Mitosis-specific phosphorylation of amyloid precursor protein at Threonine 668 leads to its altered processing and association with centrosomes
- Monique Judge†2,
- Lisa Hornbeck†1, 2,
- Huntington Potter1, 2, 3, 4 and
- Jaya Padmanabhan1, 2Email author
© Judge et al; licensee BioMed Central Ltd. 2011
Received: 25 January 2011
Accepted: 23 November 2011
Published: 23 November 2011
Atypical expression of cell cycle regulatory proteins has been implicated in Alzheimer's disease (AD), but the molecular mechanisms by which they induce neurodegeneration are not well understood. We examined transgenic mice expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) for changes in cell cycle regulatory proteins to determine whether there is a correlation between cell cycle activation and pathology development in AD.
Our studies in the AD transgenic mice show significantly higher levels of cyclin E, cyclin D1, E2F1, and P-cdc2 in the cells in the vicinity of the plaques where maximum levels of Threonine 668 (Thr668)-phosphorylated APP accumulation was observed. This suggests that the cell cycle regulatory proteins might be influencing plaque pathology by affecting APP phosphorylation. Using neuroglioma cells overexpressing APP we demonstrate that phosphorylation of APP at Thr668 is mitosis-specific. Cells undergoing mitosis show altered cellular distribution and localization of P-APP at the centrosomes. Also, Thr668 phosphorylation in mitosis correlates with increased processing of APP to generate Aβ and the C-terminal fragment of APP, which is prevented by pharmacological inhibitors of the G1/S transition.
The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of βAPP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into Aβ and the C-terminal fragment suggest that these proteins may have a normal function during mitosis.
KeywordsAmyloid precursor protein cell cycle mitosis kinases APP phosphorylation amyloid processing
The major pathological characteristics of Alzheimer's disease are the presence of neuritic plaques and neurofibrillary tangles (NFT) in the affected areas of the brain [1–3]. In addition, AD brains show neuroinflammation and neuronal loss, which is associated with aberrant expression of cell cycle regulatory proteins [4–8]. The cause or the function of the increased levels of cell cycle regulatory proteins in post-mitotic neurons is not clearly understood. Studies by different groups suggest that fully differentiated neurons in adult brains emerge from quiescence and attempt to re-enter the cell cycle under pathological conditions [4, 8–23]. This apparent upregulation of cell cycle regulatory proteins in neurons, along with the findings that the inhibitors of cell cycle activation protect neurons from undergoing apoptosis, led to the hypothesis that inappropriate attempts by neurons to re-enter the cell cycle may lead to neurodegeneration and apoptosis [6, 12, 24–32]. In addition to neuronal loss, it is possible that dysregulation of the cell cycle may lead to cell cycle-dependent modifications in the amyloid precursor protein (APP) and tau, the two major proteins associated with AD, favouring plaque and tangle formation and neurodegeneration in the AD brains.
APP is a single transmembrane protein that is sequentially cleaved by β and γ- secretases to generate the Aβ peptide, which gets deposited extracellularly to form plaques and vascular amyloid deposits . Mutations in APP and presenilin 1 (PS1) are associated with increased generation of Aβ and increased pathology development in AD . In addition to the accumulation of Aβ into amyloid, studies in neurons have shown that Aβ peptides can induce cell cycle activation and neuronal apoptosis . Expression of a mutant form of APP or PS1, as well as treatment with Aβ, have been shown to induce chromosome mis-segregation and aneuploidy in cells [36, 37], which indicates aberrant cell cycle activation under these conditions. Studies conducted in two different AD mouse models have shown an upregulation of cell cycle regulatory proteins in glial cells  and neurons . Thus, cell cycle deregulation may influence both neuronal and glial functions, and a keen analysis of the cell cycle-dependent changes in these cells may reveal the significance of the upregulated expression of cell cycle markers in AD brains. Mice generally do not show much neuronal loss, but it is possible that the upregulation of cell cycle regulatory proteins may mediate synaptic loss and neurodegeneration by inducing modifications in tau and APP. Here we analyzed the specific effects of cell cycle activation on APP modifications.
APP is phosphorylated by multiple kinases, which affects its proteolytic processing, trafficking, and protein-protein interaction [40–48]. We tested the hypothesis that cell cycle activation can affect APP modifications and plaque development, using in vitro cultured cells and transgenic mice. The studies presented here show that transgenic mice expressing mutant APP (APPV717F) and PS1 (PS1M146L) show an increase in the levels of cell cycle regulatory proteins which is associated with induction of APP phosphorylation at Thr668 and formation of Aβ and phosphorylated C-terminal fragment of APP. Experiments conducted in H4 neuroglioma cells overexpressing APP confirmed that this phosphorylation is mitosis-specific and can be inhibited by G1/S transition inhibitors, which prevent Aβ generation. A role for G1/S specific inhibition was further determined by inhibition of P-APP formation by siRNA to cdk-2. This observation, along with our finding that P-APP co-localizes with MPM2 at centrosomes in mitotic cells suggests that mitotic mechanisms may influence AD pathology by not only affecting APP phosphorylation and Aβ generation, but also by enabling it to have a role in spindle assembly and cell cycle regulation. Thus, APP may act as a cell cycle inducer under mitotic conditions and might play a feed forward role in pathology development in AD.
Upregulation of cell cycle regulatory proteins in AD transgenic mice
Phosphorylation of APP at Thr668 in mice expressing AD transgenes
APP phosphorylation and processing in AD transgenic mice
Age-dependent changes in Thr668 specific phosphorylation of APP in transgenic mice
Cell cycle-dependent phosphorylation of APP
si-cdk2 inhibits serum stimulation-induced APP phosphorylation in H4-APP cells
Since it is known that cdk5 as well as GSK-3β can induce tau hyperphosphorylation in AD brains, and since these kinases have also been shown to affect APP phosphorylation, we examined the effect of downregulation of these kinases on APP phosphorylation. Cells transfected with siRNA to GSK-3αβ (Figure 9B) and siRNA to cdk5 (Figure 9C) also showed downregulation of APP phosphorylation as expected and it correlated with the levels of down regulation of the corresponding kinases. These data thus suggest that APP and tau are phosphorylated under similar conditions, and that inhibitors of these kinases should be tested for their ability to reduce development of pathology in AD. The G1/S inhibitor roscovitine has been shown to inhibit cdk5 and therefore the effect we see with this inhibitor could be due to its effect on not only cdk2 but other responsive kinases as well.
Distribution of P-APP in asynchronously growing cells
Evidence for mitotic phosphorylation and centrosome localization of P-APP
Cell cycle activation induces altered processing of APP and Aβ generation
Upon analysis of other proteolytic fragments of APP in cultured cells, we found that, similar to our observations in AD transgenic mice, phosphorylation was associated with increased BACE cleavage of APP, as evident by the C-terminal fragment detected by the 6E10 antibody. The C-APP levels were lowest in roscovitine treated G1/S checkpoint arrested cells. Recent studies using a C-terminal fragment of APP have shown that the administration of this fragment induces apoptosis in cells of neuronal origin . Thus, our results support the suggestion that inhibitors of G1/S transition may prevent neurodegeneration by preventing unwarranted processing of APP to generate neurotoxic Aβ and C-APP.
Alzheimer's disease is characterized by the presence of neuritic plaques and neurofibrillary tangles in the affected areas of the brain. In addition, AD brains show considerable neuronal loss and neuroinflammation, the causal mechanisms of which are under active investigation. Studies from several laboratories have shown that AD brains exhibit aberrant upregulation of cell cycle regulatory proteins [4, 6, 7, 14, 22, 56]. It is suggested that the deregulated expression of cell cycle proteins in neurons may contribute to the pathology associated with Alzheimer's, possibly due to inappropriate induction of the cell cycle in post-mitotic neurons. A causal link can be established between cell cycle activation, neurodegeneration, and neuronal loss in vitro, but it has been difficult to illustrate how cell cycle activation can induce a slowly developing but ultimately catastrophic effect in human AD brain. In order to understand the mechanisms involved in cell cycle activation and AD pathogenesis, we used mice expressing APPV717F and PS1M146L mutant transgenes. The PS/APP mice develop plaques at approximately 6 months of age and the APP mice show plaques at approximately 10-12 months of age. We found that, similar to human AD, brains from these mice also show increased expression of some of the cell cycle regulatory proteins. This was associated with increased phosphorylation of APP.
In vitro analysis of asynchronously growing H4-APP cells clearly showed that the phosphorylation of APP occurs mainly in the cells that are undergoing cell division. In the interphase, cells APP phosphorylation was negligible and was induced as soon as the cells entered prophase. The experiments with si-cdk2 and pharmacological inhibitors of the G1/S checkpoint further supports the conclusion that APP phosphorylation and processing occurs in a mitosis-specific manner and reinforces the idea that inhibition of cell cycle activation at an early stage may prevent the APP modifications associated with the development of AD pathology. APP phosphorylation is not just mediated by cyclin-dependent kinases. Kinases such as GSK-3β, JNK, and cdk5 have also been shown to affect Thr668 specific phosphorylation of APP. Our studies also showed that this specific phosphorylation could be inhibited by downregulation of GSK-3β and cdk5. Both GSK-3 and cdk5 have been shown to play roles in the cell cycle and hence the possibility that these kinases are also behaving in a cell cycle-dependent manner needs to be established [57, 58]. Nocodazole-induced mitotic arrest led to a significant increase in APP phosphorylation compared to that induced by serum stimulation alone. One of the reasons for this result could be that the number of metaphase cells obtained upon treatment with nocodazole (~80% by FACS analysis) is much higher than that obtained by serum stimulation or taxol treatment (~40%). The data shown in Figure 8 agrees with this interpretation; quantitative analysis of the levels of P-APP and APP showed that while serum stimulation shows ~30% APP phosphorylation (~40% cells in G2/M), nocodazole treatment shows ~80%, both of which correlate with the percent of cells in metaphase. In addition, nocodazole, being a powerful microtubule depolymerizing agent, could affect other kinases or phosphatases and induce APP phosphorylation independent of its mitotic arrest-related effects. Treatment of cells with taxol, another mitotic inhibitor that brings about cell cycle arrest through microtubule stabilization, showed only ~40% of cells in metaphase and a P-APP level of ~30%.
The results presented here strongly indicate that Thr668 specific phosphorylation on APP is intimately associated with cell cycle activation and that the maximum phosphorylation occurs in metaphase. This phosphorylation transition was associated with increased APP processing and Aβ generation (Figure 13). Thus the cells do not have to go through a full division to bring about the modifications in APP suggesting that an attempt by the cells in AD brain to re-enter cell cycle could lead to APP phosphorylation and proteolytic cleavage without the cells undergoing cell division. The findings that AD brains show binucleated neurons , as well as aneuploidy and mis-segregation of different chromosomes [15, 61–63] further strengthens the conclusion that neurons in AD brain attempt to undergo DNA replication and cell division. It is suggested that the cell cycle regulatory proteins may have a different role in neurons compared to that in cells undergoing active cell division; studies show that terminally differentiated neurons use the mechanisms involved in proliferation to maintain the synaptic plasticity [42, 60, 64]. It is possible that the complex architecture of mature plastic neurons makes it impossible for the cells to undergo division without undergoing damage. The report that centrosomes localize to the area where the neurites sprout from and the number of centrosomes determines the number of neurites  suggest that cell cycle activation may cause asymmetric dynamics on the chromosomes leading to mis-segregation and formation of aneuploid cells in the AD brain. The localization of P-APP (data presented here) and PS1 at the centrosomes  suggest that these molecules may play a role in spindle assembly and chromosome segregation, and hence the enhanced expression or mutations of these proteins may cause chromosome mis-segregation in cells. The data from our lab support this hypothesis, in which we showed that expression of APP, Aβ, or PS1 lead to chromosome mis-segregation and aneuploidy . Aβ oligomers have been reported to induce neuronal cell cycle activation [49, 50], and this along with the data presented here, suggest that Aβ generated upon APP phosphorylation may have a feed forward role in cell cycle activation and enhanced neurodegeneration in AD brain.
Cell cycle activation not only induced the phosphorylation and proteolytic processing of APP, but also affected the localization of P-APP in cells; mitotic cells clearly showed centrosome specific localization of P-APP. It has been proposed that the phosphorylation of structural or transient components of centrosomes may affect cell cycle dependent processes such as centrosome duplication and microtubule nucleation . Thus, in addition to enhanced proteolytic cleavage, APP phosphorylation may influence cell proliferation through its association with the cell cycle machinery. The co-localization of P-APP with MPM2, a metaphase protein marker, further reiterates APP's role as a growth-promoting molecule. Therefore, it is possible that high levels of P-APP may promote proliferation in dividing cells and centrosome duplication or chromosome mis-segregation and cell death in post-mitotic neurons. APP's function as a mitogenic molecule is evident from the fact that its upregulation is associated with cancers of different organs [67, 68]; neurons being postmitotic are fully differentiated and undergo apoptosis rather than transformation upon cell cycle activation. It has been reported that APP and PS1 associate with other proteins at the centrosome and localize to centrosomes [69, 70]. An N-terminal APP antibody conjugated to an Alexa fluorophore was used to detect the localization of APP at the centrosomes. In our hand staining of the cells with the Aβ immunoreactive 6E10 antibody did not show any significant localization of non-phospho APP to the centrosomes. It is possible that either the antibody or the techniques we applied to detect the localization are not strong enough to detect non-phospho APP at the centrosomes.
Our studies showed that APP and PS/APP mice show formation of Aβ and phosphorylated C-terminal fragments of APP at a very early age (1.5 month), and the generation of these fragments are increased in an age-dependent manner. Although this is the case, PS/APP mice showed clear accumulation of P-APP and Aβ in their brains by 6 months of age whereas APP mice showed only by 10-12 months. This result suggests that unless there is an accelerating factor present, the pathology in AD develops very slowly and if diagnosed early in life it can be prevented. The facts that deregulation in PS1 can induce chromosome miss-segregation and tumour generation [36, 71], and both PS1 and APP associate with centrosomes, suggest that in addition to Aβ generation, expression of PS1 in APP transgenic mice may affect cell cycle deregulation and therefore APP phosphorylation. Whether or not these associates with early neurodegeneration and neuronal loss observed in AD brains needs to be determined. Even though the PS/APP mice we used show significantly higher levels of P-APP and accumulation of Aβ in to plaques, unlike in some of the other AD mouse models such as APPSL/PS1-KI and 5XFAD mice [68, 72, 73], we did not observe any significant neuronal loss. The reason for this is unclear. It is possible that the genetic background and the transgene expression levels play a role in plaque load and neuronal loss associated with different transgenic mouse models. The APP mice we used do not exhibit as aggressive an AD-like disease as the ones above, and probably inclusion of an additional APP mutation in the transgene may be required to obtain detectable levels of neuronal loss.
In conclusion, cell cycle deregulation may influence the pathogenesis of AD through multiple pathways: 1) through phosphorylation and processing of APP to generate Aβ leading to plaque formation, 2) through Aβ and C-terminal fragment of APP inducing tau hyperphosphorylation [66, 74–76], and 3) through both Aβ and P-APP affecting cell cycle deregulation and contributing to the unwarranted progression of cell cycle. From the data presented here it is apparent that an inhibition of aberrant activation of the cell cycle prior to G1/S checkpoint could potentially hinder the modifications in APP and therefore development of AD pathology. In this respect, G1/S inhibitors, which are known to protect neuronal apoptosis in vitro [26, 31, 32], need to be explored in vivo for their efficacy in preventing APP phosphorylation and processing. Once the neurons start expressing higher levels of cell cycle proteins due to environmental stress, or inflammation, or high levels of Aβ, the modifications in the proteins associated with the development of pathology will take place, and the cells will succumb to degeneration. The data presented above and the previous support for the cell cycle hypothesis, which suggests that the neurons in AD brain enter the G1 phase of cell cycle [6, 7, 77], indicate that inhibitors of the early phases of cell cycle such as those associated with the G1/S checkpoint may prove to be beneficial in treating neurodegenerative diseases such as Alzheimer's. However, it must be noted that microtubules are essential for many neuronal functions, and thus any drugs designed to inhibit APP modifications or Aβ generation should be tested for their effect on microtubule dynamics both in vitro and in vivo before assuming that they will be risk-free therapies for AD.
All studies involving animals were done in accord with the rules and regulations set forth by the University of South Florida's Institutional Animal Care and Use Committee (IACUC). The care for the animals was provided by the well-established animal care facility at University of South Florida (USF), which is accredited by the American Association of Laboratory Animal Care (AALAC).
The tissue culture reagents, electrophoresis supplies, and Alexa fluorphores were purchased from Gibco/Invitrogen, Carlsband, CA. Poly-D-Lysine (PDL), α-tubulin antibody and Hoechst were from Sigma, St. Louis, MO. Anti-Aβ/APP antibody (6E10 raised against Aβ1-16) was from Signet, C-terminal APP antibody was from Chemicon/Millipore, Thr668 P-APP, MPM-2, and P-cdc2 antibodies were from Cell Signaling, and cyclin D1, cyclin E, and E2F1 antibodies were from Santa Cruz Biotechnology. The reagents for brightfield staining were purchased from Vector Laboratories. Enhanced chemiluminescence (ECL) reagent was from Pierce Biotechnology Inc., Rockford, IL. H4 neuroglioma cells overexpressing WT-APP (H4-APP) was a kind gift from Dr. Todd Golde (Mayo clinic, Jacksonville, Florida).
Heterozygous PDGF-hAPP (V717F) mice (Swiss-Webster × C57BL/6) were crossed with PDGF-hPS1 (M146L) heterozygotes (Swiss-Webster × C57BL/6) to generate mice with an APP+/-, PS1+/- genotype. All offspring were screened by PCR to verify the expression of APP and PS1 gene [78, 79]. The APP mutant mice develop many of the pathological hallmarks of AD, including neuritic plaques (appear at around 10-12 months of age), and cognitive deficits in an age-dependent manner, and the expression of mutant PS1 in these mice accelerates the pathology development significantly (plaques are visible as early as 4-6 months of age) (Figure 7D). In the current study we used these transgenic and age-matched non-transgenic (Ntg) mice. Mice were anesthetized using Nembutal (10 mg/kg body weight) and perfused with saline solution. The brains were dissected out and half of each brain was immersion fixed with 4% para-formaldehyde and the other half was used for protein extraction. For protein extraction, brains were homogenized in Hepes lysis buffer (50 mM HEPES pH 7.4, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 5 mM MgCl2, 1 mM EGTA, 20 mM NaF, 2 mM Na3VO4, and protease inhibitors (Roche)). Samples were centrifuged at 14,000 rpm for 30 min and equal amounts of proteins were used for western blot analysis. The brains were processed as described before for immunohistochemical analysis . Brain sections were made using a freezing stage sliding microtome and stored at 4°C in phosphate buffered saline (PBS) containing sodium azide (0.02%) for immunohistochemical analysis.
This was done following the established protocols [80, 81]. Briefly, H4-15X cells cultured in 8-chamber tissue culture slides coated with PDL were treated with or without different inhibitors of the cell cycle for 18 hr; roscovitine (20 μM) as G1/S inhibitor, aphidicolin (5 μg/ml) as S-phase inhibitor, nocodazole or vinblastine (100 ng/ml or 10 μM respectively) or taxol (placitaxel, 100 ng/ml) as mitotic inhibitor. At the end of the treatment, cells were fixed with 4% para-formaldehyde and staining was performed using the appropriate antibodies. Staining was analyzed under a Zeiss microscope using the AxioVision Rel 4.8 software. Centrosome specific staining of P-APP in H4-APP cells was confirmed by confocal microscopy under an Olympus imaging system using Fluoview FV1000 ver.1.7 software.
For immunostaining analysis of the brain sections, sections were mounted onto superfrost slides, and non-specific binding was blocked by incubating with 10% normal goat serum (NGS)/TBST for 2 hr at room temperature. Sections were then incubated with appropriate dilutions of the primary antibody (APP (6E10), Thr668-P-APP, cyclin D1, cyclin E, E2F1, and P-cdc2 antibodies) in 1% BSA/TBST overnight at 4°C in a humidified chamber. After thorough washing, the sections were incubated with biotinylated mouse or rabbit secondary antibodies for 1 hr at room temperature and developed following the manufacturer's protocol with the DAB kit from Vector laboratories. The staining was visualized using a Nikon E1000 microscope using Image-Pro Plus software. In the case of fluorescent labeling, after primary antibody incubation as outlined above, sections were incubated with Alexa 488 or 594 fluorophores for 2 hr at room temperature protected from light. Sections were washed and nuclei were counter stained using Hoechst 33342 and washed again before mounting using aqueous Gel/Mount. Sections were stained with secondary antibody alone to determine non-specific binding of antibodies to the tissue (data not shown). The results were analysed under a Zeiss microscope using the AxioVision Rel 4.8 software. The signal intensity of the images was determined by Image J, image processing and analysis program . Adjacent sections from at least 3 independent mice expressing different transgenes were stained using the antibody of interest. Prior to measurement, the images were converted to 8-bit grayscale and the threshold of all the images from each set of experiments was adjusted to the same level. This keeps the sample-to-sample variation minimal. The intensity obtained with Hoechst staining was used as a normalizing control for each section.
Immunoprecipitation and Western blot analysis
H4-15X cells were cultured in OPTI-MEM containing 10% FBS and 50 μg/ml hygromycin in 100 mm culture dishes overnight and serum starved for 48 to 72 hr. Serum stimulation of the cells was done in the presence or absence of different pharmacological inhibitors for the indicated time periods. Cell culture supernatants and cell lysates (made in Hepes lysis buffer) were immunoprecipitated using 6E10 antibody and analyzed using the same antibody to detect secreted and cellular levels of Aβ. In the case of brain extracts, equal amounts of protein were boiled with Tricine sample buffer and PAGE and western-immunoblot analysis was performed using appropriate antibodies. For quantification, western blot images on the X-ray film were scanned and densitometric analysis was performed using the Image J, image processing and analysis tool after selecting and plotting the bands of interest.
siRNA transfection of H4-APP cells
We obtained Silencer validated siRNA to cdk2 (locus ID: 1017) from (Ambion, Inc. Applied Biosystems), siRNA to cdk5 from Santa Cruz Biotechnology and siRNA to GSK-3αβ from Invitrogen. The siRNA was used at the indicated concentrations and transfected using oligofectamine (Invitrogen) using OPTI-MEM without serum. 6 hr after transfection the media was replenished with an equal volume of OPTI-MEM containing 2X serum and cultured for 24 to 48 hr. At the end of the time period cells were harvested in sample buffer and analyzed by western blot for downregulation of the kinases using the corresponding kinase antibody and phosphorylation of APP by Thr668 P-APP antibody.
Statistical analysis was performed using Student's t-Test.
List of abbreviations
amyloid precursor protein
- Thr668 P-APP:
APP phosphorylated at Threonine 668
We would like to thank the following individuals at University of South Florida; Dr. Tiffany Hughes and Michelle Norden for help with breeding and genotyping of the transgenic mice, Dr. Byeong Cha with confocal image analysis, Dr. Karoly Szekeres for help with the FACS analysis. We are grateful to Dr. Todd Golde (Mayo Clinic, Jacksonville, FL) for kindly providing the H4 neuroglioma cells overexpressing APP. This work was supported by grants from the Alzheimer's association (IIRG-08-90842 to JP), NIH-NIA (1R21AG031429-01A2 to JP and AG25711 to HP) and funds from the USF Health Byrd Alzheimer's Institute and the Department of Molecular Medicine at USF, Tampa.
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