TY - JOUR
T1 - Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair
AU - Borgesius, Nils Z.
AU - de Waard, Monique C.
AU - van der Pluijm, Ingrid
AU - Omrani, Azar
AU - Zondag, Gerben C.M.
AU - van der Horst, Gijsbertus T.J.
AU - Melton, David W.
AU - Hoeijmakers, Jan H.J.
AU - Jaarsma, Dick
AU - Elgersma, Ype
PY - 2011/8/31
Y1 - 2011/8/31
N2 - 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 agedependent 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.
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 agedependent 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.
UR - http://www.scopus.com/inward/record.url?scp=80052359532&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1589-11.2011
DO - 10.1523/JNEUROSCI.1589-11.2011
M3 - Article
C2 - 21880916
AN - SCOPUS:80052359532
SN - 0270-6474
VL - 31
SP - 12543
EP - 12553
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -