DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease.
Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase-β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild-type and 3xTgAD mice with normal or reduced Polβ levels. Compared to wild-type control mice, Polβ heterozygous (Polβ+/-), and 3xTgAD mice, 3xTgAD/Polβ+/-mice exhibited impaired performance in a buried food test of olfaction. Polβ deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Polβ+/-and 3xTgAD mice, and by over 60% in the 3xTgAD/Polβ+/-mice compared to wild-type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Polβ+/-mice compared to 3xTgAD mice. Levels of amyloid β-peptide (Aβ) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Polβ+/-mice, and cultured Polβ-deficient neurons exhibited increased vulnerability to Aβ-induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.|Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Magdalena
M
Misiak
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Rebeca
R
Vergara Greeno
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Beverly A
BA
Baptiste
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Peter
P
Sykora
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Dong
D
Liu
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.|Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Stephanie
S
Cordonnier
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Evandro F
EF
Fang
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Deborah L
DL
Croteau
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Mark P
MP
Mattson
Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Biomedical Research Center, 251 Bayview Blvd, Baltimore, MD, 21224, USA.
Vilhelm A
VA
Bohr
D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002454:Cell Differentiation; D019069:Cell Respiration; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D057895:Haploinsufficiency; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009830:Olfactory Bulb / Q000201:enzymology* / Q000473:pathology*; D012903:Smell
D016229:Amyloid beta-Peptides; D019951:DNA Polymerase beta
Alzheimer's disease; DNA damage; DNA polymerase β; DNA repair; neurogenesis; olfactory bulb; smell
J Alzheimers Dis. 2010;22(2):443-57
20847430
Brain Res. 2014 Jul 14;1572:18-25
24842003
Ageing Res Rev. 2005 Nov;4(4):579-602
16246641
Nucleic Acids Res. 2007;35(16):5545-55
17704129
ASN Neuro. 2010 Oct 04;2(5):e00045
20957078
Acta Neuropathol. 2014 Apr;127(4):459-75
24554308
Nat Rev Mol Cell Biol. 2016 May;17 (5):308-21
26956196
Neuromolecular Med. 2002;1(2):125-35
12025858
Mech Ageing Dev. 2013 Oct;134(10):440-8
23643943
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14948-53
22927410
J Neurosci. 2013 Jul 24;33(30):12208-17
23884929
Front Neurosci. 2014 Jun 26;8:182
25018692
Neurobiol Aging. 2009 Feb;30(2):272-83
17618708
Neurobiol Aging. 1992 Jul-Aug;13(4):469-73
1508297
Mutat Res. 2002 Mar 20;500(1-2):135-45
11890943
J Neurosci. 2010 Jan 13;30(2):505-14
20071513
DNA Repair (Amst). 2014 Jul;19:14-26
24780558
Nat Neurosci. 2013 May;16(5):613-21
23525040
Gerontology. 2015;61(6):485-90
25968962
Nature. 2004 Jun 24;429(6994):883-91
15190254
Cancer Res. 2003 Sep 15;63(18):5799-807
14522902
J Neurochem. 2006 Feb;96(3):825-32
16405502
Nat Commun. 2012;3:1009
22910355
Hum Mol Genet. 2010 Apr 15;19(R1):R12-20
20413653
Learn Mem. 2011 Aug 30;18(9):605-9
21878528
Trends Neurosci. 2010 Dec;33(12):569-79
20961627
Nucleic Acids Res. 2015 Jan;43(2):943-59
25552414
EMBO J. 2000 Mar 15;19(6):1397-404
10716939
Neuron. 2008 Dec 10;60(5):748-66
19081372
J Cereb Blood Flow Metab. 2011 Feb;31(2):680-92
20736962
Neuron. 2014 Jul 16;83(2):266-82
25033177
Nature. 2004 Aug 5;430(7000):631-9
15295589
Nature. 1996 Jan 11;379(6561):183-6
8538772
Cell. 2014 May 8;157(4):882-96
24813611
Mech Ageing Dev. 2012 Apr;133(4):133-7
22019846
Ageing Res Rev. 2004 Nov;3(4):465-83
15541712
J Neurosci. 2007 Apr 4;27(14):3722-33
17409236
J Biol Chem. 2010 Sep 3;285(36):28191-9
20573957
J Neurochem. 2005 Feb;92 (4):818-23
15686483
Neuron. 2003 Jul 31;39(3):409-21
12895417
Neuromolecular Med. 2014 Mar;16(1):161-74
24114393
Neurobiol Aging. 2015 Jul;36(7):2319-30
25971543
J Neurosci. 1992 Feb;12(2):376-89
1346802
Neuropathol Appl Neurobiol. 1999 Dec;25(6):481-91
10632898
Curr Protoc Neurosci. 2009 Jul;Chapter 8:Unit 8.24
19575474