Enhancing Old Memory Pathways Through New Tricks

Whenever scientists start looking at ways to maintain memory, some of the same names keep cropping up. Cyclic AMP-response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) are two of the perennial stars of the memory game. What’s not clear, however, is how to adapt their roles into a therapy for Alzheimer’s patients. A paper in the December 13 PNAS suggests a new approach. Researchers led by Salvatore Oddo at the University of Texas in San Antonio found that plying Alzheimer’s disease model mice with CREB binding protein (CBP) rescued learning in these mice without altering Aβ or tau levels. Whether this strategy will work in people no one knows, but the new data keep the spotlight firmly planted on the CREB pathway and on the potential of viral gene delivery.

CREB is a transcription factor that affects many genes, among them the neurotrophic factor BDNF. Researchers have uncovered several ways to modulate CREB signaling and thereby improve memory, for example, by activating the CREB-regulated transcription coactivator 1 (CRTC1), or with the sirtuin SIRT1 (see ARF related news story on España et al., 2010 and Gao et al., 2010). Direct application of BDNF has also shown promise in restoring learning and memory in animal models (e.g., see ARF related news story on Blurton-Jones et al., 2009 and ARF related news story on Nagahara et al., 2009).

To explore the alteration of the CREB pathway in AD, first author Antonella Caccamo used 3xTgAD mice at six months old, an age when they show early learning problems. She trained the mice four times per day for either three or five days in the Morris water maze, then sacrificed them within 30 minutes of the last training session and snap-froze the brains to capture the immediate transcriptional changes due to learning. Normal mice boasted twice as much phosphorylated (i.e., activated) CREB as did transgenic mice at baseline and after training, which quadrupled pCREB levels in all animals. Caccamo and colleagues used several methods to show that this difference was due to Aβ. Injection of Aβ oligomers lowered pCREB still further, while injection of antibodies to Aβ increased pCREB in the AD mice. The authors also used a genetic approach, replacing the mutant PS1 gene in the 3xTg mice with its wild-type counterpart, which has been shown to abolish Aβ accumulation. Mice tinkered with in this way showed no Aβ deposits, and higher levels of pCREB.

To treat these mice, Caccamo and colleagues focused on CBP, because it is an essential coactivator that helps recruit transcriptional machinery to CREB. Caccamo and colleagues injected a lentivirus carrying the CBP gene into the lateral ventricle, from where the virus diffused into the hippocampus. In this manner, overexpression of CBP restored CREB phosphorylation in the hippocampus and rescued learning and memory in treated animals, but did not alter Aβ or tau levels. Not surprisingly, BDNF levels were also low in 3xTg mice, but restored in the hippocampus in treated mice. The authors also found evidence that higher BDNF levels potentiated signaling through NMDA-type glutamate receptors, which can further phosphorylate CREB, possibly creating a positive feed-forward loop.

The paper “reinforces the importance of CREB signaling in models of AD,” said Michael Shelanski of Columbia University Medical Center in New York City. “It’s important because it shows a different approach to increasing the activity of CREB.” Since we don’t yet know what way will work, Shelanski said, “the more we know about this pathway, the better.”

The use of a viral system to deliver therapeutic agents is a promising approach, said Philippe Marambaud at the Albert Einstein College of Medicine in Manhasset, New York. For human therapy, using an adeno-associated virus (AAV) is more appropriate than a lentivirus, Marambaud said, because the viral integration is better characterized and it is expected to have fewer side effects. Several current clinical trials in Parkinson’s patients are using AAVs to deliver various factors (e.g., neurturin, glutamic acid decarboxylase, and human aromatic L-amino acid decarboxylase). This type of system allows the delivery of large proteins that could not normally get into the brain.

The question in AD is what factor to deliver. CBP is a candidate, Marambaud said, but there are some contradictory data on whether CBP is protective or detrimental in AD (for example see Marambaud et al., 2003). Marambaud pointed out another potential problem with CBP: It is involved in several other transcriptional pathways, including some that can cause cancer. For these reasons, it might make more sense to go downstream of CBP and simply deliver BDNF through a viral vector, Marambaud suggested. This approach has shown some success in primates (see ARF related news story).

Shelanski points out, however, that most mouse models in these studies represent early stages of AD. In these animals, restoring CREB activity reverses harmful dendritic changes. “We have no idea whether that would happen in the human. By the time we make a diagnosis of AD, it may be too late to restore the synaptic activity.” If Alzheimer’s disease could be diagnosed at much earlier stages, Shelanski said, such interventions might have much greater potential to restore memory. A variety of new imaging and fluid biomarker analyses are helping to push diagnosis earlier (e.g., see ARF related news story; ARF Live Discussion from 2008; and ARF story on the Alzheimer’s Disease Neuroimaging Initiative).—Madolyn Bowman Rogers

Comments

  1. This is an interesting study that provides evidence that Aβ-induced memory deficits in 3xTg-AD transgenic mice are mediated through deregulation of the transcription factor CREB. The authors show reduced levels of phosphorylated CREB, a required step for CREB activation, in 3xTg-AD mice after a spatial learning task. Indeed, a role of CREB dysfunction on Aβ-induced memory deficits has been previously reported in other AD mouse models (Gong et al., 2004; España et al., 2010). Changes in CREB transcriptional activity induced by Aβ accumulation have been associated with memory deficits in APP transgenic mice (España et al., 2010), whereas pharmacological activation of PKA/CREB using rolipram reverses neuronal plasticity changes (Vitolo et al., 2002) and associative and spatial memory impairments in AD mouse models (Gong et al., 2004; Comery et al., 2005; Cheng et al., 2010). An intriguing question not elucidated in the present study is how a decrease of CREB phosphorylation causes learning deficits in 3xTg-AD mice. It is well established that training in spatial memory tasks induces expression of specific CREB target genes (Guzowski et al., 2001), and CREB is essential for long-lasting synaptic plasticity and memory but not for learning and short-term memory in both vertebrates and invertebrates (Bourtchuladze et al., 1994). In my view, the novelty of the present study is the finding that expression of the CREB coactivator CBP recovers the learning and memory deficits in 3xTg-AD mice, which suggests that Aβ impairs memory through CREB/CBP-dependent transcription. In support of this, expression of CBP enhances CREB phosphorylation and expression of the neurotrophic factor BDNF, a downstream CREB target gene involved in synaptic plasticity.

    Further experiments will be necessary to discern the specific CREB/CBP target genes mediating memory loss in 3xTg-AD mice, and whether the beneficial effects of CBP on memory in AD models are due to its CREB co-transcriptional activity or histone acetyltransferase (HAT) activity. This is an important point, since previous studies indicated that both of these CBP activities are involved in long-term memory (Alarcon et al., 2004; Korzus et al., 2004), and histone deacetylase inhibitors ameliorates synapse loss and memory deficits in AD mouse models (Green et al., 2008; Kilgore et al., 2010; Ricobaraza et al., 2010). In summary, these new findings further support the therapeutic potential of activating CREB signaling for memory enhancement in AD.

    References:

    Alarcón JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 2004 Jun 24;42(6):947-59. PubMed.

    Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994 Oct 7;79(1):59-68. PubMed.

    Cheng YF, Wang C, Lin HB, Li YF, Huang Y, Xu JP, Zhang HT. Inhibition of phosphodiesterase-4 reverses memory deficits produced by Aβ25-35 or Aβ1-40 peptide in rats. Psychopharmacology (Berl). 2010 Oct;212(2):181-91. PubMed.

    Comery TA, Martone RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, Marquis KL. Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2005 Sep 28;25(39):8898-902. PubMed.

    España J, Valero J, Miñano-Molina AJ, Masgrau R, Martín E, Guardia-Laguarta C, Lleó A, Giménez-Llort L, Rodríguez-Alvarez J, Saura CA. beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci. 2010 Jul 14;30(28):9402-10. PubMed.

    Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.

    Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008 Nov 5;28(45):11500-10. PubMed.

    Guzowski JF, Setlow B, Wagner EK, McGaugh JL. Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of the immediate-early genes Arc, c-fos, and zif268. J Neurosci. 2001 Jul 15;21(14):5089-98. PubMed.

    Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G. Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2010 Mar;35(4):870-80. PubMed.

    Korzus E, Rosenfeld MG, Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron. 2004 Jun 24;42(6):961-72. PubMed.

    Ricobaraza A, Cuadrado-Tejedor M, Marco S, Pérez-Otaño I, García-Osta A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2010 Nov 10; PubMed.

    Vitolo OV, Sant'Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13217-21. PubMed.

    View all comments by Carlos Saura

  2. There may be easier and safer ways to increase brain-derived growth factor. For example, eugenol (and probably a number of other phenols) increases levels of brain-derived neurotrophic factor in mice (Irie et al., 2004). Moreover, eugenol and other phenolic compounds (such as rosmarinic acid) protect against Aβ-induced memory deficits in mice (Alkam et al., 2007) and help prevent cell death caused by peroxynitrites (Chericoni et al., 2005, Irie 2006).

    Eugenol can be found in a number of essential oils, including clove, true cinnamon, rosemary, and sage essential oils. One study suggested that eugenol may be a good medicine for Alzheimer's disease (Irie, 2006). A clinical trial using rosemary, lavender, lemon, and orange essential oils found "significant improvement in personal orientation related to cognitive function" in all patients with dementia who participated in the study, including patients with Alzheimer's disease. The conclusion from this clinical trial is that aromatherapy "is an efficacious non-pharmacological treatment for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients (Jimbo et al. 2010)." Although this was a very small trial of only 28 patients, lasting only 56 days, it could be that the answer to Alzheimer's disease is lying right under our noses if we care to look.

    References:

    Irie Y, Itokazu N, Anjiki N, Ishige A, Watanabe K, Keung WM. Eugenol exhibits antidepressant-like activity in mice and induces expression of metallothionein-III in the hippocampus. Brain Res. 2004 Jun 18;1011(2):243-6. PubMed.

    Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35). Behav Brain Res. 2007 Jun 18;180(2):139-45. PubMed.

    Chericoni S, Prieto JM, Iacopini P, Cioni P, Morelli I. In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes. J Agric Food Chem. 2005 Jun 15;53(12):4762-5. PubMed.

    Irie Y. Effects of eugenol on the Central Nervous System: Its possible application to treatment of Alzheimer's disease, depression, and Parkinson's disease. Curr Bioact Comp 2006;2(1):57-66.

    Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K. Effect of aromatherapy on patients with Alzheimer's disease. Psychogeriatrics. 2009 Dec;9(4):173-9. PubMed.

    View all comments by Lane Simonian

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References

News Citations

  1. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF
  2. Support Cast: Neural Stem Cell BDNF Prompts Memory in AD Mice
  3. BDNF the Next AD Gene Therapy?
  4. Toronto: Human Amyloid Imaging Conference Showcases a Maturing Field

Webinar Citations

  1. Early Detection of Alzheimer Disease—A Virtual Town Hall Meeting

Paper Citations

  1. España J, Valero J, Miñano-Molina AJ, Masgrau R, Martín E, Guardia-Laguarta C, Lleó A, Giménez-Llort L, Rodríguez-Alvarez J, Saura CA. beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. J Neurosci. 2010 Jul 14;30(28):9402-10. PubMed.
  2. Gao J, Wang WY, Mao YW, Gräff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010 Aug 26;466(7310):1105-9. PubMed.
  3. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, Laferla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9. PubMed.
  4. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009 Mar;15(3):331-7. PubMed.
  5. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003 Sep 5;114(5):635-45. PubMed.

Other Citations

  1. 3xTgAD mice

External Citations

  1. neurturin
  2. glutamic acid decarboxylase
  3. human aromatic L-amino acid decarboxylase

Further Reading

Primary Papers

  1. Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S. CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22687-92. PubMed.

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