Differential sensitivity of prefrontal cortex and hippocampus to alcohol-induced toxicity.

The prefrontal cortex (PFC) is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus.

Impaired one carbon metabolism and DNA methylation in alcohol toxicity.

Excessive alcohol consumption is a prominent problem and one of the major causes of mortality and morbidity around the world. Long-term, heavy alcohol consumption is associated with a number of deleterious health consequences, such as cancer, heart and liver disease, a variety of neurological, cognitive, and behavioral deficits. Alcohol consumption is also associated with developmental defects.

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death.

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes.

Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear. In an effort to clarify this, we investigated the expression of gamma H2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD.

DNA damage response and neuroprotection.

The protection of genomic integrity is a major challenge for living cells that are continuously exposed to endogenous and environmental DNA-damaging insults. To cope with the consequences of DNA lesions which interfere with essential DNA-dependent processes including transcription and replication, cells are equipped with an efficient defense mechanism termed the DNA damage response. Its function is to eliminate DNA damage through DNA repair and to remove cells with incurred DNA damage by apoptosis.

Folate deficiency inhibits proliferation of adult hippocampal progenitors.

Neurogenesis in the adult hippocampus may play important roles in learning and memory, and in recovery from injury. As recent findings suggest, the perturbance of homocysteine/folate or one-carbon metabolism can adversely affect both the developing and the adult brain, and increase the risk of neural tube defects and Alzheimer's disease. We report that dietary folic acid deficiency dramatically increased blood homocysteine levels and significantly reduced the number of proliferating cells in the dentate gyrus of the hippocampus in adult mice.

Folate deficiency increases postischemic brain injury.

Background And Purpose: Folate deficiency and resultant hyperhomocysteinemia impair vascular function and increase stroke risk. We tested the hypothesis that folate deficiency and high homocysteine levels promote DNA damage and increase brain injury after cerebral ischemia/reperfusion.

Methods: 129/Sv mice, uracil-DNA glycosylase-deficient (Ung-/-) mice, and Ung+/+ littermate mice were exposed to a folate-deficient diet for 3 months and then subjected to 30-minute middle cerebral artery (MCA) occlusion and reperfusion.

Suppression of uracil-DNA glycosylase induces neuronal apoptosis.

A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival.

Why do neurons enter the cell cycle?

Increasing evidence indicates that postmitotic, terminally differentiated neurons activate the cell cycle before death. The purpose of this cell cycle activation, however, remains elusive. In proliferating cells, cell cycle machinery is a major contributor to the DNA damage response, which is comprised of growth arrest.

Cell cycle activation linked to neuronal cell death initiated by DNA damage.

Increasing evidence indicates that neurodegeneration involves the activation of the cell cycle machinery in postmitotic neurons. However, the purpose of these cell cycle-associated events in neuronal apoptosis remains unknown. Here we tested the hypothesis that cell cycle activation is a critical component of the DNA damage response in postmitotic neurons.

Folic acid and homocysteine in age-related disease.

It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease.

Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease.

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid beta-peptide (Abeta) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Abeta.

Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease.

Although the cause of Parkinson's disease (PD) is unknown, data suggest roles for environmental factors that may sensitize dopaminergic neurons to age-related dysfunction and death. Based upon epidemiological data suggesting roles for dietary factors in PD and other age-related neurodegenerative disorders, we tested the hypothesis that dietary folate can modify vulnerability of dopaminergic neurons to dysfunction and death in a mouse model of PD. We report that dietary folate deficiency sensitizes mice to MPTP-induced PD-like pathology and motor dysfunction.