L3 - DNA methylation in aging and AD Flashcards
What is epigenetics?
Changes in phenotype and/or gene expression without changes in the DNA sequence itself
List important epigenetic mechanisms:
- DNA methylation
- histone tail alterations
- micro RNA
DNMT3 and MCI
- genetic variants in DNMT3 moderate age-related cognitive decline in MCI patients
The gene associated with tau
MAPT - microtubule-associated protein tau gene
- mutations and/or age-related alterations in MAPT expression result in hyperphosphorylation of the tau protein
DNA methylation in AD
- hypomethylation in the promoter region of the APP
- CpG islands in the promoter region of the APP gene become demethylated after the age of 70
DNA methylation is carried out by…
DNA methyltransferases (DNMTs)
Maintenance vs de novo methylation:
DNMT 1 carries out maintenance methylation after each DNA replication cycle
DMNT3a and DNMT3b are de novo methyltransferases and establish DNA methylation patterns during early development
What is DNA methylation?
- the addition of a methyl group from S-adenosyl methionine (SAM) to CpG units near promoter regions of genes
List important epigenetic mechanisms
- DNA methylation
- histone tail alterations
- histone acetylation (transcriptional activation; deacetylation - repression)
- methylation at K or R residues
- phosphorylation at S or T residues
- microRNA
Three new AD susceptibility loci identified in genome-wide association studies:
Single-nucleotide polymorphisms:
- CLU (clusterin) gene (clusterin - a major brain lipoprotein; rs113600 variant is protective)
- PICALM (phosphatidylinositol-binding clathrin-assembly protein) gene
- CR1 gene
Genes with epigenetic relevance to AD
- polymorphism in MTHFR (C677T)
Which DNA methyltransferase enzyme is likely to be involved in cognitive decline?
- DNMT3a - SNPs in DNMT3a appear to moderate cognitive decline
What is SOD?
- superoxide dismutase - an enzyme catalyzing the conversion of free O2 radicals into H2O2 - reduces levels of metabolic stress
Effects of caloric restriction and overexpression of SOD on mouse life-expectancy:
- highest survival rate at 24 mo - mice with a genotype which overexpresses SOD on a caloric restriction diet
- second highest - caloric restriction; non-SOD genotype
DNMT3a levels with aging and the effects of caloric restriction on these levels
DNMT3a Type 1 cells:
- caloric restriction appears to PREVENT the INCREASE of DNMT3a with aging
DNMT3a Type 2 cells:
- caloric restriction and overexpression of SOD appears to PREVENT the DECREASE of these cells
Where are DNMT3a Type II cells found in mice?
- subgranular zone of the dentate gyrus
- subventricular zone
- olfactory bulb
- rostral migratory stream
(might they be involved in neurogenesis?)
DNMT3a type 2 and cognitive decline:
- cognitive decline in mice is associated with a decrease in DNMT3a2 expression in the hippocampus. Rescuing these levels restores cognitive function.
- hippocampal DNMT3a2 levels determine cognitive abilities in both young adult and aged mice
Age-related changes in 5mC; effects of caloric restriction on 5mC
- 5mC (5-methylcytosine) levels increase in mice with aging
- caloric restriction appears to prevent hippocampal 5mC level increase
5-hmC and its suspected involvement in aging
- 5-hmC (5-hydroxymethylcytosine) reverses methylation
Relationship between 5-mC, 5-hmC, and AD
- there is an AD-related decrease in hippocampal 5-mC and 5-hmC
- negative correlation between hippocampal AD pathology and DNA (hydroxy)methylation markers
Effect of mutant APP and PS1 on age-related methylation patterns
- mutant APP and PS1 disturb age-related increases in global methylation
