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Review
. 2020 Feb 28;21(5):1666.
doi: 10.3390/ijms21051666.

Contributions of DNA Damage to Alzheimer's Disease

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Free PMC article
Review

Contributions of DNA Damage to Alzheimer's Disease

Xiaozeng Lin et al. Int J Mol Sci. .
Free PMC article

Abstract

Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.

Keywords: Alzheimer’s disease pathogenesis; DNA damage repair; DNA damage response; diagnostic biomarkers for Alzheimer disease.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Systemic literature search and selection of articles for review.
Figure 2
Figure 2
A model showing double strand break (DSB) repair pathways. For the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways, DSBs are first recognized by either the MRN or Ku70/80 complex, followed by the recruitment of ATM or DNA-PKCS (the catalytic subunit of DNA-PK) as indicated. ATM and DNA-PK then phosphorylate H2AX at serine 139 to generate γH2AX (event 1), which initiates event 2: recruiting either BRCA1 or 53BP1; recruitment of either inhibits the recruitment of another. 53BP1: p53-binding protein 1; ATM: ataxia-telangiectasia mutated; BRCA1: breast cancer type 1 susceptibility protein; DSB: double strand DNA break; DNA-PK: DNA-dependent protein kinase; HR: homologous recombination; MRN: the complex of MRE11-NBS1-RAD50; NHEJ: non-homologous end joining.
Figure 3
Figure 3
An illustration demonstrating BER. ROS induces oxidized base lesion or SSB. The oxidized bases are removed by DNA glycosylase OGG1 and NHT1 or NEIL1 and NEIL2; the ends are then processed, followed by filling the gap with synthesis of a single nucleotide or 2-8 nucleotides; ligation via a ligase will then complete the repair. SSB was first recognized by PARP1; different ends produced by end processing are accordingly modified by the indicated proteins, followed by gap filling using either the SP-BER or the LP-BER pathway. APE-1: AP (apurine/apirimidine) endonuclease 1; APTX: ataxia with oculomotor apraxia; BER: base excision repair; dRP: 3’ phosphor-α,β-unsaturated aldehyde; FEN1: Figure 1. LIG: DNA ligase; NEIL1: Nei like DNA glycosylase 1; NEIL2: Nei like DNA glycosylase 2; NTH1: Nth like DNA glycosylase; OGG1: DNA glycosylase; PARP1: poly(ADP) ribose polymerase 1; PNKP: polynucleotide kinase phosphatase; POLβ: DNA polymerase β; ROS: reactive oxygen species; SSB: single strand DNA break; TDP1: tyrosyl-DNA phosphodiesterase 1; XRCC1: X-ray repair cross-complementing protein 1.
Figure 4
Figure 4
Summary of expression of the indicated BER genes in AD brains compared to age-matched controls. Arrows indicate upregulation and downregulation respectively. APE-1: AP (apurine/apirimidine) endonuclease 1; ND: no differences; OGG1: DNA glycosylase; PARP1: poly(ADP) ribose polymerase 1; and POLβ: DNA polymerase β.
Figure 5
Figure 5
An illustration shows the effects of CDK5 in regulating DNA repair in neurons. Arrows indicate enhancing (upward direction) and reducing (downward direction) the protein’s functions respectively. CDK5 activity towards ATM in neurons is likely via p25. APE-1: AP (apurine/apirimidine) endonuclease 1; ATM: ataxia-telangiectasia mutated; BER: base excision repair; CDK5: cyclin-dependent kinase 5.

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References

    1. Maurer K., Volk S., Gerbaldo H. Auguste D and Alzheimer’s disease. Lancet. 1997;349:1546–1549. doi: 10.1016/S0140-6736(96)10203-8. - DOI - PubMed
    1. Graeber M.B., Kosel S., Grasbon-Frodl E., Moller H.J., Mehraein P. Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics. 1998;1:223–228. doi: 10.1007/s100480050033. - DOI - PubMed
    1. Graeber M.B., Mehraein P. Reanalysis of the first case of Alzheimer’s disease. Eur. Arch. Psychiatry Clin. Neurosci. 1999;249(Suppl. 3):10–13. doi: 10.1007/PL00014167. - DOI - PubMed
    1. Baumann K., Mandelkow E.M., Biernat J., Piwnica-Worms H., Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. Febs Lett. 1993;336:417–424. doi: 10.1016/0014-5793(93)80849-P. - DOI - PubMed
    1. Wilkaniec A., Czapski G.A., Adamczyk A. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: Facts and hypotheses. J. Neurochem. 2016;136:222–233. doi: 10.1111/jnc.13365. - DOI - PubMed
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