Family Hypercholesterolemia Aggravates White Matter Lesion And Cognitive Impairment After Chronic Cerebral Hypoperfusion

Part ? White matter changes in the low density lipoprotein receptor knockout hypercholesterolemic rats Objective To investigate the microstructure difference in white matter between low density lipoprotein receptor knockout hypercholesterolemic rats and wild type Sprague-Dawley rats.Methods LDLR-/-rats(n=30)and LDLR+/+ rats(n=28)were selected for experiments.At 15 weeks,18 weeks,26 weeks,serum cholesterol levels were measured by Enzyme-linked immunosorbent assay.The axonal structure of corpus callosum were observed by transmission electron microscopy.The myelin basic protein(MBP)of corpus callosum were quantitatively analyzed by Western blots.In addition,at 26 weeks,myelin staining through chemical luxol fast blue staining,further expression of MBP and cell morphological changes were observed by immunofluorescence staining.Results Compared with the LDLR+/+ rats,the cholesterol level in LDLR-/-rats were significantly increased and up to 3.3 times at 26 weeks.The axonal injury was detected in LDLR-/-rats from 15 weeks,started to progress over time.Western blots showed that the expression of MBP in the corpus callosum region were significantly decreased at 26 week in LDLR-/-rats,while LFB showed that nerve fibers was lack,diffuse vacuole formation and demyelination(2.23±0.71)in LDLR-/-rats was more serious than LDLR+/+ rats(0.43±0.55).In addition,immunohistochemical staining displayed the number of oligodendrocytes reduced,the astrocytes and microglia were activated distinctly in LDLR-/-rats.Conclusions This study suggests that LDLR-/-rats present with spontaneous hypercholesterolemia.Axonal injury,demyelination,decreased oligodendrocytes,astrocytes and microglial activation can be observed in the white matter of early adult brain.Part ? Family hypercholesterolemia aggravates white matter lesion and cognitive impairment after chronic cerebral hypoperfusionObjective Vascular pathology and hypercholesterolemia pathology have been shown to coexist in the brains of white matter lesion patients.We investigated how white matter lesion and cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and family hypercholcsterolermia.Methods Family hypercholesterolemia was modeled by knocking out low density lipoprotein receptor(LDLR-/-)and chronic cerebral hypoperfusion was modeled by placing an ameroid constrictor on the bilateral common carotid arteries(GCAS).The experimental rats were devided evenly into 4 groups including sham rats(+/+)(n=28),LDLR-/-rats(-/-)(n=30),LDLR+/+ rats with GCAS(+/+ GCAS)(n=30),LDLR-/-rats with GCAS(-/-GCAS)(n=30).Cerebral blood flow(CBF)was recorded by Laser Doppler flowmetry(LDF),Cerebral blood flow signal,infarction,white matter anatomical connectivity were measured using 7.0 T animal MRI scanner.Western blotting,morris water maze test and histological evaluation including immunofluorescence staining,transmission electron microscopy(EM)were performed.Results There was almost no change in CBF from 1 to 12 weeks in the sham group but decreased significantly to 34.3±8.4%in the-/-group,22.9 ±12.6%in the +/+GCAS group,and 7.4 ±5.3%in the-/-GCAS group at 12 weeks.The connectivity of fiber tracts in corpus callosum was damaged in-/-groups.The connectivity and neuronal fiber bundles were severely injured in GCAS and-/-GCAS,what's more,this phenomenon was synergistically exacerbated in-/-GCAS(p=0.037).Disintegration of white matter was characterized by neuroinflammation with microglial or astroglial activation,attenuation of myelin density and loss of axons were increased in LDLR-/-group and +/+ GCAS group compared to the sham group.This disintegration was enhanced in combined injury(-/-GCAS)groups.Spatial memory impairment was synergistically exacerbated in the-/-GCAS group as compared to the +/+ GCAS or-/-groups(p<0.05).Conclusions Familial hypercholesterolemia may aggravate chronic cerebral hypoperfusion and further increase white matter damage and cognitive dysfunction in rats.