Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal. 2016 May 10;9(427):ra47. PubMed. Expression of concern.

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  1. Although the occurrence of both cancer and Alzheimer’s disease (AD) increase exponentially as people age, recent epidemiological studies focused on the curious observation that cancer patients rarely develop AD, and vice versa (Driver et al., 2012). Different studies demonstrated that this relationship may be AD-specific, as no significant correlation could be seen to non-AD diseases, such as vascular dementia (Roe et al., 2010; Musicco et al., 2013). This inverse correlation implicates the possibility that both diseases might be regulated in opposite directions at the molecular level, and that a deeper understanding may allow the development of new treatment strategies for both diseases.

    The recent study from the Malinow lab highlights the involvement of protein kinase Cα (PKCα) in AD pathology (Alfonso et al., 2016). Previously, the group reported that the PKC-binding protein (PICK1) was required for Aβ-induced synaptic depression (Alfonso et al., 2014). In the current study they now revealed the direct and selective contribution of overactivated PKCα in Aβ-mediated synaptotoxicity by using pharmacological inhibition and ex vivo analysis of PKCα-knockout mice. Intriguingly, analyzing whole-sequencing data sets from Rudi Tanzi’s Alzheimer’s Disease Genetics Initiative Study identified three unique PKCα mutations that significantly co-segregate with AD development in families with the disease. In line with their hypothesis that increased PKCα activity mediates the synaptotoxic effects of Aβ, functional cell-based analysis revealed that all three AD-associated PKCα variants were gain-of-function mutations displaying increased kinase activity.

    What about PKCα in cancer? PKC was initially described as receptor of the tumor-promoting phorbol ester, strengthening the dogma that activation of PKC drives tumorigenesis (Castagna et al., 1982). However, the group of Alexandra Newton (who was also involved in the Malinow study) challenged this dogma and revealed that most of the cancer-associated mutations of the PKC family (including the conventional α-isoform) have lost their function (Antal et al., 2015). Detailed characterization of 46 of these PKC mutations showed that the majority of these variants resulted in suppressed/abolished PKC activity. Moreover, genetic restoration of heterozygote loss-of-PKC-function nicely resulted in a reduced tumor volume, suggesting a tumor-suppressive function of PKC. This study may also explain why several PKC inhibitors failed in clinical trials. Notably, in the regard of over-activated PKC function in AD, these inhibitors may serve as a therapeutic option, at least for the subset of patients with mutated gain-of-function PKCα.

    The question now arises whether the loss/gain-of-function of PKCα explains the inverse correlation between AD and cancer. It is very intriguing that in AD only PKCα variants with gain of function were identified, whereas in the plethora of analysed cancers all PKC mutations had a loss of function or at least no gain of function. However, these opposing functions of PKC cannot solely explain the inverse AD/cancer-relationship. PKC is frequently mutated in human cancer, whereas all three identified PKC variants in AD patients were rare. Moreover, the majority of identified PKC mutations are heterozygous with an allele frequency varying from 0.05-0.67, indicating that these kinds of mutations are acquired in the later steps of tumorigenesis. In contrast, overactivated PKCα is directly contributing to Aβ-mediated synaptotoxicity, which is considered an early event in AD pathogenesis. More studies are needed to decipher how PKC functions as a tumor-suppressor and its possible connections with p53 tumor-suppressor and Hippo pathway regulators. Furthermore, recent studies also demonstrated that Pin1(Driver et al., 2015; Pastorino et al., 2006) and the amyloid precursor protein (APP) also present critical but opposite roles in AD pathogenesis and cancer. In the context of APP, we and others have demonstrated that APP and its α-cleaved sAPPα fragment are not only overexpressed in a plethora of solid and hematological cancers, but also are highly relevant for cancer survival and tumorigenesis (Venkataramani et al., 2010; Venkataramani et al., 2012). Integrating the biological function of PKC into existing molecular networks of AD and cancer may not only help explain the inverse relationship between these devastating diseases, but may also help reveal an Achilles heel for treating them both.

    References:

    Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S, Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 2012 Mar 12;344:e1442. PubMed.

    Roe CM, Fitzpatrick AL, Xiong C, Sieh W, Kuller L, Miller JP, Williams MM, Kopan R, Behrens MI, Morris JC. Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. Epub 2009 Dec 23 PubMed.

    Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, Palmer K, Russo A. Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study. Neurology. 2013 Jul 23;81(4):322-8. Epub 2013 Jul 10 PubMed.

    Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R. Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal. 2016 May 10;9(427):ra47. PubMed. Expression of concern.

    Alfonso S, Kessels HW, Banos CC, Chan TR, Lin ET, Kumaravel G, Scannevin RH, Rhodes KJ, Huganir R, Guckian KM, Dunah AW, Malinow R. Synapto-depressive effects of amyloid beta require PICK1. Eur J Neurosci. 2014 Apr;39(7):1225-33. PubMed.

    Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982 Jul 10;257(13):7847-51. PubMed.

    Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, Trotter EW, Gallegos LL, Miller CJ, Furnari FB, Hunter T, Brognard J, Newton AC. Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell. 2015 Jan 29;160(3):489-502. Epub 2015 Jan 22 PubMed.

    Driver JA, Zhou XZ, Lu KP. Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. Biochim Biophys Acta. 2015 Oct;1850(10):2069-76. Epub 2015 Jan 10 PubMed.

    Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature. 2006 Mar 23;440(7083):528-34. PubMed.

    Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, Wirths O, Bayer TA. Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010 Apr 2;285(14):10678-89. Epub 2010 Feb 9 PubMed.

    Venkataramani V, Thiele K, Behnes CL, Wulf GG, Thelen P, Opitz L, Salinas-Riester G, Wirths O, Bayer TA, Schweyer S. Amyloid precursor protein is a biomarker for transformed human pluripotent stem cells. Am J Pathol. 2012 Apr;180(4):1636-52. Epub 2012 Feb 1 PubMed.

    View all comments by Vivek Venkataramani

  2. In 1990, a series of independent papers converged to implicate a role for protein kinase C (PKC) in AD. Eliezer Masliah and Greg Cole, working in Tsunao Saitoh’s lab, discovered deficiencies in PKC activity in AD brain and fibroblasts (Masliah et al., 1990; Masliah et al., 1991). Working with Paul Greengard, I had discovered the direct phosphorylation of APP by PKC in 1988 (Gandy et al., 1988); then, Joseph Buxbaum worked together with us and we extended this observation and showed that PKC activation stimulates activity of the α-secretase, increasing sAPPα release (Buxbaum et al., 1990) and reducing Aβ generation (Buxbaum et al., 1992). This work was instantly confirmed in identical studies that emerged from the collaborative program involving Roger Nitsch, John Growdon, Dick Wurtman, Christian Haass, and Dennis Selkoe (Nitsch et al., 1992; Hung et al., 1993). Conveniently, Du-Sup Choi and Robert Messing demonstrated that PKC activates a second Aβ-reducing pathway by stimulating degradation by endothelin converting enzyme (ECE) (Choi et al., 2006). Taken together, all these data accumulating over two decades pointed to PKC activation as a potential therapeutic strategy for AD, and, indeed, forms part of the basis of Dan Alkon’s clinical trial with the PKC activator bryostatin (Etcheberrigaray et al., 2004). 

    This has been by no means a straightforward path because: (1) PKC levels rapidly downregulate following stimulation; (2) the main laboratory activators of PKC (or inactivators of the corresponding protein phosphatase) are tumor promoters; and (3) the promoter of APP is sensitive to PKC activation.  Odete da Cruz e Silva, working with the late Edgar da Cruz e Silva, in a collaboration between the Greengard lab and my lab, showed that, somewhat unexpectedly, with chronic PKC activation, Aβ accumulates (implying that the APP transcriptional activation outstrips both the differential processing by α-secretase and the activated Aβ degradation by ECE) and PKC levels are downregulated (da Cruz e Silva, 2009). This new discovery by Rudy Tanzi, Roberto Malinow, and Alexandra Newton of mutations in PKC that cause gain of function would potentially fall into this latter category, doing more harm than good.

    Moreover, this new synaptic role for PKC in modulating Aβ-induced synaptic depression potentially yields a genetic double whammy if the overactive PKC clinical mutation drives both Aβ accumulation and Aβ-induced synaptic depression. This discovery provides yet another illustration of how the initiation of the pathway to AD might begin at one or multiple levels culminating in a concatenation of pathology involving amyloidosis, immune dysfunction, tauopathy, and failure and death of synapses and neurons.

    References:

    Masliah E, Cole G, Shimohama S, Hansen L, DeTeresa R, Terry RD, Saitoh T. Differential involvement of protein kinase C isozymes in Alzheimer's disease. J Neurosci. 1990 Jul;10(7):2113-24. PubMed.

    Masliah E, Cole GM, Hansen LA, Mallory M, Albright T, Terry RD, Saitoh T. Protein kinase C alteration is an early biochemical marker in Alzheimer's disease. J Neurosci. 1991 Sep;11(9):2759-67. PubMed.

    Gandy S, Czernik AJ, Greengard P. Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6218-21. PubMed.

    Buxbaum JD, Gandy SE, Cicchetti P, Ehrlich ME, Czernik AJ, Fracasso RP, Ramabhadran TV, Unterbeck AJ, Greengard P. Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):6003-6. PubMed.

    Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe EA, Gandy SE, Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075-8. PubMed.

    Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992 Oct 9;258(5080):304-7. PubMed.

    Hung AY, Haass C, Nitsch RM, Qiu WQ, Citron M, Wurtman RJ, Growdon JH, Selkoe DJ. Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J Biol Chem. 1993 Nov 5;268(31):22959-62. PubMed.

    Choi DS, Wang D, Yu GQ, Zhu G, Kharazia VN, Paredes JP, Chang WS, Deitchman JK, Mucke L, Messing RO. PKCepsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8215-20. Epub 2006 May 12 PubMed.

    Etcheberrigaray R, Tan M, Dewachter I, Kuipéri C, Van der Auwera I, Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, Van Leuven F, Alkon DL. Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):11141-6. Epub 2004 Jul 19 PubMed.

    da Cruz e Silva OA, Rebelo S, Vieira SI, Gandy S, da Cruz e Silva EF, Greengard P. Enhanced generation of Alzheimer's amyloid-beta following chronic exposure to phorbol ester correlates with differential effects on alpha and epsilon isozymes of protein kinase C. J Neurochem. 2009 Jan;108(2):319-30. Epub 2008 Dec 2 PubMed.

    View all comments by Sam Gandy

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