Journal
ACTA NEUROPATHOLOGICA
Volume 131, Issue 3, Pages 453-464Publisher
SPRINGER
DOI: 10.1007/s00401-015-1520-2
Keywords
ALS; Blood-brain barrier; Small vessel disease; Cerebral blood flow; Neuroprotection
Categories
Funding
- Thierry Latran Foundation
- Leducq Foundation
- Swedish Research Council [2011-3861, 524-2008-785, 524-2008-777, 521-2012-1853]
- Swedish Governmental Agency for Innovation Systems (VINNOVA) [2011-03503]
- Ragnar Soderberg Foundation [M245/11]
- Swedish Brain Foundation [FO2012-0055]
- Hallsten Research Foundation
- Birgit Backmark Donation
- Ahlen's Foundation [mA9/11, mA5/h12, mB8/h13]
- Swedish Stroke Foundation
- National Institutes of Health [R01 NS079639]
- Karolinska Institutet
- Vinnova [2011-03503] Funding Source: Vinnova
- Swedish Research Council [2011-03503] Funding Source: Swedish Research Council
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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.
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