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

• Published in: The Journal of neuroscience 2011-08, Vol.31 (35), p.12543-12553
• Main Authors: Borgesius, Nils Z, de Waard, Monique C, van der Pluijm, Ingrid, Omrani, Azar, Zondag, Gerben C M, van der Horst, Gijsbertus T J, Melton, David W, Hoeijmakers, Jan H J, Jaarsma, Dick, Elgersma, Ype
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 3 - metabolism; Age Factors; Aging; Analysis of Variance; Animals; Caspase 3 - metabolism; Cognition Disorders - etiology; Cognition Disorders - genetics; Cognition Disorders - metabolism; Disease Models, Animal; DNA Repair-Deficiency Disorders - complications; DNA Repair-Deficiency Disorders - genetics; DNA-Binding Proteins - deficiency; Electric Stimulation; Endonucleases - deficiency; Fear - psychology; Gene Expression Regulation - genetics; Glial Fibrillary Acidic Protein - metabolism; Hippocampus - pathology; Hippocampus - physiopathology; In Vitro Techniques; Long-Term Potentiation - genetics; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration - etiology; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Neuronal Plasticity - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1589-11.2011

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 Ercc1(Δ/-) 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.