Induction of hyperhomocysteinemia models vascular dementia by induction of cerebral microhemorrhages and neuroinflammation.
Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders.
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40536, USA.
Tiffany L
TL
Sudduth
David K
DK
Powell
Charles D
CD
Smith
Abigail
A
Greenstein
Donna M
DM
Wilcock
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D015140:Dementia, Vascular / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000276:immunology; D053583:Interleukin-1beta / Q000032:analysis / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology*; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014805:Vitamin B 12 / Q000378:metabolism; D025101:Vitamin B 6 / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D025101:Vitamin B 6; D005492:Folic Acid; D008715:Methionine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D014805:Vitamin B 12