TY  - JOUR
AU  - Kraft, Peter
AU  - Schuhmann, Michael K
AU  - Garz, Cornelia
AU  - Jandke, Solveig
AU  - Urlaub, Daniela
AU  - Mencl, Stine
AU  - Zernecke, Alma
AU  - Heinze, Hans-Jochen
AU  - Carare, Roxana O
AU  - Kleinschnitz, Christoph
AU  - Schreiber, Stefanie
TI  - Hypercholesterolemia induced cerebral small vessel disease.
JO  - PLOS ONE
VL  - 12
IS  - 8
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-05764
SP  - e0182822
PY  - 2017
AB  - BackgroundWhile hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr-/- mouse model.MethodsWe used Ldlr-/- mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr-/- mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.ResultsWe found a significant increase in the number of erythrocyte stases in 6 months old Ldlr-/- mice compared to all other groups (P < 0.05). Ldlr-/- animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr-/- mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.ConclusionsIn Ldlr-/- mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr-/- mice appear to be an adequate animal model for research into CSVD.
KW  - Animals
KW  - Blood-Brain Barrier: physiopathology
KW  - Brain: physiopathology
KW  - Cerebral Small Vessel Diseases: blood
KW  - Cerebral Small Vessel Diseases: etiology
KW  - Cerebral Small Vessel Diseases: genetics
KW  - Cerebral Small Vessel Diseases: physiopathology
KW  - Cholesterol: blood
KW  - Diet, High-Fat
KW  - Disease Models, Animal
KW  - Hypercholesterolemia: blood
KW  - Hypercholesterolemia: complications
KW  - Hypercholesterolemia: genetics
KW  - Hypercholesterolemia: physiopathology
KW  - Male
KW  - Mice
KW  - Mice, Knockout
KW  - Receptors, LDL: genetics
KW  - Receptors, LDL (NLM Chemicals)
KW  - Cholesterol (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28796818
C2  - pmc:PMC5552130
DO  - DOI:10.1371/journal.pone.0182822
UR  - https://pub.dzne.de/record/139442
ER  -