, 100069, China

    Liangyun Jin

  4. Beijing Engineering Research Center of Radiographic Techniques and Equipment, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China

    Binbin Nie

Authors
  1. Xin Mao
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  2. Ding Han
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  3. Wensheng Guo
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  4. Wanning Zhang
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  5. Hongqi Wang
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  6. Guitao Zhang
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  7. Ning Zhang
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  8. Liangyun Jin
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  9. Binbin Nie
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  10. Hui Li
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  11. Yizhi Song
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  12. Yan Wu
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  13. Lirong Chang
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Contributions

Y. W. and L. C. conceived and designed the study. X. M. and D. H. performed animal experiments. B. N. and H. L. performed MRI data processing, L. J. performed the experiment of transmission electron microscopy, and W. G., W. Z., and H. W. performed data analyses. X. M., D. H., and L. C. interpreted the data and wrote the original manuscript. G. Z., N. Z., Y. S., and Y. W. provided constructive comments and discussion of the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Yan Wu or Lirong Chang.

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Supplementary Information

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11357_2023_1000_MOESM1_ESM.tif

Supplementary file1 (TIF 2752 KB) Sleep deprivation combined with AβO aggravated the cognitive decline. (a) Timeline of the experimental design, indicating OPR task was conducted after sleep deprivation. (b) Diagram of the object place recognition test. (c) Quantification of average locomotor speed. (d) Quantification of discrimination ratio for novel place of object. (e) Quantification of times of interaction with novel place of object. Error bars represent standard deviations; One-way ANOVA with Turkey's multiple comparison test between four groups. * vs Con, ***p < 0.001; △vs SD, △△p < 0.01, △△△p < 0.001; n = 5-8 rats /group.

11357_2023_1000_MOESM2_ESM.tif

Supplementary file2 (TIF 13138 KB) Maps of volume for white matter in voxel-wise analysis. Regional difference between Con and SD (a), Aβ (b), SA (c) groups were compared, and specific significant clusters were showed in Supplementary Table S1-S3.

11357_2023_1000_MOESM3_ESM.tif

Supplementary file3 (TIF 474 KB) Bilateral difference between left and right hippocampus and mPFC of rats in tractography. (a, c) Quantification of the number (a) and mean FA value (c) of tracts between left and right hippocampus. (b, d) Estimation plots reevaluate the bilateral difference of hippocampal tracts. (e, g) Quantification of bilateral difference of the number (e) and mean FA value (g) of tracts in left and right mPFC. (f, h) Estimation plots reevaluate the difference between left and right mPFCs. Dots with wathet, pink, green and purple in estimation plots represent Con, SD, Aβ and SA groups respectively. Error bars represent standard deviations; Paired samples t test between bilateral number and mean FA value of tracts in four groups, #p < 0.05, ##p < 0.01; n = 6-11 rats /group.

11357_2023_1000_MOESM4_ESM.tif

Supplementary file4 (TIF 2112 KB) The AxD and RD values changed asymmetrically in specific tracts linking cognition related regions. (a) A heat map for AxD value change in related association fasciculi and commissural fibers. (b-h) Quantification of AxD value difference in bilateral forceps minor of corpus callosum (b), anterior commissure (c), cingulum (d), ventral hippocampal commissure (e), fornix (f), dorsal hippocampal commissure (g) and forceps major of corpus callosum (h) within four groups. (i) A bar chart for bilateral difference of AxD value in above tracts. (j) A heat map for RD value change in related association fasciculus and commissural fibers. (k-q) Quantification of RD value difference in bilateral forceps minor of corpus callosum (k), anterior commissure (l), cingulum (m), ventral hippocampal commissure (n), fornix (o), dorsal hippocampal commissure (p) and forceps major of corpus callosum (q) within four groups. (r) A bar chart for bilateral difference of RD value in above tracts. Error bars represent standard deviations; One-way ANOVA with Turkey's multiple comparison test between ipsilateral tracts in four groups. * vs Con, *p < 0.05, **p < 0.01, ***p < 0.001; △ vs SD, △p < 0.05, △△p < 0.01, △△△p < 0.001; + vs Aβ, +p < 0.05, ++p < 0.01; Paired samples T test between bilateral ROIs in four groups, #p < 0.05, ##p < 0.01; n = 6-11 rats /group.

11357_2023_1000_MOESM5_ESM.tif

Supplementary file5 (TIF 812 KB) The FA, ADC and volume changed in corpus callosum and hippocampus commissure. (a-d) Quantification of FA value difference in forceps minor of corpus callosum (a), forceps major of corpus callosum (b), ventral hippocampal commissure (c), and dorsal hippocampal commissure (d) within four groups. (e-g) Quantification of ADC value difference in forceps minor of corpus callosum (e), forceps major of corpus callosum (f), ventral hippocampal commissure (g), and dorsal hippocampal commissure (h) within four groups. (i-l) Quantification of difference of white matter volume in forceps minor of corpus callosum (i), forceps major of corpus callosum (j), ventral hippocampal commissure (k), and dorsal hippocampal commissure (l) within four groups. Error bars represent standard deviations; One-way ANOVA with Turkey's multiple comparison test between ipsilateral tracts in four groups. * vs Con, *p < 0.05, **p < 0.01, ***p < 0.001; △ vs SD, △p < 0.05, △△p < 0.01, △△△p < 0.001; + vs Aβ, +p < 0.05, +++p < 0.001; Paired samples T test between bilateral ROIs in four groups, #p < 0.05, ##p < 0.01, ###p < 0.001; n = 6-11 rats /group.

11357_2023_1000_MOESM6_ESM.tif

Supplementary file6 (TIF 1030 KB) Bilateral difference of FA value in association fasciculi and commissural fibers. (a) Abar chart for bilateral difference of FA value in some related association fasciculi and commissural fibers. (b, d, f, h, j, l and n) Quantification of the FA value change within bilateral forceps minor of corpus callosum (b), anterior commissure (d), cingulum (f), ventral hippocampal commissure (h), fornix (j), dorsal hippocampal commissure (l) and forceps major of corpus callosum (n) within four groups. (c, e, g, i, k, m and o) Estimation plots reevaluate the bilateral susceptibility in above tracts when weighting different interventions. Dots with wathet, pink, green and purple represent Con, SD, Aβ and SA groups respectively. Error bars represent standard deviations; Paired samples t test between bilateral mean FA values of tracts in four groups, #p < 0.05, ##p < 0.01, ###p < 0.001; n = 6-11 rats /group.

11357_2023_1000_MOESM7_ESM.tif

Supplementary file7 (TIF 1033 KB) Bilateral difference of ADC value in association fasciculi and commissural fibers. (a) A bar chart for bilateral difference of ADC value in some related association fasciculi and commissural fibers. (b, d, f, h, j, l and n) Quantification of the ADC value change within bilateral forceps minor of corpus callosum (b), anterior commissure (d), cingulum (f), ventral hippocampal commissure (h), fornix (j), dorsal hippocampal commissure (l) and forceps major of corpus callosum (n) within four groups. (c, e, g, i, k, m and o) Estimation plots reevaluate the bilateral susceptibility in above tracts when weighting different interventions. Dots with wathet, pink, green and purple represent Con, SD, Aβ and SA groups respectively. Error bars represent standard deviations; Paired samples t test between bilateral mean ADC value of tracts in four groups, #p < 0.05, ##p < 0.01, ###p < 0.001; n = 6-11 rats /group.

11357_2023_1000_MOESM8_ESM.tif

Supplementary file8 (TIF 978 KB) Bilateral difference of volumes in association fasciculi and commissural fibers. (a) A bar chart for bilateral difference of volumes in some related association fasciculi and commissural fibers. (b, d, f, h, j, l and n) Quantification of the volumes change within bilateral forceps minor of corpus callosum (b), anterior commissure (d), cingulum (f), ventral hippocampal commissure (h), fornix (j), dorsal hippocampal commissure (l) and forceps major of corpus callosum (n) within four groups. (c, e, g, i, k, m and o) Estimation plots reevaluate the bilateral susceptibility in above tracts when weighting different interventions. Dots with wathet, pink, green and purple represent Con, SD, Aβ and SA groups respectively. Error bars represent standard deviations; Paired samples t test between bilateral mean volume of tracts in four groups, #p < 0.05, ##p < 0.01; n = 6-11 rats /group.

Supplementary file9 (DOCX 70 KB)

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Mao, X., Han, D., Guo, W. et al. Lateralized brunt of sleep deprivation on white matter injury in a rat model of Alzheimer’s disease. GeroScience 46, 2295–2315 (2024). https://doi.org/10.1007/s11357-023-01000-3

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