The p38 MAP kinase signaling pathway in Alzheimer’s disease

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Experimental Neurology 183 (2003) 263–268

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Commentary

The p38 MAP kinase signaling pathway in Alzheimer’s disease Gail V.W. Johnson* and Craig D.C. Bailey Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA Received 23 April 2003; revised 8 May 2003; accepted 8 May 2003

Introduction Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. AD is characterized by progressive neuronal degeneration that is accompanied by the formation of extracellular senile plaques and intracellular neurofibrillary tangles (NFTs). Although the neuropathological features of AD have been well defined, the underlying mechanisms responsible for the pathogenic processes have not been clearly delineated. This lack of understanding of the fundamental processes that are responsible for the neurodegeneration in AD likely is the reason there are no effective treatments to prevent the onset and/or progression of the disease. However, research advances over the past several years have begun to provide some insight into the molecular mechanisms of AD. One particularly important area of investigation is the contribution of aberrant cell signaling events to the pathogenic process. For example, recent findings have provided strong evidence that the p38 mitogenactivated protein (MAP) kinase signaling cascade is one signaling pathway that may be overactivated in AD. In this issue of Experimental Neurology, Sun et al. (2003) provide supporting evidence that the p38 pathway is activated in the early stages of AD and thus may contribute to the neurodegenerative processes. p38 therefore may be an important therapeutic target for the treatment of AD (Dalrymple, 2002). Overview of the p38 MAP kinase family MAP kinases are members of specific signaling cascades that serve as convergent points for numerous and diverse extracellular signals and thus are critically important integrators of signaling events. Four distinct groups of MAP * Corresponding author. Department of Psychiatry, 1720 7th Avenue South, SC1061, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35294-0017, USA. Fax: ⫹1-205-934-3709. E-mail address: [email protected] (G.V.W. Johnson).

kinases have been identified: (1) the extracellular signalregulated kinases (ERKs); (2) the c-jun N-terminal protein kinases (JNKs), which are also referred to as stress-activated protein kinases (SAPKs); (3) big MAP kinase 1 (BMK1, also known as ERK5); and (4) the p38 MAP kinases (Ono and Han, 2000). Over the past several years there has been increasing interest in the p38 group of MAP kinases in the AD research field, as these kinases are involved in inflammation and cell death pathways and therefore could contribute to the pathogenic events that occur in AD brain. Four isoforms of p38 have been identified: p38 (also called p38␣, CSBP, MPK2, RK, Mxi2, or SAPK2a), p38␤ (also called p38-2, p38␤2, or SAPK2b), p38␥ (also called ERK6 or SAPK3), and p38␦ (also called SAPK4) (Ono and Han, 2000). p38 and p38␤ are expressed in almost all tissues and are particularly abundant in brain and heart (Jiang et al., 1996). In contrast, p38␥ and p38␦ show very selective tissue distribution and do not appear to be expressed in brain (Kumar et al., 1997; Lechner et al., 1996; Li et al., 1996). All members of the p38 family have the dual phosphorylation motif TGY, which is located between subdomains VII and VIII (Jiang et al., 1996). Both the Thr and Tyr residues become phosphorylated in response to specific stimuli, resulting in p38 activation. In many studies activated p38 is detected by using antibodies that specifically recognize p38 when both the Thr and Tyr residues in the TGY motif are phosphorylated. Given that the amino acid sequences surrounding this dual phosphorylation epitope are identical in p38 and p38␤, immunoanalysis with these phospho-dependent antibodies cannot differentiate between the active forms of these two p38 isoforms. p38 MAP kinase activation and function p38 MAP kinases are activated by numerous unique signals. Environmental stressors and toxins, cellular injury,

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growth factors, cytokines, and many other stimuli have been reported to activate members of the p38 MAP kinase family (Harper and LoGrasso, 2001; Obata et al., 2000). In neuronal systems many stimuli that increase p38 phosphorylation/ activation have been identified. Moreover, p38 activation has been demonstrated to be involved in cell death mechanisms in neuronal models. Treatment of neuronal cultures with arsenite (Namgung and Xia, 2000), the sulfhydryloxidizing agent DTDP (McLaughlin et al., 2001), C2-ceramide (Willaime et al., 2001), or lipopolysaccharide (LPS) (Jeohn et al., 2002) results in p38 activation, which then facilitates apoptotic processes in these model systems. Fasinduced apoptosis in neuronal systems (Hou et al., 2002; Raoul et al., 2002), dopamine-induced apoptosis in human neuroblastoma SH-SY5Y cells (Junn and Mouradian, 2001), and axotomy-induced apoptosis in rat retinal ganglion cells (Kikuchi et al., 2000) are also mediated, at least in part, by p38 MAP kinases. These data indicate that p38 is activated under stress conditions and can be deleterious to neuronal cell survival. Activation of p38 also has been implicated in the neuropathology associated with AD. Injection of preaggregated A␤(1– 42) in rat nucleus basalis resulted in microglial and astrocyte activation and phospho-p38 immunoreactivity that colocalized with microglial cells, but not astrocytes (Giovannini et al., 2002). In mice that were double transgenic for mutant amyloid precursor protein (Swedish mutations) and mutated presenilin-1 (P264L) the p38 pathways were activated in the cerebral cortex (Savage et al., 2002). These data provide evidence that the increased levels of oligomeric A␤ that occur in AD brain could activate signaling cascades that increase p38 activity. Like all members of the MAP kinase families, the p38 family members are activated by upstream dual-specificity kinases called MAP kinase kinases (MKKs). Although the dual phosphorylation motif is conserved in all members of the p38 family, selective activation by specific MKKs has been observed. For example, MKK6 phosphorylates all four p38 isoforms, but MKK3, which is 80% homologous to MKK6, does not efficiently phosphorylate p38␤ (Ono and Han, 2000). Upstream of the MKKs are the MKK kinases. These kinases include MTK1/MEKK4 (Mita et al., 2002), ASK1 (Galvan et al., 2003), and TAK1 (Edlund et al., 2003), among many others. These various MKK kinases respond to selective but diverse stimuli. Interestingly, overexpression of MKK kinases often results in activation of both the p38 and JNK pathways, which may explain the fact that coactivation of p38 and JNK is often observed (Harper and LoGrasso, 2001).

p38 MAP kinase substrates The substrates of p38 MAP kinases are usually either transcription factors or other protein kinases. p38 has been shown to phosphorylate CHOP, a member of the C/EBP

family of transcription factors (Wang and Ron, 1996), the ternary complex factor (TCF) Sap-1a (Janknecht and Hunter, 1997), AFT-2, and ATF-6 (Stein et al., 1997; Thuerauf et al., 1998). p38 also plays an important role in phosphorylating and activating other protein kinases that phosphorylate and activate specific transcription factors. For example, p38 can phosphorylate and activate MAPKAP kinase-2, which in turn can phosphorylate and activate CREB, ATF-1, and SRF (Heidenreich et al., 1999; Tan et al., 1996). Mitogen and stress-activated protein kinase-1 (MSK1) and MSK2 are also substrates of p38, and once activated these kinases can then phosphorylate and activate CREB and ATF-1 (Deak et al., 1998; Wiggin et al., 2002). MAPKAP kinase-3 also is activated by p38 and subsequently phosphorylates and activates the molecular chaperone protein, heat shock protein 27 (hsp27) (Dorion et al., 2002; Dorion and Landry, 2002; McLaughlin et al., 1996). There are also data to suggest that p38 family members can phosphorylate the microtubule-associated protein tau. This of interest because tau is hyperphosphorylated in AD brain and accumulates to form the intracellular NFTs. In vitro p38 and p38␤ can phosphorylate tau, although not with high efficiency (Goedert et al., 1997; Reynolds et al., 1997). Further, when overexpressed in cells, neither p38 nor p38␤ was considered to be a “good” tau kinase (BueeScherrer and Goedert, 2002). In human neuroblastoma SHSY5Y cells treatment with osmotic stress resulted in a robust increase in the activation of p38/p38␤, and tau phosphorylation also was significantly increased. However, inhibition of p38/p38␤ activity with the selective inhibitor SB202190 did not decrease the osmotic stress-induced increase in tau phosphorylation, indicating that tau was not a substrate for p38/p38␤ in this model system (Jenkins et al., 2000). These data suggest that tau may not be a direct substrate of p38/p38␤, although tau may be a downstream target of kinases that are activated by p38/p38␤. Research is still ongoing to elucidate the relationship between p38 activation, tau hyperphosphorylation, and NFT formation in AD.

p38 MAP kinase and tau pathology in AD The study by Sun et al. (2003) provides an in-depth analysis of changes in phospho-p38 immunoreactivity in AD cases and confirms and extends previous studies. One of the first studies to show increased phospho-p38 immunoreactivity in AD brain was Hensley et al. (1999). In this study immunohistochemical reactivity to phospho-p38 was increased in the AD hippocampus. Further, phospho-p38 staining resembled the pattern of NFTs within neurons as assessed by staining with the phospho-tau antibody PHF-1 in adjacent sections. Subsequently, in a study from another group, p38 was found to copurify with PHF-tau and p38 immunoprecipitates from AD frontal cortex brought down PHF-1-immunoreactive material (Zhu et al., 2000), thus supporting the findings of Hensley et al. (1999). However,

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the findings of Sun et al. (2003) differed somewhat from these two previous studies, as it was found that NFTs that were densely stained with phospho-tau antibodies were usually not stained by the phospho-p38 antibody. In addition, phospho-p38 did not coimmunoprecipitate AT8-tau (phospho-tau) from AD hippocampus (Sun et al., 2003). This may suggest that activation of p38 decreases its association with phospho-tau, as it was p38 (not phospho-p38) that was found to coimmunoprecipitate PHF-1 immunoreactivity (Zhu et al., 2000). Some colocalization of phospho-tau and phospho-p38 antibody staining was observed by Sun et al. (2003), just not at the level of the NFTs. Further, most of the colocalization of phospho-p38 was with either the 12E8 or AT8 phospho-tau antibodies, whereas the PHF-1 and TG-3 phospho-tau antibodies showed only minimal colocalization with phospho-p38 immunoreactivity in AD brain (Sun et al., 2003). In the study by Sun et al. (2003) phospho-p38 immunoreactivity was increased in early AD cases (Braak stages IV and V), predominantly in the CA2 and subiculum regions of the hippocampal formation, with increases also being noted in the CA1 region of the hippocampus. Further, phosphop38 immunoreactivity was mainly limited to the hippocampus, with only weak and variable staining in the cerebral cortical regions of AD brain, although it was noted that “remarkable” phospho-p38 immunoreactivity occurred in the neocortex of one AD case (Sun et al., 2003). Similar results were reported by Pei et al. (2001) in terms of staging of the appearance of phospho-p38 staining, although an earlier presentation of phospho-p38 immunoreactivity was observed. In the study by Pei et al. (2001) immunohistochemical staining of AD brain revealed faint phospho-p38 staining in the pre-NFT entorhinal cortex but not in hippocampus or temporal cortex. In Braak stages I–II entorhinal cortex and hippocampus, phospho-p38 staining was more intense and showed an “NFT-like” staining pattern (Pei et al., 2001). The phospho-p38 staining became more intense and more neurons were labeled for phospho-p38 as NFT formation progressed into later Braak stages (Pei et al., 2001). Using double immunofluorescent labeling techniques, Sun et al. (2003) clearly demonstrated that phospho-p38 rarely colocalized with dense AT8-tau staining, which is indicative of NFTs. That phospho-p38 did not stain NFTs was further confirmed by double labeling with phospho-p38 antibodies and thioflavin-S (Sun et al. 2003). Nonetheless, some overlap between AT8-tau and phospho-p38 was observed, which is in agreement with the findings of Pei et al. (2001) where some neuronal colocalization of phospho-p38 and phosphorylated tau (at the AT8 epitope) in AD brain was observed based on double immunofluorescence studies, although no images were shown (Pei et al., 2001). However the findings of Sun et al. (2003) contrast with the results of another study where staining of serial sections revealed that 90% of AT8-positive NFTs also labeled with an antibody to p38 (Zhu et al., 2000). Almost identical findings were obtained with an antibody to phospho-MKK6, an upstream activator of p38 (Zhu et al., 2001). Although it was dem-

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onstrated that the staining patterns of p38 and phospho-p38 were virtually identical, serial section staining with AT8 and phospho-p38 antibodies was not shown (Zhu et al., 2000). Further, in a study by Atzori et al. (2001) complete overlap between phospho-p38 and AT8 immunoreactivity in AD brain at the level of the NFTs was reported by using doublelabeling immunohistochemistry. One possible explanation for the discrepancies between these previous studies and the current report (Sun et al., 2003) is that in the study by Sun et al. (2003) immunofluorescent colocalization studies were performed by using the same AD brain sections, which had not previously been done. Although differences have been noted, both the current study by Sun et al. (2003) and the previous studies by Zhu et al. (2000, 2001) observed phospho-p38/p38 granulovacuolar degeneration (GVD) staining, which is discussed in more detail below.

p38 MAP kinase activation in other neurodegenerative diseases p38 pathways are activated by stress and inflammation (Kyriakis and Avruch, 2001) and therefore it is not surprising that there is increasing evidence that p38 and its downstream targets are activated in numerous neurological diseases. For example, activation of p38 has been implicated in the pathogenesis of amyotrophic lateral sclerosis (Raoul et al., 2002), Parkinson’s disease (Wilms et al., 2003), and multiple sclerosis (D’Aversa et al., 2002; Lee et al., 2000). Increased immunohistochemical staining for phospho-p38 has been observed in Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (Atzori et al., 2001; Ferrer et al., 2001). In these studies, phospho-p38 staining was often localized to areas of tau pathology. Moreover, there was a close relationship between the neurons that stained for phospho-p38 and for AT8-tau by double immunohistochemistry in FTDP-17 brains (Atzori et al., 2001). As previously observed for AD, both phospho-MKK6 and phospho-p38 were found in the same neurons that appear to exhibit tau pathology in adjacent 6-␮m sections from the cerebral cortex of Pick’s disease cases and from the substantia nigra of progressive supernuclear palsy cases (Hartzler et al., 2002).

p38 MAP kinase and granulovacuolar degeneration (GVD) A prominent feature of the immunohistochemical staining pattern of phospho-p38 in AD brain reported by Sun et al. (2003) was that it often resembled GVD bodies. This same pattern of p38 staining in AD brain was observed previously (Zhu et al., 2000). GVD bodies are small cytoplasmic vacuoles within neurons that slightly increase in number during normal aging, but show significant increases

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in AD brain (Ball and Lo, 1977). GVD bodies are especially abundant in pyramidal neurons of the AD hippocampus (Mann, 1978), where they may contribute to, or be related to, cell death mechanisms. Indeed, it has been postulated that GVD bodies may represent an attempt by the cell to sequester potentially detrimental proteins (Jellinger and Stadelmann, 2000). For example, in AD brain, activated caspase-3 and caspase-cleaved amyloid precursor protein colocalize within GVD bodies (Stadelmann et al., 1999; Su et al., 2002). Glycogen synthase kinase 3␤ (GSK3␤) is an effective tau kinase and plays a key role in cell death signaling pathways (Grimes and Jope, 2001; Song et al., 2002). Phosphorylation of Tyr216 in GSK3␤ increases its activity (Grimes and Jope, 2001), and immunohistochemical staining has revealed that tyrosine-phosphorylated GSK3␤ is found in GVD bodies in AD brain. Further, GSK3␤ was not found in the PHF-tau-enriched fractions, indicating that GSK3␤ only loosely associated, if at all, with NFTs (Leroy et al., 2002). These findings are similar to those of Sun et al. (2003), as no specific association between phospho-p38 and phospho-tau was observed, although by immunohistochemical analysis GVD bodies have been shown to contain tau, as well as other cytoskeletal elements (Bondareff et al., 1991; Dickson et al., 1987; Price et al., 1986), and some of the GVD bodies label intensely with phospho-tau antibodies (Leroy et al., 2002). However, it is not clear whether the tau was phosphorylated prior to or after it was incorporated into the vacuoles. Given the findings that proteins known to be involved in apoptotic processes (caspase 3, GSK3␤) are sequestered into GVD bodies, it seems likely that the formation of these vacuoles may represent an attempt by the cell to downregulate cell death pathways. The recent findings that phospho-p38 also is found in GVD bodies (Sun et al., 2003; Zhu et al., 2000, 2001) suggest that activation of p38 is deleterious to the cell’s survival and thus could contribute to the neurodegenerative processes in AD.

Summary In conclusion, there is overwhelming evidence that phospho-p38 immunoreactivity is significantly increased in AD brain. Although there are some disagreements between the studies in terms of exactly where phospho-p38 is found in AD brain, this is actually secondary to the finding that phospho-p38 is increased in areas of AD brain that are affected by the disease. There is increasing evidence that inhibiting p38 activity may be an important therapeutic strategy in the treatment of brain disease or injury. For example, inhibition of p38 activity significantly attenuates brain injury and neurological deficits after cerebral focal ischemia (Barone et al., 2001). One of minocycline’s therapeutic targets includes p38 inhibition, and minocycline has been demonstrated to decrease disease progression in a mouse model of amyotrophic lateral sclerosis (Zhu et al.,

2002) and attenuate dopaminergic neuronal cell death in the MPTP model of Parkinson’s disease (Du et al., 2001). These and other findings clearly indicate that p38 inhibition may provide a rationale drug target for the treatment of AD, as well as other neurodegenerative conditions.

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