Acta Neuropathologica

, Volume 131, Issue 3, pp 453–464 | Cite as

Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration

  • Sebastian A. Lewandowski
  • Ingrid Nilsson
  • Linda Fredriksson
  • Peter Lönnerberg
  • Lars Muhl
  • Manuel Zeitelhofer
  • Milena Z. Adzemovic
  • Susanne Nichterwitz
  • Daniel A. Lawrence
  • Eva Hedlund
  • Ulf Eriksson
Original Paper


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown origins. Neurodegeneration in ALS mouse models occurs together with signs of disrupted blood–spinal cord barrier (BSCB) and regressed capillary network, but the molecular pathways contributing to these vascular pathologies remain unknown. We show that motor neurons of human sporadic ALS patients (n = 12) have increased gene expression of PDGFC and its activator PLAT and presymptomatic activation of the PDGF-CC pathway in SOD1 G93A mice leads to BSCB dysfunction. Decrease of Pdgfc expression in SOD1 G93A mice restored vascular barrier properties, reduced motor neuron loss and delayed symptom onset by up to 3 weeks. Similarly, lower expression levels of PDGFC or PLAT in motor neurons of sporadic ALS patients were correlated with older age at disease onset. PDGF-CC inhibition and restoration of BSCB integrity did not prevent capillary regression at disease end stage. Lower vessel density was found in spinal cords of sporadic ALS patients and the degree of regression in SOD1 G93A mice correlated with more aggressive progression after onset regardless of BSCB status. We conclude that PDGF-CC-induced BSCB dysfunction can contribute to timing of ALS onset, allow insight into disease origins and development of targeted novel therapies.


ALS Blood–brain barrier Small vessel disease Cerebral blood flow Neuroprotection 



This work was supported by grants from the Thierry Latran Foundation (U. E.), the Leducq Foundation (U. E.), Swedish Research Council (U.E. 2011-3861), the Swedish Governmental Agency for Innovation Systems (VINNOVA, U. E., L. F. 2011-03503), the Ragnar Söderberg Foundation (E. H. M245/11), the Swedish Brain Foundation (U. E., E. H. FO2012-0055) and the Hållsten Research Foundation (U. E.), the Birgit Backmark Donation (E. H.), the Åhlen’s Foundation (E. H. mA9/11, mA5/h12 and mB8/h13), the Swedish Stroke Foundation (I. N.), the Swedish Research Council (I. N. 524-2008-785, L. F. 524-2008-777 and 521-2012-1853), the National Institutes of Health (D. A. L. R01 NS079639) and Karolinska Institutet. Human post mortem tissues were provided by the Netherland’s Brain Bank (NBB). We would like to thank Sofia Wittgren and Mark Warnock for technical assistance. We would also like to thank R. K. Filipkowski for comments on the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that no conflict of interest exists.

Supplementary material

Supplementary Video 1 (WMV 24231 kb)

401_2015_1520_MOESM2_ESM.pdf (6.3 mb)
Supplementary Figures 1–13 (PDF 6228 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Sebastian A. Lewandowski
    • 1
  • Ingrid Nilsson
    • 1
  • Linda Fredriksson
    • 2
    • 3
  • Peter Lönnerberg
    • 2
  • Lars Muhl
    • 1
  • Manuel Zeitelhofer
    • 1
  • Milena Z. Adzemovic
    • 1
  • Susanne Nichterwitz
    • 4
  • Daniel A. Lawrence
    • 3
  • Eva Hedlund
    • 4
  • Ulf Eriksson
    • 1
  1. 1.Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  2. 2.Vascular Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  3. 3.Department of Internal Medicine, Division of Cardiovascular MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  4. 4.Department of NeuroscienceKarolinska InstitutetStockholmSweden

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