DCP-LA, a New Strategy for Alzheimer's Disease Therapy

Tomoyuki Nishizaki*

Innovative Bioinformation Research Organization, 2-3-14 Katsuragi, Kita-ku, Kobe 651-1223, Japan

Alzheimer’s disease (AD) is characterized by extensive deposition of amyloid β (Aβ) and formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau. So far, a variety of AD drugs targeting Aβ have been developed, but ended in failure. A recent focus on AD therapy, therefore, is development of Tau-targeted drugs. Aβ activates glycogen synthase kinase-3β (GSK-3β), that plays a central role in Tau phosphorylation, responsible for NFT formation. The linoleic acid derivative DCP-LA has been developed as a promising drug for AD therapy. DCP-LA serves as a selective activator of PKCε and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA restrains Tau phosphorylation efficiently due to PKCε-mediated direct inactivation of GSK-3β, to PKCε/Akt-mediated inactivation of GSK-3β, and to receptor tyrosine kinase/insulin receptor substrate 1/phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/Akt-mediated inactivation of GSK-3β in association with PTP1B inhibition. Moreover, DCP-LA ameliorates spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. Consequently, combination of PKCβ activation and PTP1B inhibition must be an innovative strategy for AD therapy.

Accumulating evidence has pointed to the role of amyloid β (Aβ), a main body of amyloid (senile) plaques, and Tau protein, a main body of neurofibrillary tangles (NFTs), in the pathogenesis of Alzheimer’s disease (AD). Huge studies have been done for development of AD drug targeting Aβ, but no expecting drug has been obtained. Recent target, therefore, has been turned to Tau.

Tau is abundantly expressed in neurons of the central nervous system and stabilizes microtubules by interacting with tubulin. Microtubules are the tracks for motor proteins bearing intracellular transport of vesicles, organelles and protein complexes1,2, and Tau modulates microtubule dynamics including axonal transport3-6. Tau is upregulated during neuronal development, to promote generation of cell processes and establish cell polarity7.

When hyperphosphorylated, Tau detaches from the microtubules and forms fibrils in an insoluble form, referred to as paired helical filaments (PHFs), and NFTs comprises aggregation of PHFs8,9. Tau is phosphorylated by a variety of serine/threonine protein kinases such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (Cdk5)/p25, extracellular signal-regulated kinase 2 (ERK2), S6 kinase (S6K), microtubule affinity-regulating kinase (MARK), SAD kinase (SADK), protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII) or Src family kinases such as Fyn and c-Abl (Figure 1)10-14.


Figure 1: Protein kinases relevant to Tau phosphorylation. The proline-directed kinases GSK-3β, Cdk5/p25, ERK2, and S6K and the non-proline-directed kinases MARK, SADK, PKA, and CaMKII phosphorylate Tau at the Ser/Thr residues. The non-receptor tyrosine kinases Fyn and c-Alb phosphorylate Tau at the tyrosine residues.

Tau from the AD brain is phosphorylated at eleven Ser/Thr-Pro and nine Ser/Thr-X sites. Proline-directed kinases such as GSK-3β, Cdk5/p25, ERK2, and S6K phosphorylate Tau at Thr181, Ser202/T205, Thr212/S214, Thr231/Ser235, and Ser396/Ser404 on Ser-Pro or Thr-Pro motifs in the regions flanking the repeat domains10-12. Non-proline-directed kinases such as MARK, SADK, PKA, and CaMKII phosphorylate Tau at Ser262, Ser 320, Ser324, and Ser356 on KXGS motifs in the repeat domains (R1-R4)11,13,14. Fyn and c-Abl, on the other hand, phosphorylate Tau at Tyr-18 and Tyr-39411.

GSK-3β is abundantly expressed in the brain, preferentially in the hippocampus. GSK-3β acts as the main executioner of Tau phosphorylation in PHFs15,16. Intriguingly, GSK-3 accelerates the rate of Tau phosphorylation several-fold, if Tau is pre-phosphorylated by priming kinases such as non-proline-directed kinases17-19. Of Tau phosphorylation sites, Ser396 phosphorylation is a key step in the PHF formation20. Once a priming kinase phosphorylates Tau at Ser404, GSK-3β phosphorylates Tau at Ser400, followed by sequential phosphorylation of Ser396 (Figure 2)20. GSK-3β, alternatively, phosphorylates Tau at Ser202 directly, but Thr231 phosphorylation requires for Ser235 pre-phosphorylation20.


Figure 2: GSK-3β plays a critical role in PHF-Tau phosphorylation. Tau is initially phosphorylated by priming kinases such as non-proline-directed kinases (non-PDK). When GSK-3β activation is enhanced by Aβ, GSK-3β accelerates Tau-Ser396 phosphorylation, responsible for PHFs and NFTs, causing AD.

GSK-3β is originally in the active form. When phosphorylated at Ser9, GSK-3β is inactivated, but when phosphorylated at Tyr216, GSK-3β activation is enhanced21.

Aβ activates the non-receptor tyrosine kinase Fyn, to phosphorylate and activates GSK-3β, leading to somatodendritic accumulation of phosphorylated Tau22. Aβ1-42 phosphorylates GSK-3β at Tyr216 and promotes Tau phosphorylation in PC-12 cells23. Aβ, alternatively, activates GSK-3β by decreasing serine phosphorylation as a result of phosphoinositide 3-kinase (PI3K) inhibition/inactivation24. Chronic exposure of Aβ downregulates Akt phosphorylation, to activate GSK-3β and increase Tau phosphorylation25. Soluble Aβ oligomers inhibit insulin signaling relevant to Akt activation, to activate GSK-3β and increase Tau phosphorylation26. Intracellular Aβ1-42 promotes Tau phosphorylation and induces neuronal loss27. GSK-3β exacerbates Aβ-induced neurotoxicity and cell death28.

Amyloid precursor protein (APP) intracellular domain (AICD), that is produced from γ-secretase-mediated APP cleavage, activates GSK-3β29 or enters the nucleus and activates gene transcription, increasing the GSK-3β mRNA and protein30. C-terminal fragments of APP stimulate GSK-3β activation, to increase Tau phosphorylation and induce apoptosis31.

The serine/threonine protein kinases such as PKCε32, Akt32, PKA33, integrin-linked kinase (ILK)34, Ca2+/calmodulin-dependent protein kinase II (CaMKII)35, p90 ribosomal protein S6 kinase (p90RSK)36, and protein kinase C-related kinase 2 (Prk2)37 inactivate GSK-3β by directly phosphorylating at Ser9 (Figure 3). Pyk238, that binds to SH2 and SH3 domain-containing proteins like Src kinases, and Fyn22 activate GSK-3β by phosphorylating at Tyr216 directly (Figure 3).


Figure 3: Inactivation and activation of GSK-3β.PKCε, Akt, PKA, ILK, CaMKII, p90RSK, and Prk2 phosphorylate GSK-3β at Ser9 and inactivate GSK-3β. Pyk2 and Fyn phosphorylate GSK-3β at Tyr216 and activate GSK-3β.

Akt1 is activated by being phosphorylated at Thr308 and Ser473 through the major pathway along a receptor tyrosine kinase (RTK)/insulin receptor substrate 1 (IRS-1)/PI3K/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt axis32. Then, Akt inactivates GSK-3β by phosphorylating at Ser9 and restrains Tau phosphoryaltion32. In the brain, insulin or insulin-like growth-factor 1(IGF1) binds to and activates the RTK insulin receptor involving GSK-3β inactivation.


Figure 4: RTK-mediated GSK-3β inactivation. Akt is activated through a pathway along a RTK/IRS-1/PI3K/PDK1/Akt axis and inactivate GSK-3β by phosphorylating at Ser9.

AMP-activated protein kinase (AMPK) is also shown to phosphorylate and inactivate GSK-3β39. Aβ1-42 upregulates expression of adenylate kinase-1 (AK1), to inhibit AMPK, thereby leading to GSK-3β activation and Tau phosphorylation40. A contradictory finding is that AMPK by itself phosphorylates Tau at Ser262 and induces tauopathy41. Moreover, a specific agonist of sphingosine-1-phosphate receptor 1 (S1PR1) linked to Gi protein reduces Tau-Ser262 phosphorylation in rat hippocampal slices42. This effect may be caused by AMPKα inactivation due to protein phosphatase 2A (PP2A) activation through a pathway along an S1PR1/Gi protein/(Cdc42/Rac1)/Pak1/PP2A axis.

Aging, inflammation, and stress activate GSK-3β, which triggers Tau phosphorylation, responsible for mild cognitive impairment (MCI), a preliminary group of AD (Figure 5). Aβ further activates GSK-3β and accelerates Tau phosphorylation, leading to progression into AD from MCI (Figure 5)43,44. Aggregation of hyperphosphorylated Tau causes tauopathies, a class of neurodegenerative diseases, that include frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, Pick's disease, and corticobasal degeneration as well as AD. Agents that have the potential to suppress GSK-3β activation, thus, could become beneficial preventive and therapeutic drugs for AD.


Figure 5: GSK-3β is a key factor for MCI and AD. Aging, inflammation, and stress activate GSK-3β and phosphorylate Tau, causing MCI. Aβ enhances GSK-3β activation and accelerates Tau phosphorylation, leading to progression into AD from MCI.

Aβ and Tau serve as an initiator and an executor of AD, respectively45. Current AD therapeutic approaches focus upon targeting Tau pathologies. A variety of Tau-targeting drugs have been developed as follows: i) Hsp90 inhibitors such as geldanamycin, radicicol, and 17AAG, that degrade and dispose of hyperphosphorylated Tau46, ii) Inhibitors of Aβ-induced Tau phosphorylation such as kamikihito, DHA, and curcumin47,48, iii) Tau aggregation inhibitors such as methylthioninium chloride and leucomethylthioninium, iv) O-GlcNAcase inhibitors49. Tau is subjected to O-GlcNAc transferase-mediated O-GlcNAcylation at the Ser/Thr residues, that is the same sites as phosphorylation, and O-GlcNAcase neutralizes Tau O-GlcNAcylation. O-GlcNAcase inhibitors, therefore, promote Tau O-GlcNAcylation, thereby preventing Tau phosphorylation and aggregation50, v) GSK-3β inhibitors such as pyrazine, the flavonoid morin, MMBO, the thiadiazolidinone derivative NP-12, and the traditional Chinese herbal medicine Angelica sinensis51-55, vi) mTOR inhibitors56,57. Aβ activates mTOR, followed by activation of S6K, that phosphorylates Tau at Ser262, Ser214, and Thr21212. mTOR inhibitors, therefore, could prevent Tau phosphorylation, vii) Inhibitors of Tau fibrillization such as phenothiazine, the cyanine dye N744, polyphenol, porphyrin, anthracyclines, phenylthiazolyl-hydrazide, rhodanine, and aminothienopyridazine58,59, and viii) microtubule stabilizing agents including natural products such as taxanes, epothilones, discodermolide, dictyostatin, eleutherobin, sarcodyctins, laulimalide, peloruside A, cyclostreptin, taccalonolides, zampanolide, dactylolide, ceratamines, dicumarol, jatrophanes, tubercidin, lutein, and davunetide, and synthetic agents such as GS-164, estradiol analogues, 5HPP-33, triazolopyrimidines, phenylpyrimidines, pyridopyridazines, pyridotriazines, and pyridazines60-62. Successful results in the AD therapy, however, have not been obtained with any drugs as yet.

Several lines of evidence have pointed to the role of cis-unsaturated free fatty acids (uFFAs) such as arachidonic, linoleic, linolenic, oleic, and docosahexaenoic acid in cognitive functions63-71. Then, one would think that uFFAs might be available as an anti-dementia drug. uFFAs, however, are promptly metabolized and decomposed before arriving in the brain, even though orally or intravenously taken into the body. To address this issue, we have synthesized the linoleic acid derivative DCP-LA with cyclopropane rings instead of cis-double bonds, that exhibits stable bioactivities (Figure 6 A,B)72.

DCP-LA induces a long-lasting facilitation of hippocampal synaptic transmission by enhancing presynaptic α7 ACh receptor responses to stimulate glutamate release under the control of PKCε72-75. In addition, DCP-LA activates CaMKII due to inhibition of protein phosphatase 1 (PP1), to enhance postsynaptic AMPA receptor responses and facilitate hippocampal synaptic transmission76.

The facilitatory action of DCP-LA on hippocampal synaptic transmission accounts for improvement of Aβ,sub>1-40

- and mutant Aβ-induced spatial learning deficits in rats77,78, scopolamine-induced spatial learning and memory disorders in rats77, spatial learning and memory deterioration in senescence accelerated mice 8 (SAMP8)79,80, and spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD32.


PKC is classified into the conventional PKC isozymes α, βI, βII, and γ, the novel PKC isozymes δ, ε, η, and θ, the atypical PKC isozymes α/&gamm a; and ζ, and the PKC-like isozymes μ and ν. All the PKCs have the phosphatidylserine (PS) binding site and are activated by diacylglycerol (DG). Much interestingly, DCP-LA is capable of selectively activating PKCε in a Ca2+- and DG-independent manner81. DCP-LA binds to the PS binding/associating sites Arg50 and Ile89 in the C2-like domain of PKCε, which are distinct from the DG binding site in the C1 domain, at the carboxyl-terminal end and the cyclopropane rings, respectively82.

Racemic DCP-LA contains possible 4 diastereomers such as α,-, α,β-, β,α-, and β,-DCP-LA (Figure 6C). To develop DCP-LA as a medical drug, each diastereomer was separated and each characteristic was examined. Of 4 diastereomers α,β-DCP-LA activates PKCε selectively and stimulates presynaptic release of glutamate, dopamine, and serotonin, with the highest potency83.Of great interest is that DCP-PA serves as not only a selective PKCε activator but a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA inhibits PTP1B by its direct interaction84.


Figure 6: Structure of DCP-LA. DCP-LA has cyclopropane rings instead of cis-double bonds on linoleic acid (A,B). Racemic DCP-LA contains possible 4 diastereomers such as α,-, α,β-, β,α-, and β,β-DCP-LA (C).

PKCε, activated by DCP-LA, inactivates GSK-3β by directly phosphorylating at Ser9 (Figure 6)32. Activated PKCε, alternatively, activates Akt by directly phosphorylating at the serine residue, followed by inactivation of GSK-3β (Figure 6)32.

When activated, RTK phosphorylates its own receptor at Tyr1185 and activates IRS-1 by phosphorylating at Tyr1222. Activated IRS-1 recruits and activates PI3K, which produces phosphatidylinositol 3,4,5-triphosphate (PIP3) by phosphorylating phosphatidylinositol 4,5-bisphosphate (PIP2). PIP3 binds to and activates PDK1. PI3K and/or PDK1 activate Akt by phosphorylating at the serine and threonine residues. RTK and IRS-1 are inactivated through PTP1B-mediated tyrosine dephosphorylation. DCP-LA-induced PTP1B inhibition, therefore, represses inactivation of RTK and IRS-1, allowing Akt activation through a RTK/IRS-1/PI3K/PDK1/Akt pathway, to phosphorylate and inactivate GSK-3β (Figure 6)32.

PKCε activation or PTP1B inhibition, thus, has the potential to restrain Tau phosphorylation by inactivating GSK-3β each independently. Cooperation of PKCε activation and PTP1B inhibition, however, could inactivate GSK-3β and restrain Tau phosphorylation more efficiently than each solitary treatment32. In experiments using PC-12 cells, PKCε overexpression and PTP1B deficiency activate Akt and inactivate GSK-3β synergistically32. Aβ1-42 activates GSK-3β by reducing Ser9 phosphorylation and increases Tau phosphorylation at Ser202/Thr205 and Ser396, and the effects of Aβ1-42 are clearly neutralized by DCP-LA32.

5xFAD mice are widely used as an animal model of AD. 5xFAD mice are APP/presenilin 1 (PS1) double transgenic mice that coexpress five familial forms of AD mutations such as the Swedish/London/Florida mutations and the M146L/L286V mutations85. The Aβ1-42 levels in the 5xFAD mouse brain is shown to increase in an age-dependent manner and spatial memory deficits are found from 4-5 months of age85. The significantly higher levels of GSK-3β-Ser9 phosphorylation is also found in the hippocampus of 5xFAD mice from 4-5 months of age as compared with the levels for wild-type control mice, indicating that the GSK-3β activity is enhanced in 5xFAD mice, possibly in association with Aβ1-42 increase86. Moreover, a greater deal of Tau-Ser396 phosphorylation, responsible for PHF formation, is found in the hippocampus of 5xFAD mice86. DCP-LA suppresses GSK-3β activation and reduces Tau-Ser396 phosphorylation in the hippocampus of 5xFAD mice to an extent similar to that for wild-type control mice32. DCP-LA, thus, enables efficient suppression of Tau-Ser396 hyperphosphorylation by activating PKCε and inhibiting PTP1B simultaneously.

DCP-LA ameliorates spatial learning and memory decline in 5xFAD mice, that occurs in parallel with GSK-β activation and an increase in Tau phosphorylation, but such effect is not obtained with galanthamine, that is clinically used for treatment of mild to moderate AD32. In addition, DCP-LA improves Aβ1-40- and mutant Aβ-induced spatial learning deficits in rats77,78, scopolamine-induced spatial learning and memory disorders in rats77, spatial learning and memory deterioration in senescence accelerated mice79,80. DCP-LA-induced improvement of cognitive decline is not due to only inhibition of GSK-β and restraint of Tau phosphorylation. Facilitation of synaptic transmission in alive neurons would be required for improvement of cognitive decline. DCP-LA has the potential to facilitate hippocampal synaptic transmission by enhancing presynaptic α7 ACh receptor responses under the control of PKCε72-75 and postsynaptic AMPA receptor responses under the control of CaMKII in association with PP1 inhibition76. This action of DCP-LA is also a strong advantage as an AD therapeutic drug as compared with Tau-targeted drugs including GSK-β inhibitors. Tau-targeted drugs proposed possess no direct facilitatory action on synaptic transmission, and therefore, early improvement of cognitive decline would not be expected by those drugs.

A beneficial effect on 5xFAD mice is obtained with oral administration of DCP-LA at a dose of 1 mg/kg body weight, corresponding to ~3 μM. This dose, in the light of the fact that the optimal concentration of DCP-LA in the in vitro experiments is 100 nM, seems to be appropriate and possible for clinical use. Overall, DCP-LA may shed a beam of hope on AD prevention and treatment.


Figure 7: DCP-LA-induced suppression of Tau phosphorylation. PKCε, activated by DCP-LA, inactivates GSK-3β by phosphorylating Ser9 directly or through a PKCε/Akt pathway, to restrain Tau phosphorylation (pTau). DCP-LA-induced PTP1B inhibition, alternatively, activates Akt through a RTK/IRS-1/PI3K/PDK1/Akt pathway by repressing tyrosine dephosphorylation of RTK and IRS-1, followed by Ser9 phosphorylation and inactivation of GSK-3β, to restrain Tau phosphorylation.

Tau-targeted drugs for AD therapy under development include i) Hsp90 inhibitors, ii) inhibitors of Aβ-induced Tau phosphorylation, iii) Tau aggregation inhibitors, iv) O-GlcNAcase inhibitors, v) GSK-3β inhibitors, vi) mTOR inhibitors, vii) inhibitors of Tau fibrillization, and viii) microtubule stabilizing agents. The mechanism underlying the inhibitory effect of DCP-LA on Tau phosphorylation is distinct from that for any drugs provided until now. DCP-LA restrains Tau phosphorylation efficiently due to PKCε-mediated direct inactivation of GSK-3β, to PKCβ/Akt-mediated inactivation of GSK-3β, and to RTK/IRS-1/PI3K/PDK1/Akt-mediated inactivation of GSK-3β in association with PTP1B inhibition. Consequently, combination of PKCε activation and PTP1B inhibition must be an innovative strategy for AD therapy.

The author declares no conflict of interests.

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Article Info

  • Journal of Neurology & Neuromedicine
  • Article Type : Mini Review
  • View/Download pdf
  • DOI : 10.29245/2572.942X/2017/9.1159

Article Notes

  • Published on: October 12, 2017


  • DCP-LA

  • Protein tyrosine phosphatase 1B
  • Akt
  • GSK-3
  • Tau
  • Alzheimer's disease


 Dr. Tomoyuki Nishizaki
Innovative Bioinformation Research Organization 2-3-14 Katsuragi, Kita-ku, Kobe 651-1223, Japan
Email: tnishizaki@bioresorganazation.com
Copyright: ©2017 Nishizaki T. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Citation: Nishizaki T. DCP-LA, a New Strategy for Alzheimer’s Disease Therapy. J Neurol Neuromed (2017) 2(9): 1-8