Noncanonical regulation of imprinted gene Igf2 by amyloid-beta 1–42 in Alzheimer’s disease

Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer’s disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1–42 ( Aβ 42 ) accumulation and epig...

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Published in:	Scientific reports Vol. 13; no. 1; p. 2043
Main Authors:	Fertan, Emre, Gendron, William H., Wong, Aimée A., Hanson, Gabrielle M., Brown, Richard E., Weaver, Ian C. G.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-02-2023 Nature Publishing Group Nature Portfolio
Subjects:	631/378 631/378/2584 631/378/2611 631/378/340 692/699/375 692/699/375/132/1283 Acetylation Age Alzheimer Disease - genetics Alzheimer's disease Animals Cell culture Cerebrum Cortex (frontal) Dementia disorders Deoxyribonucleic acid DNA DNA Methylation Epigenesis, Genetic Epigenetics Female Females Gender differences Genomic Imprinting H19 gene HEK293 Cells Histones Histones - metabolism Humanities and Social Sciences Humans Insulin Insulin-like growth factor II Insulin-Like Growth Factor II - genetics Insulin-Like Growth Factor II - metabolism Male Metabolic disorders Methylation Mice Mice, Inbred ICR multidisciplinary Neurodegenerative diseases RNA, Long Noncoding - genetics Science Science (multidisciplinary) Sex differences
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Summary:	Reduced insulin-like growth factor 2 (IGF2) levels in Alzheimer’s disease (AD) may be the mechanism relating age-related metabolic disorders to dementia. Since Igf2 is an imprinted gene, we examined age and sex differences in the relationship between amyloid-beta 1–42 ( Aβ 42 ) accumulation and epigenetic regulation of the Igf2/H19 gene cluster in cerebrum, liver, and plasma of young and old male and female 5xFAD mice, in frontal cortex of male and female AD and non-AD patients, and in HEK293 cell cultures. We show IGF2 levels, Igf2 expression, histone acetylation, and H19 ICR methylation are lower in females than males. However, elevated Aβ 42 levels are associated with Aβ 42 binding to Igf2 DMR2, increased DNA and histone methylation, and a reduction in Igf2 expression and IGF2 levels in 5xFAD mice and AD patients, independent of H19 ICR methylation. Cell culture results confirmed the binding of Aβ 42 to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aβ 42 levels, epigenomic state, and Igf2 expression in AD and provide a potential mechanism for Igf2 regulation in normal and pathological conditions, suggesting IGF2 levels may be a useful diagnostic biomarker for Aβ 42 targeted AD therapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-023-29248-x