DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Abstract

We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ+/− mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.

DNA Polymerase Beta Participates in Mitochondrial DNA Repair

“…Mice with Pol␤ heterozygosity have defects in mitochondrion-related pathways in the brain, including oxidative phosphorylation (25). Further, using large-scale mitochondrial extracts from bovine heart, a Pol␤-like activity has been reported (23).…”

“…For this experiment, we used brain tissue extracts from Pol␤ heterozygous (HT) mice. Pol␤ HT mice have accelerated age-related neurodegeneration, suggesting that the brain may be selectively affected by Pol␤ heterozygosity (25). WT mitochondrial samples (Fig.…”

“…However, Pol␤ HT mice are viable but have altered life span characteristics (36) and elevated carcinogenic risk (37). We have previously extensively characterized the Pol␤ HT mouse and observed a range of differences, particularly in aged mice, that are reflective of an animal with mitochondrial dysfunction (25). Pol␤ HT mice have accelerated neurodegenerative decline and metabolic dysfunction, including an altered respiratory exchange rate (RER) (Fig.…”

Antioxidants as a preventive therapeutic option for age related neurodegenerative diseases

“…Exhaustive research is undergoing in this field but still the enigma behind such progressive neuronal death is not well understood. Over the last several decades the studies have showed that the progression of neurodegenerative diseases involve the decreased antioxidant levels, impaired mitochondrial activity, increased oxidative damage protein, lipid peroxidation, protein modification, DNA damage and apoptosis [4][5][6][7][8][9] . Oxidative protein modifications occur at a low and persistent level in diverse cells and tissues and accumulate in aging and neurodegenerative diseases [10][11][12][13][14][15][16][17][18][19] .…”

APOE4, oxidative stress and decreased repair capacity - a no-brainer. Faulty lipid metabolism and increased levels of oxidative damage may be risk factors in the pathogenesis of late-onset dementia

“…Variant alleles of polymorphisms in the genes coding for human apurinic/apyrimidinic endonuclease APE1 (the main nuclease hydrolysing the phosphodiester backbone 5'-from the abasic site generated by BER glycosylases) and the gene coding for XRCC1, the stabilising factor of ligase III (the primary ligase of BER) were identified as predisposing factors for sporadic Parkinson's disease [138]. Deficiency of DNA polymerase beta was reported to accelerate cognitive decline in transgenic mice modelling AD [139].…”