title: Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.
abstract: In Parkinson's and Alzheimer's diseases, the allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in allocortex.
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Posimo
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Titler
authors.forename: Hailey J H
authors.initials: HJ
authors.lastname: Choi
authors.forename: Ajay S
authors.initials: AS
authors.lastname: Unnithan
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
mesh_terms: D000818:Animals; D001343:Autophagy; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007976:Leupeptins / Q000633:toxicity; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D013312:Stress, Physiological; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D007976:Leupeptins; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin; D006861:Hydrogen Peroxide; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
references.citation: FASEB J. 2005 Nov;19(13):1851-3
references.pmid: 16150804
references.citation: Free Radic Biol Med. 1998 Oct;25(6):676-81
references.pmid: 9801067
references.citation: J Biol Chem. 2005 Dec 2;280(48):40282-92
references.pmid: 16192271
references.citation: J Neural Transm (Vienna). 2009 Sep;116(9):1111-62
references.pmid: 19707851
references.citation: J Alzheimers Dis. 2011;26(1):59-68
references.pmid: 21593563
references.citation: Lancet. 1986 Sep 13;2(8507):639-40
references.pmid: 2875360
references.citation: FASEB J. 2009 Oct;23(10):3263-72
references.pmid: 19542204
references.citation: J Trace Elem Med Biol. 2000 Oct;14(3):174-8
references.pmid: 11130855
references.citation: J Neurol. 2002 Oct;249 Suppl 3:III/1-5
references.pmid: 12528692
references.citation: Neurology. 2005 Apr 26;64(8):1404-10
references.pmid: 15851731
references.citation: Free Radic Biol Med. 1999 Sep;27(5-6):544-53
references.pmid: 10490274
references.citation: J Neurol Sci. 2011 Nov 15;310(1-2):70-4
references.pmid: 21864849
references.citation: Biometals. 2008 Jun;21(3):367-72
references.pmid: 18060472
references.citation: J Gerontol. 1956 Jul;11(3):298-300
references.pmid: 13332224
references.citation: Neurosci Lett. 1993 Nov 12;162(1-2):179-82
references.pmid: 8121624
references.citation: Mech Ageing Dev. 2009 Nov-Dec;130(11-12):777-83
references.pmid: 19896962
references.citation: Acta Neuropathol. 2009 Jul;118(1):5-36
references.pmid: 19381658
references.citation: J Biol Chem. 2010 Apr 2;285(14):10850-61
references.pmid: 20123989
references.citation: Brain Res. 2006 Sep 13;1109(1):201-6
references.pmid: 16872586
references.citation: Biochem Pharmacol. 2003 Oct 15;66(8):1499-503
references.pmid: 14555227
references.citation: Biochem J. 2003 Oct 1;375(Pt 1):75-86
references.pmid: 12841850
references.citation: J Neurochem. 2011 May;117(3):375-87
references.pmid: 21219333
references.citation: J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):1033-7
references.pmid: 21335570
references.citation: Mol Neurobiol. 2000 Feb-Apr;21(1-2):83-95
references.pmid: 11327151
references.citation: Curr Pharm Biotechnol. 2010 Feb;11(2):188-97
references.pmid: 20166962
references.citation: J Cell Physiol. 2005 Aug;204(2):623-31
references.pmid: 15744747
references.citation: Free Radic Res. 2001 Aug;35(2):111-8
references.pmid: 11697191
references.citation: Rheumatol Int. 2002 Mar;21(5):200-4
references.pmid: 11958437
references.citation: Ann Neurol. 1997 Jan;41(1):17-24
references.pmid: 9005861
references.citation: Mov Disord. 1998;13 Suppl 1:24-34
references.pmid: 9613715
references.citation: J Neurol Sci. 2010 Dec 15;299(1-2):51-4
references.pmid: 20851426
references.citation: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):163-72
references.pmid: 16487050
references.citation: Mov Disord. 2010 Nov 15;25(15):2508-15
references.pmid: 20818670
references.citation: Acta Neuropathol. 1998 Jun;95(6):576-82
references.pmid: 9650749
references.citation: Biochim Biophys Acta. 2012 May;1822(5):625-30
references.pmid: 22015471
references.citation: CNS Neurol Disord Drug Targets. 2010 Dec;9(6):701-19
references.pmid: 20942791
references.citation: Brain. 2011 Jan;134(Pt 1):50-8
references.pmid: 21109502
references.citation: J Neurol. 2008 Dec;255(12):1957-62
references.pmid: 19159062
references.citation: Cell Biochem Funct. 2008 Apr;26(3):392-8
references.pmid: 18236383
references.citation: Free Radic Biol Med. 1998 Jul 15;25(2):169-74
references.pmid: 9667492
references.citation: Prog Neurobiol. 2000 Dec;62(6):649-71
references.pmid: 10880854
references.citation: Mov Disord. 2011 Jan;26(1):6-17
references.pmid: 21322014
references.citation: Neurology. 2001 Oct 23;57(8):1515-7
references.pmid: 11673605
references.citation: Antioxid Redox Signal. 2011 Oct 1;15(7):1835-46
references.pmid: 21091076
references.citation: PLoS One. 2011;6(9):e25077
references.pmid: 21949858
references.citation: Acta Neuropathol. 2009 Nov;118(5):587-98
references.pmid: 19820956
references.citation: Glia. 2010 Nov 1;58(14):1766-74
references.pmid: 20645412
references.citation: Brain. 2002 Aug;125(Pt 8):1772-81
references.pmid: 12135968
references.citation: Methods Enzymol. 2009;452:297-324
references.pmid: 19200890
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10966-71
references.pmid: 11526211
references.citation: Exp Clin Endocrinol Diabetes. 2010 Jan;118(1):64-7
references.pmid: 19834873
references.citation: J Alzheimers Dis. 2009;17(1):143-9
references.pmid: 19494439
references.citation: Cell Stress Chaperones. 2012 Jan;17(1):1-9
references.pmid: 21874533
references.citation: J Biol Chem. 2005 Jul 8;280(27):25305-12
references.pmid: 15883162
references.citation: Neuron. 2007 May 3;54(3):357-69
references.pmid: 17481390
references.citation: J Diabetes Complications. 2004 Jul-Aug;18(4):193-7
references.pmid: 15207835
references.citation: Curr Alzheimer Res. 2006 Jul;3(3):221-7
references.pmid: 16842099
references.citation: Mech Ageing Dev. 2000 Jan 24;113(1):61-70
references.pmid: 10708250
references.citation: Cereb Cortex. 1997 Jan-Feb;7(1):86-95
references.pmid: 9023436
references.citation: Lancet Neurol. 2010 Nov;9(11):1128-38
references.pmid: 20846907
references.citation: Neurochem Res. 2011 Nov;36(11):2127-35
references.pmid: 21706374
references.citation: J Neurochem. 2000 Jul;75(1):436-9
references.pmid: 10854289
references.citation: Neurology. 2000 May 23;54(10):1916-21
references.pmid: 10822429
references.citation: Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84
references.pmid: 7566337
references.citation: Neurology. 2008 Sep 2;71(10):743-9
references.pmid: 18765650
references.citation: PLoS One. 2010 Aug 23;5(8):e12333
references.pmid: 20808797
references.citation: Mov Disord. 2010;25 Suppl 1:S78-82
references.pmid: 20187227
references.citation: Neurosci Lett. 1985 Sep 30;60(2):109-14
references.pmid: 3877260
references.citation: Clin Chim Acta. 2003 Jul 1;333(1):19-39
references.pmid: 12809732
references.citation: J Alzheimers Dis. 2008 Sep;15(1):117-28
references.pmid: 18780972
references.citation: Cardiovasc Res. 2009 Jul 15;83(2):354-61
references.pmid: 19351736
references.citation: Cell. 2004 Jan 23;116(2):181-90
references.pmid: 14744430
references.citation: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references.pmid: 12498954
references.citation: Arch Neurol. 2009 Feb;66(2):167-72
references.pmid: 19204152
references.citation: J Neurosci Res. 2000 Oct 15;62(2):302-10
references.pmid: 11020223
references.citation: Neurochem Res. 2008 Sep;33(9):1717-23
references.pmid: 18307039
references.citation: J Neurol Sci. 2011 Nov 15;310(1-2):107-11
references.pmid: 21570091
references.citation: Neurosci Lett. 2001 Jan 19;297(3):191-4
references.pmid: 11137760
references.citation: J Biol Chem. 2003 Sep 5;278(36):33714-23
references.pmid: 12821677
references.citation: Brain Res. 1996 Nov 4;738(2):265-74
references.pmid: 8955522
references.citation: J Neurosci Methods. 2010 Aug 30;191(2):234-8
references.pmid: 20600314
references.citation: J Neural Transm (Vienna). 2003 May;110(5):517-36
references.pmid: 12721813
references.citation: Am J Alzheimers Dis Other Demen. 2010 Sep;25(6):490-7
references.pmid: 20631161
references.citation: Crit Rev Toxicol. 2008;38(7):623-7
references.pmid: 18709570
references.citation: Brain Res. 1989 Jun 19;490(1):110-25
references.pmid: 2569350
references.citation: Exp Gerontol. 2000 Sep;35(6-7):821-30
references.pmid: 11053673
references.citation: J Cell Mol Med. 2009 Apr;13(4):619-30
references.pmid: 19449461
references.citation: Biochim Biophys Acta. 2008 Dec;1782(12):691-9
references.pmid: 18930136
references.citation: Cell Death Differ. 2011 Apr;18(4):571-80
references.pmid: 21311563
references.citation: Int J Clin Exp Pathol. 2009 Aug 25;3(1):1-23
references.pmid: 19918325
references.citation: J Neurochem. 1997 Sep;69(3):1326-9
references.pmid: 9282961
references.citation: J Neuropathol Exp Neurol. 2005 Sep;64(9):816-30
references.pmid: 16141792
references.citation: Neurosci Lett. 2002 Jul 5;326(3):155-8
references.pmid: 12095645
references.citation: Physiol Rev. 2002 Apr;82(2):373-428
references.pmid: 11917093
references.citation: Neurosci Lett. 2008 Nov 28;446(1):56-8
references.pmid: 18804145
references.citation: Neurochem Int. 2012 Aug;61(3):356-68
references.pmid: 22691629
references.citation: J Am Soc Nephrol. 2006 Jul;17(7):1807-19
references.pmid: 16738015
references.citation: Acta Neuropathol. 2003 Jul;106(1):83-8
references.pmid: 12687392
references.citation: J Neurochem. 1998 Jan;70(1):268-75
references.pmid: 9422371
references.citation: Ann Neurol. 1994 Sep;36(3):348-55
references.pmid: 8080242
references.citation: Autophagy. 2007 May-Jun;3(3):181-206
references.pmid: 17224625
references.citation: Eur J Neurol. 2009 Oct;16(10):1130-7
references.pmid: 19572946
references.citation: Histopathology. 1981 Sep;5(5):549-64
references.pmid: 7286917
references.citation: Ann N Y Acad Sci. 2000 Jun;911:221-39
references.pmid: 10911877
references.citation: Brain Res. 2000 Mar 17;859(1):173-5
references.pmid: 10720628
references.citation: Am J Pathol. 2007 Aug;171(2):513-24
references.pmid: 17620365
references.citation: Autophagy. 2007 Nov-Dec;3(6):542-5
references.pmid: 17611390
references.citation: Ann Neurol. 2003 Sep;54(3):343-51
references.pmid: 12953266
references.citation: Ann Neurol. 1992 Dec;32(6):804-12
references.pmid: 1471873
references.citation: J Alzheimers Dis. 2006;9(3 Suppl):35-44
references.pmid: 16914843
references.citation: Cancer Res. 2006 Apr 1;66(7):3754-63
references.pmid: 16585202
references.citation: Annu Rev Biochem. 1999;68:1015-68
references.pmid: 10872471
references.citation: Autophagy. 2006 Jul-Sep;2(3):224-5
references.pmid: 16874096
references.citation: J Neurochem. 2009 Jul;110(2):469-85
references.pmid: 19457088
references.citation: Free Radic Biol Med. 2011 Jul 1;51(1):5-16
references.pmid: 21530648
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1986;10(3-5):297-308
references.pmid: 3492011
references.citation: Int J Oncol. 2002 Oct;21(4):857-65
references.pmid: 12239627
references.citation: J Neurochem. 2003 Mar;84(5):1173-83
references.pmid: 12603840
references.citation: Cell Mol Biol (Noisy-le-grand). 2007 Apr 15;53(1):48-55
references.pmid: 17519111
references.citation: Prion. 2008 Jan-Mar;2(1):23-7
references.pmid: 19164917
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13547-51
references.pmid: 8942970
references.citation: J Neurol Sci. 2006 Oct 25;248(1-2):167-72
references.pmid: 16797594
references.citation: Eur Neurol. 1993;33(6):403-8
references.pmid: 8307060
references.citation: J Neurosci. 1996 Jul 15;16(14):4491-500
references.pmid: 8699259
references.citation: J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1467-9
references.pmid: 15377698
references.citation: Exp Neurol. 2003 Jan;179(1):38-46
references.pmid: 12504866
references.citation: Ageing Res Rev. 2002 Apr;1(2):279-93
references.pmid: 12039443
references.citation: Biochem J. 2010 Dec 15;432(3):585-94
references.pmid: 20919990
references.citation: Neurology. 1992 Mar;42(3 Pt 1):631-9
references.pmid: 1549228
references.citation: Neural Plast. 2010;2010:108190
references.pmid: 21331296
references.citation: Hum Exp Toxicol. 2010 Apr;29(4):249-61
references.pmid: 20332169
references.citation: Nature. 1999 Dec 9;402(6762):672-6
references.pmid: 10604474
references.citation: Cent Nerv Syst Agents Med Chem. 2010 Dec 1;10(4):310-6
references.pmid: 20868356
references.citation: Biomed Pharmacother. 2008 Apr-May;62(4):236-49
references.pmid: 18400456
references.citation: Ann N Y Acad Sci. 2000;924:53-61
references.pmid: 11193802
references.citation: Mov Disord. 2006 Dec;21(12):2217-20
references.pmid: 17013908
references.citation: Nat Rev Drug Discov. 2007 Apr;6(4):304-12
references.pmid: 17396135
references.citation: Sci Aging Knowledge Environ. 2004 Jun 09;2004(23):pe26
references.pmid: 15190177
references.citation: Neurology. 2001 Mar 27;56(6):730-6
references.pmid: 11274306
references.citation: J Neural Transm (Vienna). 2006 Nov;113(11):1763-9
references.pmid: 16736242
references.citation: Front Biosci (Landmark Ed). 2009 Jun 01;14:5188-238
references.pmid: 19482612
references.citation: Neurosci Lett. 1992 Aug 17;142(2):128-30
references.pmid: 1454205
references.citation: Neurochem Res. 2012 Aug;37(8):1601-14
references.pmid: 22461064
references.citation: Neurochem Int. 2000 Mar;36(3):185-91
references.pmid: 10676851
references.citation: Cell. 2009 Jul 10;138(1):25-8
references.pmid: 19596233
references.citation: Dementia. 1996 Nov-Dec;7(6):304-13
references.pmid: 8915036
references.citation: Antioxid Redox Signal. 2006 Nov-Dec;8(11-12):1975-86
references.pmid: 17034343
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: Ann Neurol. 2008 Feb;63(2):204-12
references.pmid: 17894374
references.citation: Autophagy. 2005 Oct-Dec;1(3):141-5
references.pmid: 16874031
references.citation: Trends Neurosci. 2006 Aug;29(8):438-43
references.pmid: 16806508
references.citation: Neuroreport. 1998 May 11;9(7):1507-11
references.pmid: 9631457
references.citation: J Am Geriatr Soc. 1996 Jul;44(7):823-7
references.pmid: 8675932
references.citation: J Neurochem. 2008 Jul;106(2):860-74
references.pmid: 18466318
references.citation: J Neurol Sci. 2006 Oct 25;248(1-2):255-8
references.pmid: 16814807
references.citation: Biopolymers. 2010 Mar;93(3):218-28
references.pmid: 19768775
references.citation: Ageing Res Rev. 2008 Jan;7(1):1-7
references.pmid: 18162444
references.citation: J Neurosci. 2011 Dec 14;31(50):18568-77
references.pmid: 22171055
references.citation: Acta Neuropathol. 2000 Sep;100(3):285-90
references.pmid: 10965798
references.citation: Neurodegener Dis. 2011;8(4):155-68
references.pmid: 21212626
references.citation: Neurology. 2004 Nov 23;63(10):1912-7
references.pmid: 15557511
references.citation: Neurology. 2004 Mar 23;62(6):925-31
references.pmid: 15037694
references.citation: Clin Sci (Lond). 2012 Feb;122(3):93-103
references.pmid: 21992109
references.citation: Toxicol Sci. 2006 May;91(1):192-201
references.pmid: 16500925
references.citation: Neurology. 2002 Jun 25;58(12):1791-800
references.pmid: 12084879