Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 42, Issue 5, Pages 771-787Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X211069006
Keywords
APOE; VCID; inflammation; metabolism; SERPIN
Categories
Funding
- National Institute of Neurological Disorders and Stroke [RO1 NS097722, 5T32NS077889-09]
- National Institute on Aging [RF1 AG057754, R56 AG057191-02, R01 AG060056, R01 AG062550]
- National Institute of General Medical Sciences [5T32GM118292-02]
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Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia. The Apolipoprotein E (ApoE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease and is also a risk factor for VCID. Mice with the ApoE ε4 allele show significant resistance to hyperhomocysteinemia (HHcy) induction, with differences in homocysteine metabolism and methylation cycle compared to mice with the ε3 allele. There are also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as reduced expression of the serine protease inhibitor Serpina3n in ε4 HHcy mice. Lastly, there is evidence of pervasive sex differences in response to HHcy induction within both genotypes.
Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer's disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE epsilon 4 allele is the strongest genetic risk factor for late onset Alzheimer's disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE epsilon 4 compared to epsilon 3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in epsilon 4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between epsilon 3 and epsilon 4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE epsilon 4, expression in epsilon 4 HHcy mice relative to epsilon 4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.
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