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

Abstract

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 (Aβ42) 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 Aβ42 levels are associated with Aβ42 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 Aβ42 to Igf2 DMR2 increased DNA and histone methylation, and reduced Igf2 expression. These results indicate an age- and sex-related causal relationship among Aβ42 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 Aβ42 targeted AD therapies.

Transgenerational Epigenetic DNA Methylation Editing and Human Disease

“…Other examples include promoter-CGI hypermethylation of the tumor suppressor MutL Homolog 1 (MLH1) in colorectal, esophageal, and thymic epithelial tumors [43][44][45][46][47] and promoter TP53 DNAme in several cancers and in stroke patients [48][49][50]. Specific DNAme changes are also observed in atherosclerosis and cardiovascular disease (e.g., ABCG1), metabolic disorders (e.g., ANKRD26, IGF2), Alzheimer's disease, and other nervous system disorders (e.g., IGF2) [36,37,[51][52][53][54][55][56][57][58][59][60]. DNAme is highly predictive of biological age, and several pathological states accelerate DNAme age [6,9,10,37,38,[61][62][63][64].…”

“…Differential DNAme was noted at the progesterone receptor and insulin-like growth factor (Igf2), which may also extend to the imprinting control region [112][113][114]. Given the role Igf2 differential methylation may play in Alzheimer's and major psychosis events, transgenerational DNAme at this locus may provide an epigenetic basis for potential neurological conditions associated with ancestral exposures [51,52,113]. For DDT, the transgenerational effects appear to be mediated through specific changes in sperm DNAme, with many DMRs that occur at genes known to promote obesity.…”