Journal of Neuropathology & Experimental Neurology:
Caspase-6 Activation in Familial Alzheimer Disease Brains Carrying Amyloid Precursor Protein or Presenilin I or Presenilin II Mutations
Albrecht, Steffen MD; Bogdanovic, Nenad MD, PhD; Ghetti, Bernardino MD; Winblad, Bengt MD, PhD; LeBlanc, Andréa C. PhD
From the Department of Pathology, McGill University (SA); and Department of Pathology, Montréal Children's Hospital, Montréal, Quebec, Canada (SA); Karolinska Institutet Alzheimer Disease Research Center, Stockholm, Sweden (NB, BW); Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana (BG); The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital (ACL); and Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada (ACL).
Send correspondence and reprint requests to: Andréa C. LeBlanc, PhD, The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B Davis Jewish, General Hospital,3755 Ch. Côte Ste-Catherine, Montréal, Québec, Canada H3T 1E2; E-mail: firstname.lastname@example.org
This work was supported by CIHR MOP81146 and FRSQ to Andréa LeBlanc, Swedish Research Council to Nenad Bogdanovic and Bengt Winblad, and NIA P30 AG10133 to Bernardino Ghetti.
We previously demonstrated the activation of caspase-6 (Casp-6) in the hippocampus and cortex in cases of mild, moderate, severe, and very severe Alzheimer disease (AD). To determine whether Casp-6 is also activated in familial AD, we performed an immunohistochemical analysis of active Casp-6 and Tau cleaved by Casp-6 in temporal cortex and hippocampal tissue sections from cases of familial AD. The cases included 5 carrying the amyloid precursor protein K670N and M671L Swedish mutation, 1 carrying the amyloid precursor protein E693G Arctic mutation, 2 each carrying the Presenilin I M146V, F105L, A431E, V261F, and Y115C mutations, and 1 with the Presenilin II N141I mutation. Active Casp-6 immunoreactivity was found in all cases. Caspase-6 immunoreactivity was observed in neuritic plaques or in some cases cotton-wool plaques, and in neuropil threads and neurofibrillary tangles. These results indicate that Casp-6 is activated in familial forms of AD, as previously observed in sporadic forms. Because sporadic and familial AD cases have similar pathological features, these results support a fundamental role of Casp-6 in the pathophysiology of both familial and sporadic AD.
Caspases (Casps), a group of cysteinyl endoproteases that cleave proteins after aspartic acid residues, are activated in inflammatory and apoptotic conditions (1). Caspase-dependent increased β-amyloid peptide production occurs in various cell types (2-4). For example, in primary cultures of human neurons, the Casp responsible for increasing β-amyloid peptide is Casp-6 (3). We previously demonstrated that neoepitope antiserum to active Casp-6 and to Tau protein cleaved by Casp-6 (TauΔCasp-6) highlights the presence of activated Casp-6 in neuropil threads (NPTs), neurofibrillary tangles (NFTs), and neuritic plaques (NPs) in the hippocampus and temporal cortex in sporadic Alzheimer disease (AD) (5). Activation of Casp-6 is observed in cases of mild cognitive impairment as well as in mild, moderate, severe, and very severe AD (6). Furthermore, abundant active Casp-6 and TauΔCasp-6 were detected in the entorhinal cortex of a few noncognitively impaired aged individuals who had the lowest global cognitive scores of the group studied (6). These findings suggest that Casp-6 activation is an early event in AD and that it may precede the development of frank lesions.
Because Casp-6 is part of the group of effector Casps, it may cause apoptotic cell death when it is activated. Unlike the rapid induction of apoptosis by the effectors Casp-3 or Casp-7 (3, 7), Casp-6 activation is associated with a protracted type of cell death in serum-deprived human primary neurons. Moreover, Casp-6 activation in human embryonic kidney cells does not result in apoptotic cell death (8). In sporadic AD, Casp-6 activation is present in neurons that lack the typical morphology of apoptotic neurons. In ischemic human fetal and adult brains, Casp-6 activation is both neuritic and nuclear, and immunopositive neurons have the condensed chromatin appearance of apoptotic cells (5). Nuclear Casp-6 is required for apoptotic cell death (9), whereas active Casp-6 in sporadic AD is only present in nonnuclear compartments (i.e. cell body and neurites) (5). Taken together, these data suggest that activation of Casp-6 is more likely associated with neurodegeneration than with apoptotic cell death in sporadic AD. Furthermore, a proteomic study of primary human neuronal proteins identified several cytoskeletal and cytoskeleton-associated proteins as potential substrates of Casp-6 (10). One of these, α-tubulin is cleaved by Casp-6 and is present in neurons in sporadic AD. Recently, Casp-6 has also been shown to regulate axonal pruning of sensory and retinocollicular axons and axonal degeneration in sensory and motor mouse neurons (11). Thus, because it can cleave important synaptic and cytoskeleton proteins (10), generate high levels of β-amyloid peptide (3, 12), and is activated very early in cognitive impairment and AD (5, 6), Casp-6 activation may play a key role in the development of AD. Because sporadic AD and familial AD share similar pathological features, Casp-6 activity would also likely be involved in the pathogenesis of familial AD. Here, we investigated familial AD brains for immunohistochemical evidence of active Casp-6.
MATERIALS AND METHODS
Familial AD cases (8-02, 4-93, 25-98, 46-02, 69-01, 77-95, 140-96, and 397-94) were obtained from Huddinge Brain Bank at the Karolinska Institute, Stockholm, Sweden. The postmortem interval ranged from 12 to 30 hours. After dissection, brain tissue was placed in buffered 4% formaldehyde for 1 month. The solicitation and storage of the brains were approved by the local ethical committee at Karolinska Institute; all patients (or their nearest relatives) had given informed consent to participate in donation according to the Huddinge Brain Bank routine procedures and provisions of the Helsinki declaration. Familial AD cases 2003-002, 2006-093, 2001-090, 2008-073, 2002-066, 2000-007, 2002-086, 2003-041, 2007-093 were obtained with informed consent from the patients or their nearest relative by the Indiana Alzheimer Disease Center (Indiana University Medical Center, Indianapolis, IN). The postmortem interval for these cases ranged from 2.5 to 8 hours in all cases except 2001-090 (27 hours) and 2002-086 (26 hours). The brains were fixed in formalin and paraffin embedded. Ages at onset and death are provided in Table 1. Sporadic AD (woman, 76 years old) and non-AD (woman, 85 years old) cases, used as positive and negative controls, respectively, were obtained from Dr Catherine Bergeron (University of Toronto, Toronto, Canada) and processed as previously described (5, 6).
The temporal cortex, hippocampus, and entorhinal cortex were immunostained; in some cases, only one of these areas was available. Paraffin-embedded tissues were cut at 4-μm thickness and processed for immunoreactivity with anti-active Casp-6 and Tau cleaved by Casp-6 (TauΔCasp-6) antisera on a Ventana Automated immunostainer (Ventana Medical Systems, Tucson, AZ), as previously described (5, 6). The anti-active Casp-6 antiserum 1277 was used at a dilution of 1:1000 and the anti-TauΔCasp-6 antiserum 10635 was used at a 1:12,000 dilution. Detection of immunostaining was done with diaminobenzidine using the iview-DAB kit (Ventana Medical Systems). The paired helical filament 1 (PHF-1) antibody was a kind gift from Dr Peter Davis (Department of Pathology, Albert Einstein College of Medicine, Bronx, NY) and was used at a dilution of 1:100. For double staining, anti-active Casp-6 was first applied and detected with diaminobenzidine using the iview-DAB kit and PHF-1 followed and was detected with Fast Red A and B using the Enhanced V-Red kit (Ventana Medical Systems).
Semiquantitative Scoring of Immunostaining
Neurofibrillary tangles, NPTs, and NPs were identified using conventional neuropathologic diagnostic criteria, and tau immunostaining by S.A. Flame-shaped filamentous tau-positive neuronal inclusions were considered to represent NFTs. Diffuse finely granular or homogeneous perikaryal tau positivity was considered pretangle, and tau-positive thin linear profiles in the neuropil were considered NPTs. The NPs were identified as an amyloid core surrounded by a halo of radially arranged, thickened, and beaded Tau-positive neurites. So-called cotton-wool plaques in presenilin (PSEN) mutant brains were included in the assessment. We considered structures to be Tau positive when they were stained with either the anti-TauΔCasp-6 antiserum or the PHF-1 antibody; there were no identifiable differences in the structures observed with either. Semiquantitative scoring was done based on the Consortium to Establish a Registry for Alzheimer's Disease protocol (13) by neuropathologist Steffen Albrecht in a blinded manner. The densities of NFTs, NPs, and NPTs stained with anti-active Casp-6, TauΔCasp-6, or PHF-1 were scored as absent, 0; low/mild, 1; moderate, 2; high/severe, 3; or extremely high, 4.
Collection of Photomicrographs
The superior/medial temporal gyrus (STG) and the CA2/CA3 area of the hippocampus were chosen as representative areas to assess the intensity and density of the staining. Micrographs were taken with a Nikon CoolPix 4500 digital camera on an Olympus BX41 microscope with 2× and 40× objectives. The same area was photographed in each of the different immunostains. Micrographs were imported and assembled into Canvas 9.0 (ACD Systems of America Inc, Miami, FL) and scaled down to 35% to show the entire image. Micrographs showing anti-active Casp-6 and PHF-1 were taken with the 40× or 60× objective, imported, and scaled down by 50%. Otherwise, no other manipulation was done to the micrographs.
Sections from the hippocampus/entorhinal cortex and the STG were immunostained with either the anti-active Casp-6 antiserum or TauΔCasp-6 antiserum or were double stained with anti-active Casp-6 antiserum and anti-PHF-1 antibody (Fig. 1). Low-magnification micrographs of a representative case showed a similar distribution of immunopositivity with the 2 antisera and the combination. Anti-active Casp-6 staining was less intense than that of the TauΔCasp-6 or PHF-1 stains, consistent with a lower abundance of enzymes relative to cytoskeleton proteins in the cells. Figure 1 also indicates specificity of the immunostains because some areas are unstained.
The sporadic AD positive control shows positive active Casp-6 in NFTs, NPs, and NPTs (Fig. 2A); the noncognitively impaired negative control confirmed the specificity of the anti-active Casp-6 immunoreactivity (Fig. 2B). Immunoreactivity was observed in all familial AD cases but differed among them (Figs. 2C-J; Table 2). Immunoreactivity was easily detected in most PSEN I mutants and the PSEN II mutant but was less intense and frequent in the amyloid precursor protein (APP) mutants, especially in the hippocampus.
All cases showed some anti-active Casp-6-positive structures with the shape of NFTs (Figs. 2C-J). In most cases, equivalent amounts were present in the hippocampus and entorhinal cortex, and these were similar or greater than the amount present in the STG (Table 2). Cases with the same mutation mostly showed similar staining. One PSEN I F105L (2001-090) mutant had relatively less staining for active Casp-6 than the other case. This individual lived 30 years with the disease compared with 9 years in the F105L mutant with more active Casp-6 staining. Similarly, the PSEN I A431 mutant with a disease duration of 1 year (2006-093) showed strong immunopositive NFT staining, whereas the other patient who lived relatively longer (8 years) had only moderate NFT immunoreactivity in the STG and entorhinal cortex.
Immunopositivity for active Casp-6 was also present in NPs. This was not observed in the APP mutants or in the PSEN I V261F (2000-007) case hippocampus but was scored as moderate and severe in the other areas in the other PSEN I mutants and in the PSEN II mutant. In the STG of the PSEN I V261F mutant (Fig. 2H), these had the appearance of cotton-wool plaques (14-16). In the PSEN I F105L, PSEN I Y115C, and the PSEN II N141I mutants, there were more Casp-6-immunopositive NPs than NFTs in the STG and the entorhinal cortex, and often more NFTs than NPs in the hippocampus. Low levels of anti-active Casp-6 immunoreactivity was also observed in NPTs of 2 of the APP Swedish cases, in most PSEN I mutants, and in the PSEN II mutant.
Although there was more immunoreactive active Casp-6 in the PSEN mutants than in the APP mutants, this difference could simply be the result of an artifact of epitope conservation. Furthermore, because the anti-active Casp-6 detects only the large subunit of the active form of Casp-6, it is possible that the active form of Casp-6 would be inhibited. Therefore, to confirm Casp-6 activity in these brains, we used another antiserum directed against a protein cleaved by Casp-6, that is, TauΔCasp-6.
As previously observed in sporadic AD, immunoreactivity with the TauΔCasp-6 antiserum was much stronger than with the anti-active Casp-6 antiserum (Fig. 3). This was expected because a cytoskeleton protein such as Tau is more abundant and stable than the Casp-6 enzyme. Almost all cases showed "frequent" NPs, NFTs, and NPTs labeled with the anti-TauΔCasp-6 antiserum (Fig. 3; Table 3). Because TauΔCasp-6 must be generated from active Casp-6, these results indicate that the lower abundance of active Casp-6 immunoreactivity in the APP mutants was likely caused by loss of the active Casp-6 epitope. Nevertheless, all APP and PSEN mutants were scored 2 or 3 for NFTs, and in all 3 areas, the APP Arctic case showed sparse TauΔCasp-6 immunoreactivity in the STG but retained moderate to severe immunopositive reactivity in the hippocampus and entorhinal cortex. Furthermore, the PSEN I F105L (2001-090) mutant had low levels of immunoreactive NPs and NPTs in the hippocampus; the PSEN I V261F (2000-007) mutant had negligible TauΔCasp-6-immunopositive NPs in the hippocampus, and the PSEN I A431E (2006-093) mutant showed low levels of TauΔCasp-6-positive NPTs in the STG. These results indicate that there is significant Casp-6 activity in the STG, the hippocampus, and the entorhinal cortex in most of the familial AD cases.
Double Staining of Active Casp-6 and PHF-1
To determine if the active Casp-6 colocalized with NFTs, NPs, and NPTs, we performed double immunostaining with anti-active Casp-6 and PHF-1 in the cases from which we had both temporal cortex and hippocampus/entorhinal cortex sections. The PHF-1 immunoreactivity was very strong and often overpowered that of the active Casp-6. The PHF-1 immunostaining was strong in all areas of each case, except in PSEN I F105L (2001-090), in which staining of NPs and NPTs was low in the hippocampus and in the PSEN I V261F (2000-007) mutant, in which there was no staining of NPs in the hippocampus (Table 4). This was consistent with the TauΔCasp-6 immunostaining results. The PHF-1 immunoreactivity was strong in the other 2 cases that had lower TauΔCasp-6 (APP Arctic and PSEN I A431 2006-093 S/MTG), however. Most NFTs and many NPTs were stained with both the anti-active Casp-6 and the PHF-1 antibodies (Figs. 4A and B), but NFTs and NPTs with only PHF-1 and some with only active Casp-6 were also observed (Fig. 4B). In the Arctic case, many neurons had prominent punctate Casp-6 immunoreactivity throughout the cytoplasm, which was distinct from diffuse staining of pretangles. On double immunolabeling, a few of the neurons showed punctate staining with both anti-Casp-6 and the PHF-1 antibodies (Fig. 4C).
To provide evidence in support of the hypothesis that activated Casp-6 is an important upstream component of AD pathogenesis, we investigated whether Casp-6 was activated in familial forms of AD. Our results indicate that Casp-6 is activated in the brains of familial AD cases because of a variety of distinct mutations. This was shown using the neoepitope antiserum 1277, which detects the large p20 subunit necessary for the active form of Casp-6 and by showing immunoreactivity with the 10635 neoepitope antiserum against Tau protein truncated at amino acid 402 (VSGD) by Casp-6 (5); this neoepitope antiserum does not detect full-length Tau protein.
The immunoreactivity with anti-active Casp-6 was less intense in the APP and the PSEN I M146V mutants than in the other PSEN I mutants and the PSEN II mutant. Because all cases showed considerable immunoreactivity against TauΔCasp-6, a more abundant and stable protein than Casp-6, this indicates that the Casp-6 was activated in these cases. Loss of the active Casp-6 epitope might be caused by several factors. Because the PSEN I mutant (2002-086) showed strong immunoreactivity despite having a postmortem interval of 27 hours, it is unlikely to be an artifact caused by postmortem delay. There was also no effect of disease duration on the level of active Casp-6 immunoreactivity. It is possible, however, that Casp-6 was activated earlier in these cases and became attenuated at the end stage of disease. Consistent with this idea, Casp-6 is activated early in sporadic AD (as shown in mild cognitively impaired brains) and decreases in the end stage of disease (6). Alternatively, the active Casp-6 epitope was less well preserved in the APP and PSEN I M146V familial AD cases.
As in sporadic AD, anti-active Casp-6 and TauΔCasp-6 immunoreactivity in neurons was not associated with the chromatin condensation characteristic of apoptotic cell death. Therefore, it is likely that in both sporadic and familial AD cases, the active Casp-6 performs a different function. Because several of the Casp-6 substrates are cytoskeleton and cytoskeleton-associated proteins (10) and Casp-6 activity results in axonal pruning and degeneration in mice neurons in culture (11), active Casp-6 may play a role in neurodegeneration rather than in cell death in AD. Exceptions were the 1 Arctic case and 1 APP Swedish case (69-01), both of which had anti-active Casp-6 nuclear staining in numerous neurons. These neurons had small condensed nuclei and their cytoplasm was shrunken often leaving a pericellular halo; they were, therefore, most likely ischemic neurons. Indeed, nuclear active Casp-6 immunoreactivity was previously observed in ischemic neurons (5). The active Casp-6 in the nucleus of cells is associated with apoptotic cell death as Casp-6 cleaves the lamins, especially lamin A, resulting in chromatin condensation (9). Because these occurred only in a few cases, ischemia was not likely directly related to the familial AD mutations.
There was considerable variability among the different cases. For example, in the Arctic case, TauΔCasp-6 immunoreactivity in neuropil threads that are occasionally arranged in a circular fashion was reminiscent of the coreless ring-like amyloid plaques observed in these cases (17). In a few of the PSEN cases, there were cotton-wool plaques that stained with both the anti-active Casp-6 and the TauΔCasp-6 antibodies. In the Arctic case, punctate active Casp-6 immunoreactivity that often did not colocalize with PHF-1 immunoreactivity was observed throughout the cytoplasm, although some punctate staining was observed with both antibodies in some neurons.
Active Casp-6 staining in neuronal round cytoplasmic inclusions was obvious in the Swedish and Arctic cases but was also seen in PSEN I and PSEN II cases; this was unexpected and differed from our previous observations of active Casp-6 in mild and moderate forms of sporadic AD (5, 6). Similar inclusions were, however, previously observed in PHF-1-positive NFTs in very severe sporadic AD (6), and such inclusions are generally considered to represent end-stage pathological events (18). Therefore, the presence of active Casp-6 inclusions could be caused by more widespread simultaneous neuronal involvement in familial AD than in sporadic AD. Accumulation of active Casp-6 in inclusions is also not unique to this Casp. Active Casp-3 is abundant in ubiquitin- and cytokeratin-positive inclusions that form in apoptotic epithelial cells in culture, and these inclusions might sequester active Casps, thereby delaying apoptosis (19, 20). Similar sequestration of active Casp-6 in degenerating neurons might prevent the complete demise of the affected neurons because complete destruction of the neurites would have a severe irreversible impact on brain function.
The amyloid hypothesis predicts oligomeric β-amyloid peptide to be responsible for the activation of Casp-6 in familial AD. Although primary neurons resist extracellular β-amyloid peptide toxicity unless they are coincubated with the phosphoinositide 3-kinase inhibitor, wortmannin, the intracellular β-amyloid peptide is highly toxic to human neurons, and this toxicity is dependent on Casp-6 activation (21). Consistent with this hypothesis, Casp-6 is more strongly activated in the APP Swedish and PSEN I hippocampus, which increases the levels of β-amyloid peptide compared with those of the Arctic case, which simply increases the propensity of the β-amyloid peptide to aggregate (22, 23). The other areas of the Arctic case did not differ significantly from the APP Swedish, PSEN I, and PSEN II cases, however. Consequently, we cannot exclude the possibility that the familial AD-linked mutations initially disrupt cellular homeostasis to result in Casp-6 activation independently of the production of β-amyloid peptide. Indeed, serum deprivation in human primary neurons results in Casp-6-dependent increase of β-amyloid peptide (3, 12). Furthermore, pro-Casp-6 expression, modulated by p53 activation, increases in AD (24, 25). Overexpression of pro-Casp-6 in the human embryonic kidney 293 cell line results in Casp-6 self-activation (8), indicating that overexpression of Casp-6 is sufficient to result in its activation. Therefore, a disruption of cellular homeostasis by familial AD mutant proteins that would increase pro-Casp-6 protein levels could result in the activation of Casp-6 in all of these cases.
In conclusion, the presence of Casp-6 activity in familial AD APP, PSEN I, and PSEN II mutants supports the hypothesis that Casp-6 activity is involved in the pathophysiology of AD.
The authors thank Dr Catherine Bergeron (University of Toronto, Toronto, Canada) for the sporadic AD and control tissues. The authors thank Jocelyne Jacques from the Department of Pathology at the JGH for technical assistance. The authors also thank Dalia Halawani and Andrea Lee from the LeBlanc laboratory for reading the manuscript. Several cases were provided by the Indiana Alzheimer Disease Center (Indiana University, Indianapolis, IN).
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Alzheimer disease; Arctic mutation; Casp-6; Familial Alzheimer disease; Presenilin I mutation; Sporadic Alzheimer disease; Swedish mutation; Tau cleaved by Casp-6
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