The aging brain: Less neurons could be better
ABSTRACT Molecular and cellular markers of age-related alterations in the brain vary significantly between different brain regions and between different types of neurons. In contrast to what had been thought for years, it has recently become clear that only specific types of neurons show an age-related loss of cells. Based on previous work we hypothesize that there is an interrelationship between two important processes in the aging brain: some types of neurons in the aging brain show an accumulation of unrepaired nuclear (n) nDNA damage since no cells are lost during aging. In contrast, other types of neurons show no accumulation of unrepaired nDNA damage since the cells with the greatest decline in nDNA repair capacity and the highest amount of nDNA damage are lost during aging. Most interestingly, the former types of neurons seem to correlate strongly with those types of neurons afflicted in age-related cognitive decline and in the selective neuronal vulnerability in Alzheimer's disease. Therefore, modulation of the nDNA damage response by stimulation of nDNA repair processes, or by elimination of neurons with a high amount of unrepaired nDNA damage in the aging brain, may lead to a functional improvement in networks of these types of neurons and to a better functioning of the aging brain in general. Ultimately, the implication of this strategy may lead to the prevention of AD.
- SourceAvailable from: Yan Wang
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- "decline is associated with an accumulation of nDNA damage in the neurons (Rutten et al. 2003, 2007); this effect may be due to insufficient nDNA repair. Our data show that noradrenergic SH-SY5Y cells and primary LC neuronal cultures exhibit an enhance sensitivity to CPT treatment, which results in accumulation of DNA damage (Fig. 2, 3, 4). "
ABSTRACT: Degeneration of the noradrenergic neurons has been reported in the brain of patients suffering from neurodegenerative diseases. However, their pathological characteristics during the neurodegenerative course and underlying mechanisms remain to be elucidated. In the present study, we used the neurotoxin camptothecin (CPT) to induce the DNA damage response in neuroblastoma SH-SY5Y cells, normal fibroblast cells, and primarily cultured locus coeruleus (LC) and raphe neurons to examine cellular responses and repair capabilities after neurotoxin exposure. To our knowledge, the present study is the first to show that noradrenergic SH-SY5Y cells are more sensitive to CPT-induced DNA damage and deficient in DNA repair, as compared to fibroblast cells. Furthermore, similar to SH-SY5Y cells, primarily cultured LC neurons are more sensitive to CPT-induced DNA damage and show a deficiency in repairing this damage. Moreover, while N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) exposure also results in DNA damage in cultured LC neurons, neither CPT nor DSP4 induce DNA damage in neuronal cultures from the raphe nuclei. Taken together, noradrenergic SH-SY5Y cells and LC neurons are sensitive to CPT-induced DNA damage and exhibit a repair deficiency, providing a mechanistic explanation for the pathological characteristics of LC degeneration when facing endogenous and environmental DNA-damaging insults in vivo.Neurotoxicity Research 03/2015; 27(4). DOI:10.1007/s12640-015-9521-4 · 3.54 Impact Factor
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- "Aging of the brain is associated with various molecular and morphological alterations that can lead to cognitive decline and increased risk for the development of neurodegenerative diseases. Brain shrinkage, neuronal loss, increased DNA damage, vascular dysfunction, and changes in numbers and morphology of dendritic spines have all been linked with the selective vulnerability to aging of hippocampal and neocortical circuits (Dickstein et al., 2007, 2010; Luebke et al., 2010; Rutten et al., 2003, 2007). Recently, the epigenetic mechanism of DNA methylation, has been linked to mediation of the age-related alterations in gene expression and with memory formation (Calvanese et al., 2009; Chouliaras et al., 2010a; Day and Sweatt, 2010; Fraga and Esteller, 2007; Levenson et al., 2006; Liu et al., 2009; Miller and Sweatt, 2007; Murgatroyd et al., 2010; Penner et al., 2010a). "
ABSTRACT: Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1-2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.Neurobiology of aging 07/2011; 33(8):1672-81. DOI:10.1016/j.neurobiolaging.2011.06.003 · 5.01 Impact Factor
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- "A further mode of investigating the neuropathology of schizophrenia is at the neurochemical level. N-acetyl aspartate (NAA) loss and impaired mitochondrial function are characteristic of several neurodegenerative diseases, including Alzheimer's Disease and multiple sclerosis (Perry et al., 2002; Rutten et al., 2003). These findings suggest that NAA concentration may be an indicator of mitochondrial function. "
ABSTRACT: This study investigated the clinical and neuropsychological correlates of N-acetyl aspartate (NAA) concentration in the anterior cingulate cortex (ACC) in schizophrenia, and explored whether ACC NAA concentration is sensitive to symptom change following cognitive behaviour therapy for psychosis (CBTp). Participants comprised 30 patients and 15 healthy controls who underwent magnetic resonance spectroscopy of the ACC and were assessed on frontal lobe based neuropsychological tasks. Twenty-four (of 30) patients were followed-up; 11 subsequently received 8-9 months of CBTp in addition to standard care (CBTp+SC) and 13 received SC only. At baseline (i) NAA and Cr concentrations were lower in patients compared to controls, (ii) in patients, NAA concentration correlated inversely with positive symptoms and general psychopathology (positive symptoms explained 21% of the variance; total variance explained=25%) and Cho concentration correlated inversely with positive symptoms, and (iii) in controls, NAA concentration correlated positively with working and short-term memory and Cr concentration inversely with executive function. NAA concentration tended to increase in CBTp+SC patients at follow-up (n=7 with usable data) concomitant with improvement in positive symptoms. NAA concentration may be more closely associated with symptoms and symptom change than frontal lobe based neuropsychological function in schizophrenia, perhaps because the latter is relatively stable during the long-term illness course.Psychiatry Research 06/2010; 182(3):251-60. DOI:10.1016/j.pscychresns.2010.02.008 · 2.47 Impact Factor