One-Carbon Metabolism and Alzheimers Disease: Focus on Epigenetics

Abstract

Alzheimer’s disease (AD) represents the most common form of dementia in the elderly, characterized by progressive loss of memory and cognitive capacity severe enough to interfere with daily functioning and the quality of life. Rare, fully penetrant mutations in three genes (APP, PSEN1 and PSEN2) are responsible for familial forms of the disease. However, more than 90% of AD is sporadic, likely resulting from complex interactions between genetic and environmental factors. Increasing evidence supports a role for epigenetic modifications in AD pathogenesis. Folate metabolism, also known as one-carbon metabolism, is required for the production of S-adenosylmethionine (SAM), which is the major DNA methylating agent. AD individuals are characterized by decreased plasma folate values, as well as increased plasma homocysteine (Hcy) levels, and there is indication of impaired SAM levels in AD brains. Polymorphisms of genes participating in one-carbon metabolism have been associated with AD risk and/or with increased Hcy levels in AD individuals. Studies in rodents suggest that early life exposure to neurotoxicants or dietary restriction of folate and other B vitamins result in epigenetic modifications of AD related genes in the animal brains. Similarly, studies performed on human neuronal cell cultures revealed that folate and other B vitamins deprivation from the media resulted in epigenetic modification of the PSEN1 gene. There is also evidence of epigenetic modifications in the DNA extracted from blood and brains of AD subjects. Here I review one-carbon metabolism in AD, with emphasis on possible epigenetic consequences.

Accumulated hippocampal formaldehyde induces age-dependent memory decline

“…(3) Diet: Formaldehyde participates in the "onecarbon cycle" (Kalász 2003). Deficiencies of vitamin B 12 or folate in the diet lead to dysfunction of onecarbon metabolism in Alzheimer's patients (Coppedè 2010). (4) Tumor: Cancer is known to be related to the occurrence of Alzheimer's disease (Burke et al 1994), and cancer cells and tumor tissues release higher levels of formaldehyde than normal cells and tissues (Tong et (Teng et al 2001), are related to memory.…”

Uric formaldehyde levels are negatively correlated with cognitive abilities in healthy older adults

“…Diet is one of the infl uential factors for the physiological and/or pathological accumulation of formaldehyde, as deficiencies of vitamin B12 or folate in the diet lead to dysfunction of one-carbon metabolism in AD patients [69] , while formaldehyde participates in the "onecarbon cycle" [51] .…”

Basic concepts of epigenetics

“…1,17,43 miRNAs can also influence the epigenome itself. This is exemplified by the fact that GpG islands are often occupied by miRNAs that specifically degrade mRNA transcripts that encode for proteins involved in silencing or histone constriction, such as MeCP2, DNMTs, HDACs and EZH2 44 (all of which are discussed further below).…”

“…In other imprinting, 12 histone modifications and the establishment of specific expression profiles of non-coding miRNAs. 13,14 Given the enormous impact of early epigenetic programming and the serious nature of related developmental conditions, such as Praeder-Willi, Angelman and Beckwith-Wiedemann syndromes, neural tube defects, adult onset psychiatric disorders, obesity, cancer and schizophrenia, [15][16][17][18][19] considerable attention is given to the "nurture of the epigenome" prior to birth. A number of community outreach projects such as the CDC's National Center on Birth Defects and Developmental Disabilities promote awareness about reducing the risk of epigenetic related defects such as spina bifida by suggesting an adequate intake of epigenetic-related nutrients (e.g., choline, vitamin B 12 , B 6 and folate) during pregnancy.…”