RT Journal Article
SR Electronic
T1 Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12543
OP 12553
DO 10.1523/JNEUROSCI.1589-11.2011
VO 31
IS 35
A1 Nils Z. Borgesius
A1 Monique C. de Waard
A1 Ingrid van der Pluijm
A1 Azar Omrani
A1 Gerben C. M. Zondag
A1 Gijsbertus T. J. van der Horst
A1 David W. Melton
A1 Jan H. J. Hoeijmakers
A1 Dick Jaarsma
A1 Ype Elgersma
YR 2011
UL http://www.jneurosci.org/content/31/35/12543.abstract
AB Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1Δ/− mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.