Accelerated age-related cognitive decline and neurodegeneration, caused by deficient DNA repair

Nils Z. Borgesius, Monique C. de Waard, Ingrid van der Pluijm, Azar Omrani, Gerben C.M. Zondag, Gijsbertus T.J. van der Horst, David W. Melton, Jan H.J. Hoeijmakers, Dick Jaarsma, Ype Elgersma

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

96 Citaten (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)12543-12553
Aantal pagina's11
TijdschriftJournal of Neuroscience
Nummer van het tijdschrift35
StatusGepubliceerd - 31 aug. 2011
Extern gepubliceerdJa


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