Article

The aging brain: less neurons could be better.

Department of Psychiatry and Neuropsychology, Division of Neuroscience, University of Maastricht, P.O. Box 616, Universiteitssingel 50, 6200 MD, Maastricht, The Netherlands.
Mechanisms of Ageing and Development (Impact Factor: 3.26). 04/2003; 124(3):349-55. DOI: 10.1016/S0047-6374(03)00002-2
Source: PubMed

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.

0 Bookmarks
 · 
57 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aging process in the hippocampus is associated with aberrant epigenetic marks, such as DNA methylation and histone tail alterations. Recent evidence suggests that caloric restriction (CR) can potentially delay the aging process, while upregulation of antioxidants may also have a beneficial effect in this respect. We have recently observed that CR attenuates age-related changes in the levels of the epigenetic molecules DNA methyltransferase 3a, 5-methylcytidine (5- mC) and 5-hydroxymethylcytosine in the mouse hippocampus while overexpression of the antioxidant Cu/Zn superoxide dismutase 1 (SOD1) does not. However, the impact of aging on the levels of histone-modifying enzymes such as histone deacetylase 2 (HDAC2) in the hippocampus has not been studied in much detail. Here, we investigated immunoreactivity (IR) of HDAC2 in three subregions of the hippocampus (dentate gyrus, CA3 and CA1-2) of mice taken from large cohorts of aging wild-type and transgenic mice overexpressing normal human SOD1, which were kept under normal diet or CR from weaning onwards. Independent from the genotype, aging (between 12 and 24 months) increased levels of HDAC2 IR in the hippocampus. Moreover, CR prevented this age-related increase, particularly in the CA3 and CA1-2 subregions, while SOD1 overexpression did not. Quantitative image analyses showed that HDAC2 IR correlated positively with 5-mC IR while these markers were shown to colocalize in the nucleus of hippocampal cells. Together with recent literature reports, these findings suggest that altered levels of epigenetic regulatory proteins including HDAC2 regulate age-related changes in the mouse hippocampus and that CR may prevent these age-related changes.
    Current Alzheimer research 10/2013; 10(8):868-876. · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A hallmark of neurodegenerative diseases is impairment of certain aspects of "brain functionality". Brain functionality is defined as the total input and output of the brain's neural circuits and networks. A given brain degenerative disorder does not deregulate total brain functionality but rather the activity of specific circuits in a given network, affecting their organization and topology, their cell numbers, their cellular functionality, and the interactions between neural circuits. Similarly, our concept of neurodegenerative diseases, which for many years revolved around neural survival or death, has now been extended to emphasize the role of glia. In particular, the role of glial cells in neuro-vascular communication is now known to be central to the effect of insults to the nervous system. In addition, a malfunctioning vascular system likely plays a role in the etiology of certain neurodegenerative diseases. Thus, the symptoms of neurodegenerative or more correctly brain degenerative disease are, to a very large extent, a result of impairment in glial cells that lead to pathological neuro-vascular interactions that, in turn, generate a rather "hostile" environment in which the neurons fail to function. These events lead to systematic neural cell death on a scale that appears to be proportional to the severity of the neurological deficit.
    DNA repair 05/2013; · 4.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dynamin (DNM) plays roles in membrane dynamics, vesicle formation, and transport. In the present study, we compared DNM-1 and DNM-2 protein expressions between the adult (postnatal month 6) and aged (postnatal month 24) gerbil hippocampus using immunohistochemistry and western blot analysis. DNM-1 and DNM-2 immunoreactivities were primarily observed in hippocampal principal neurons: pyramidal cells in the hippocampus proper (CA1-CA3) and granule cells in the dentate gyrus. DNM-1 and DNM-2 immunoreactivities in principal neurons were significantly increased in the aged group compared with the adult group. In addition, DNM-1 and DNM-2 protein levels as well as phospho-DNM-1 level were significantly increased in the aged group. These results indicate that the increases of DNM-1 and DNM-2 protein expressions may reflect the age-related changes in hippocampal function.
    Cellular and Molecular Neurobiology 04/2014; · 2.29 Impact Factor