Evidence for the Involvement of Apoptosis-Inducing Factor–Mediated Caspase-Independent Neuronal Death in Alzheimer Disease

Accumulating evidence suggests the involvement of caspase-dependent and -independent mechanisms in neuronal cell death in Alzheimer disease (AD). The apoptosis-inducing factor (AIF) is a mitochondrial oxido-reductase originally characterized as a mediator of caspase-independent programmed cell death (PCD). In this postmortem study, we investigated the distribution of AIF and its possible morphological association with pathological features in the hippocampus, as well as entorhinal and medial gyrus of temporal cortices of late stage AD, dementia with Lewy bodies (DLB), and control subjects. In comparison with controls, a significant increase in neuronal AIF immunoreactivity (AIF-ir) was observed in the hippocampus and the superficial layers of entorhinal and medial gyrus of temporal cortices in AD—but not DLB—samples. AIF-ir in neuronal nuclei was also significantly more widespread in AD compared with control and DLB samples. Furthermore, AIF-ir was found to be colocalized with neurofibrillary tangles (NFTs) in AD brains. Interestingly, a significant positive correlation was seen between nuclear AIF-ir and Braak stage in CA1 of the hippocampus as well as in entorhinal and temporal cortices in AD samples. These data show for the first time: (1) the nuclear localization of AIF in the AD brain and (2) its colocalization with NFTs, suggesting a possible involvement of AIF-mediated caspase-independent PCD, at least in the late stage of this neuropathology. Accumulating evidence suggests the involvement of caspase-dependent and -independent mechanisms in neuronal cell death in Alzheimer disease (AD). The apoptosis-inducing factor (AIF) is a mitochondrial oxido-reductase originally characterized as a mediator of caspase-independent programmed cell death (PCD). In this postmortem study, we investigated the distribution of AIF and its possible morphological association with pathological features in the hippocampus, as well as entorhinal and medial gyrus of temporal cortices of late stage AD, dementia with Lewy bodies (DLB), and control subjects. In comparison with controls, a significant increase in neuronal AIF immunoreactivity (AIF-ir) was observed in the hippocampus and the superficial layers of entorhinal and medial gyrus of temporal cortices in AD—but not DLB—samples. AIF-ir in neuronal nuclei was also significantly more widespread in AD compared with control and DLB samples. Furthermore, AIF-ir was found to be colocalized with neurofibrillary tangles (NFTs) in AD brains. Interestingly, a significant positive correlation was seen between nuclear AIF-ir and Braak stage in CA1 of the hippocampus as well as in entorhinal and temporal cortices in AD samples. These data show for the first time: (1) the nuclear localization of AIF in the AD brain and (2) its colocalization with NFTs, suggesting a possible involvement of AIF-mediated caspase-independent PCD, at least in the late stage of this neuropathology. Programmed cell death (PCD) is thought to contribute significantly to neuronal cell loss in Alzheimer disease (AD).1Marx J Neuroscience. 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Full Text Full Text PDF PubMed Scopus Google Scholar However, the distribution of AIF and its possible morphological association with features and neurofibrillary tangles in the AD brain to be Interestingly, studies have activated caspases and in AD brain in amyloid TT Head E Nesse WH Cotman CW Cribbs DH Activation of caspase-8 in the Alzheimer's disease brain.Neurobiol Dis. 2001; 8: 1006-1016Crossref PubMed Scopus (144) Google Scholar, 10Rohn TT Rissman RA Davis MC Kim YE Cotman CW Head E Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain.Neurobiol Dis. 2002; 11: 341-354Crossref PubMed Scopus (212) Google Scholar The of the was to the and of AIF in the hippocampus, and medial temporal cortices in postmortem of late stage AD neuronal loss also in the hippocampus of dementia with Lewy bodies AJ GM neuron loss in dementia with Lewy 2002; PubMed Scopus Google Scholar we also the with DLB to data between neurodegenerative the C of AIF and from was from was from and protein G from by the brain from of AD, of controls, and of from the at the brains the was into and at The was in and by a for and temporal from also for amyloid and and for Braak by of to H Braak E of PubMed Scopus Google Scholar including postmortem and Braak in The AD by the on the of a to the with a Braak amyloid stage of C and a Braak stage between and A D SM BJ LM JP G L The to a for Alzheimer's of the of Alzheimer's PubMed Google Scholar In with the Braak to the into (1) of dementia and including a of amyloid and NFTs, and (2) with AD and tangles with the for AD The of a Braak amyloid stage of A and a Braak stage of with The DLB by the DLB on of Lewy bodies of with D DW DP J G Bergeron C A Miller S D C RA for the and of dementia with Lewy bodies of the on DLB PubMed Scopus Google Scholar, I J D D H J D H S G C J J J with Lewy 2004; Full Text Full Text PDF PubMed Scopus Google of in the to and Braak and of AD on amyloid to Braak and of AD on the distribution and of neurofibrillary disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease disease DLB DLB DLB DLB DLB DLB DLB DLB AD, Alzheimer with Lewy postmortem and Braak and of AD on amyloid Braak and of AD on the distribution and of neurofibrillary in a C AD, Alzheimer with Lewy postmortem and from the entorhinal and medial gyrus of the temporal brain of the hippocampus and the temporal from the for the and the C of AIF was characterized in brain by of brain to and to with the at by with and with the AIF and at in the as in and brain with a S Mechawar N Susin SA Quirion R S of and apoptosis-inducing factor (AIF) in and Alzheimer's 2007; Full Text Full Text PDF PubMed Scopus Google Scholar was on as N A of on in the brains of with Alzheimer's disease and a possible association with neuritic 2005; PubMed Scopus Google Scholar and in and with to in for in and with the to at a in with for at was and to the (AIF-ir) in to amyloid and NFTs, by AIF and AIF and first with at and the was with as with at the immunoreactivity was with the second the with its peptide in a of the a to a of AIF by in a and on the J JC F J R D C J N D C P J A of a role for in Alzheimer's disease.Am J Pathol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, M P N JH C G P J P and factor the of in by J Pathol. Full Text Full Text PDF PubMed Scopus Google A of was to in AIF was and to with and AIF and was to as to to to to and to of the neuronal a for the with a from to the of neuronal nuclei in brain was as a of the of from in brain The for the in this from to and was in the observed in AIF distribution not to the in we the effects of on the distribution of AIF in AD, and control brains. significant correlation between the and AIF-ir at the and AIF distribution at observed in brain with the nuclear to the The of the nuclear was with a a nuclear protein by from AD and control brains was on to and to with and with at with for at and with the was by with the of the with of as was as A of and in the brain of 2007; PubMed Scopus Google Scholar from the temporal and hippocampus of AD and control brains and protein was for The with and with protein G at was as and in on to and to with the The immunoreactivity was by was with the The was to the of AIF immunoreactivity and of was to the in of AIF-ir neuronal nuclei AD, and The correlation between nuclear AIF immunoreactivity and Braak stage was with the correlation and significant P in AD, and control brains in of the hippocampus and gyrus entorhinal and medial gyrus of the temporal with In the hippocampus, in the of and and AIF-ir was in layers of the entorhinal and temporal the layers AIF-ir superficial M and the AIF immunoreactivity was observed in immunoreactivity (AIF-ir) in the entorhinal and temporal cortices of AD, control with AD and control brains. AIF was in the of AIF in control DLB as well as the nuclear of AIF in AD brains. show of by the of AIF in entorhinal and temporal cortices in AD DLB control with AD as well as control brains as compared with control A significant increase in neuronal AIF-ir was observed in the DG as well as in the superficial layers of entorhinal and temporal cortices in AD compared with M and significant in neuronal AIF-ir was observed between DLB and and M and The nuclear of AIF apoptotic neuronal death in a caspase-independent SA Lorenzo HK Zamzami N Marzo I Snow BE Brothers GM Mangion J Jacotot E Costantini P Loeffler M Larochette N Goodlett DR Aebersold R Siderovski DP Penninger JM Kroemer G Molecular characterization of mitochondrial apoptosis-inducing 1999; PubMed Scopus Google Scholar, E Susin SA Zamzami N Ferri KF T Larochette N MC D Penninger J Kroemer G of AIF in and 2000; PubMed Scopus Google Scholar the of a nuclear localization of AIF In AD, and control the of a nuclear of AIF nuclear nuclei in the layers increase in nuclear of AIF was in the layers of the hippocampus and and entorhinal and temporal cortices in AD compared with J and in AIF nuclear was between DLB and control in of the brain J and These by of AIF protein in nuclear from the brain and temporal of AD and control brains for AIF and in nuclear protein at and The of AIF in the nuclear of the hippocampus and temporal significantly in AD control brains A and AIF protein in the nuclear is in AD hippocampus and temporal compared with control of AIF protein in the nuclear from AD and control brains. nuclear by on to and with AIF of the AIF protein in the hippocampus and temporal of AD and control subjects. was in a of AD and control and as a of control samples. as compared with has been AD the of resulting in a of JC AL of and Alzheimer's Mol 2001; PubMed Scopus Google Scholar, DC LM and in evidence for Alzheimer disease in PubMed Scopus Google Scholar the in the distribution of AIF-ir in the control brains with of AD for AD These as of the stage of AD significant in the distribution of neuronal AIF-ir nuclear AIF-ir was in the hippocampus, entorhinal as well as temporal cortices of control brains with AD compared with the control brains AD M and and J and the in the nuclear localization of AIF with to disease nuclear AIF-ir in AD was in to Braak H Braak E of PubMed Scopus Google Scholar a significantly positive correlation between nuclear AIF-ir and Braak stage in the as well as entorhinal and temporal not in and DG of the hippocampus In the of the we observed a of AIF-ir in AD of to the between AIF and by the with the AIF was in with features in AD brains In the colocalization was in the and medial gyrus of temporal a of with with AIF and In the and a of the between AIF immunoreactivity and amyloid with and amyloid was In was colocalization of AIF-ir and neuritic observed the observed colocalization of AIF and NFTs, we to AIF with the of a by with association between AIF and in from hippocampus and temporal cortices in AD brains with AIF by with the association between AIF and in AD brains In association between AIF and was not in the brain of control subjects. The was to and the and of AIF in AD, and DLB as well as the possible association of this protein with AD features and The (1) neuronal AIF-ir was observed in of the hippocampus and entorhinal of AD not DLB (2) AIF nuclear in was significantly more widespread in AD in control and DLB and AIF-ir was colocalized with NFTs, not with amyloid in AD brains. this the first of nuclear of AIF and its colocalization with in the AD The increase in neuronal AIF-ir in the hippocampus and entorhinal in AD brains a as and MP and from Alzheimer's 2004; PubMed Scopus Google Scholar, G LM N in PubMed Scopus Google Scholar, of and of in the brain in and Alzheimer's Full Text Full Text PDF PubMed Scopus Google Scholar AIF as a as has been shown from with AIF more to cell death, be by the of AIF in MP The apoptosis-inducing 2002; PubMed Scopus Google Scholar, SA E of AIF in cell death and 2002; Full Text Full Text PDF PubMed Scopus Google Scholar the of AIF observed to in the AD P A CW DP of neuronal in Alzheimer's disease.Am J Pathol. Google Scholar The into the cell has been to role in the of X G Smith Alzheimer's the 2004; Full Text Full Text PDF PubMed Scopus Google Scholar The of the cell in has been with the and of neuronal cell A F E Slack R Park DS Involvement of cell and in neuronal death.J Biol Chem. 1999; PubMed Scopus Google Scholar, DS A A Cell in neuronal death by excitotoxic for neurodegeneration and its 2000; Full Text Full Text PDF PubMed Scopus Google Scholar Interestingly, this cell is to X G Smith Alzheimer the 2007; PubMed Scopus Google Scholar increase in AIF-ir a cell in AIF has important role in SA Lorenzo HK Zamzami N Marzo I Snow BE Brothers GM Mangion J Jacotot E Costantini P Loeffler M Larochette N Goodlett DR Aebersold R Siderovski DP Penninger JM Kroemer G Molecular characterization of mitochondrial apoptosis-inducing 1999; PubMed Scopus Google Scholar, N C P N Larochette N N N S S F M Penninger JM H P Kroemer G AIF 2004; PubMed Scopus Google Scholar its to the leads to cell death in a caspase-independent SA Lorenzo HK Zamzami N Marzo I Snow BE Brothers GM Mangion J Jacotot E Costantini P Loeffler M Larochette N Goodlett DR Aebersold R Siderovski DP Penninger JM Kroemer G Molecular characterization of mitochondrial apoptosis-inducing 1999; PubMed Scopus Google Scholar, E Susin SA Zamzami N Ferri KF T Larochette N MC D Penninger J Kroemer G of AIF in and 2000; PubMed Scopus Google Scholar In the study, we increase in the of the nuclear AIF in hippocampus and temporal and more widespread nuclear localization of AIF in the AD hippocampus and The of in nuclear AIF-ir by was not as important as by is to the in the nuclear by of nuclear not nuclear of AIF also with AIF as by Interestingly, the nuclear localization of AIF was observed in layers of the hippocampus and temporal In studies have the neuronal in in AD, with the in and the T DW JC JH loss of entorhinal in Alzheimer's Google Scholar, JH and cell Full Text PDF PubMed Scopus Google Scholar, DG JC in the of neuronal loss in and Alzheimer's PubMed Scopus Google Scholar AIF-mediated caspase-independent apoptotic also be involved in the cell death of and neuronal be with data mitochondrial and nuclear of AIF in activation cell death in neuronal and of and apoptosis-inducing 2004; PubMed Scopus Google Scholar However, a association between AIF-ir and between AIF and amyloid the of J The amyloid of Alzheimer's and on the to 2002; PubMed Scopus Google Scholar in be more for nuclear of AIF in AD has been to the of resulting in a A C The of brain and Alzheimer PubMed Scopus Google Scholar a of show significant of plaques, NFTs, and in by JC AL of and Alzheimer's Mol 2001; PubMed Scopus Google Scholar significant neuronal loss is observed in the brains of compared with AD the pathological in the be as the of cell distribution in the AD brain and found significant between AD compared with control brains. These in AIF distribution in the the stage of for this was the observed correlation between the nuclear localization of AIF in AD brains and Braak stage the of The of with the of AD precursor and for the and of Alzheimer's PubMed Scopus Google Scholar, A RJ Zhu X G Smith Involvement of in Alzheimer PubMed Scopus Google Scholar The of AIF for be a as a in control with AD the for AD MP The apoptosis-inducing 2002; PubMed Scopus Google Scholar by and the of neuronal loss and neurodegeneration the of the AIF of its MP The apoptosis-inducing 2002; PubMed Scopus Google Scholar AIF be involved in the control of neuronal from to of AD involvement more at of the this AD into the involved in AD The points to a colocalization of AIF-ir and in AD brains. of tau in the entorhinal and CA1 of the H Braak E of PubMed Scopus Google Scholar, I M MS protein A of Alzheimer Biol Chem. Full Text PDF PubMed Google Scholar, M A RA characterization of the of the of Alzheimer disease.Proc Natl Acad Sci U S A. PubMed Scopus Google Scholar tau leads to the of NFTs, the AC I Alzheimer's disease tau tau into tangles of and Med. 2: PubMed Scopus Google Scholar, M R tau at in Alzheimer's disease and to Full Text PDF PubMed Scopus Google Scholar tau has for to the of and to the neuronal observed in M R tau at in Alzheimer's disease and to Full Text PDF PubMed Scopus Google Scholar, J N G E of of tau to between immunoreactivity and 11: Full Text PDF PubMed Scopus Google Scholar studies have shown tau is a cleavage for activated and apoptotic CW Song YH Kim IK Yoon WJ Ryu BR Jo DG Woo HN Kwon YK Kim HH Gwag BJ Mook-Jung IH Jung YK Proapoptotic effects of tau cleavage product generated by caspase-3.Neurobiol Dis. 2001; 8: 162-172Crossref PubMed Scopus (188) Google Scholar, 5Gamblin TC Chen F Zambrano A Abraha A Lagalwar S Guillozet AL Lu M Fu Y Garcia-Sierra F LaPointe N Miller R Berry RW Binder LI Cryns VL Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.Proc Natl Acad Sci U S A. 2003; 100: 10032-10037Crossref PubMed Scopus (681) Google Scholar, 7Guo H Albrecht S Bourdeau M Petzke T Bergeron C LeBlanc AC Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease.Am J Pathol. 2004; 165: 523-531Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 10Rohn TT Rissman RA Davis MC Kim YE Cotman CW Head E Caspase-9 activation and caspase cleavage of tau in the Alzheimer's disease brain.Neurobiol Dis. 2002; 11: 341-354Crossref PubMed Scopus (212) Google Scholar, TT Head E JH AJ Cotman CW Cribbs DH between caspase activation and neurofibrillary in Alzheimer's disease.Am J Pathol. 2001; 158: Full Text Full Text PDF PubMed Scopus Google Scholar The caspase cleavage of tau a proteolytic product more and into pathological tau TC Chen F Zambrano A Abraha A Lagalwar S Guillozet AL Lu M Fu Y Garcia-Sierra F LaPointe N Miller R Berry RW Binder LI Cryns VL Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.Proc Natl Acad Sci U S A. 2003; 100: 10032-10037Crossref PubMed Scopus (681) Google Scholar, JH beta caspase-cleaved tau in Biol Chem. 2004; PubMed Scopus Google Scholar The data the main mediator of caspase-independent apoptotic AIF is with the be to the role of AIF in tau of and AD pathological of S A MP R R MP Y of Alzheimer's disease with and and 2003; Full Text Full Text PDF PubMed Scopus Google Scholar The AIF-ir in the AD hippocampus and entorhinal at with the of AIF in and temporal cortices of AD is in S Mechawar N Susin SA Quirion R S of and apoptosis-inducing factor (AIF) in and Alzheimer's 2007; Full Text Full Text PDF PubMed Scopus Google Scholar is to the in in and the of and in AIF is brain cell of AIF and have in In neuronal AIF is in the AD hippocampus and entorhinal we AIF is to the nuclear localization of AIF in the AD brain suggests a possible role for AIF in caspase-independent and neuronal at of this neurodegenerative for is by the and also the of in and for and the with with with

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