Copper Mountain: Can CREB Save Memory?

25 Jan 2010

Called “Alzheimer’s Disease Beyond Aβ,” the Keystone Symposium held 10-15 January 2010 at Copper Mountain, Colorado, was convened to discuss therapeutic approaches to Alzheimer disease besides those that target amyloid-β (Aβ). Organized by Tony Wyss-Coray of Stanford University, California, and JoAnne McLaurin, University of Toronto, Canada, the meeting didn’t truly get away from Aβ, but it did feature novel presentations on alternative approaches to treatment.

Sheena Josselyn, Hospital for Sick Children, Toronto, Canada, raised the prospect of targeting cAMP response element binding protein, or CREB for short, to boost memory. CREB is known to be a key player in the formation of new memories, with early work led by Nobel laureate Eric Kandel, Columbia University, amongst others, showing that knocking out the protein disrupts memory. While in Alcino Silva’s lab at University of California, Los Angeles, Josselyn showed that poor memory in CREB knockout mice is not simply a result of neurodevelopment gone awry. She and colleague Satoshi Kida at Tokyo University of Agriculture, Japan, made a CREB conditional repressor mouse and showed that memory test performance suffered in adult mice even when CREB was suppressed just prior to training in a fear conditioning paradigm (see Kida et al., 2002). At the symposium, Josselyn showed how CREB might be useful to enhance adult memory as well.

Josselyn’s lab uses herpes simplex virus 1 (HSV1) to target CREB expression to specific sites in the mouse brain. In Copper Mountain, she showed that this approach can overcome reduced auditory fear conditioning (achieved by accompanying a tone with a mild foot shock) in CREB-negative mice. This works by injecting the CREB-carrying HSV1 into the amygdala, where the association of the tone and shock is thought to take place. Curiously, though, infection of only 12-15 percent of neurons in the amygdala was sufficient to restore performance in this test, leading Josselyn to wonder if a subset of neurons, specifically those expressing CREB, was adequate to establish the auditory fear memory trace. To test this idea, she looked at expression of the gene for Arc (activity-regulated cytoskeleton-associated protein), which is rapidly but transiently turned on when neurons are activated. She found that after the auditory fear conditioning, neurons that labeled positive for Arc mRNA, i.e., were active, were almost always the same neurons infected with the CREB viral vector, suggesting that neurons with higher levels of CREB preferentially participate in the memory trace.

Because the CREB/Arc connection was correlative, Josselyn tried an alternative approach to probe the link between CREB expression and memory traces. She used diphtheria toxin, which induces apoptosis, to selectively ablate CREB-overexpressing neurons and then looked to see if the memory trace still formed. Because mice do not normally express the diphtheria toxin receptor (DTR), Josselyn’s lab used mice that express a simian DTR gene that is silenced by a stop codon flanked by flox motifs. Into the amygdala of these animals, she injected a vector that carries CREB and cre recombinase genes, the latter excising the floxed stop codon and turning on DTR expression. Josselyn showed that the DTR mice carrying the cre/CREB vector learn better in the contextual fear paradigm, yet giving diphtheria toxin completely reversed this. The work, she said, suggests that cells expressing CREB are preferentially incorporated into memory traces in the brain (see Han et al., 2009).

How does this matter to Alzheimer disease? Josselyn has more recently taken up study of the hippocampus, testing the role of CREB in memory traces induced by training in the Morris water maze that is commonly used to test spatial memory in AD model mice. She showed that spatial memory in CREB-negative animals can be restored by targeting CREB expression to the CA1 regions of the dorsal hippocampus. Together with graduate student Adelaide Yiu, she tested this approach in CRND8 AD mice, which express human APP with Swedish and Indiana mutations. CRND8 mice do poorly in the water maze test and also have low levels of CREB activation in the hippocampus. Yiu found that targeting CREB expression to the hippocampus rescued spatial memory in these mice, but injecting the vector into the dentate gyrus did not. “We think that overexpressing CREB in this region might not rescue the memory deficit because the dentate gyrus likely encodes information in a very sparse manner and increasing CREB using viral vectors may interfere with this sparse encoding,” Josselyn said. The CREB effect may be downstream of Aβ, since the researchers found no difference in plaque load between treated and untreated mice. They did find that the CREB vector restored the number of dendritic spines on both apical and basal dendrites of hippocampal pyramidal neurons. Spinal loss is a key feature of these transgenic mice and probably accounts for their memory loss.

In conclusion, Josselyn noted that CREB is particularly important for memory, and that increasing it might treat memory loss in AD. But she cautioned that CREB is no magic bullet. The same CREB vector injection strategy failed to rescue memory loss associated with ablating calmodulin kinase II, which also results in poor spatial memory in mice.

One “druggable” way to boost CREB activity is to block phosphodiesterase enzymes that degrade the cyclic diester bond in cAMP. This strategy is being pursued by pharmaceutical companies (see ARF related news story). In his presentation, Menelas Pangalos, previously at Wyeth and now at Pfizer after the two companies’ merger last fall, noted that another cyclic nucleotide, cyclic GMP (cGMP), which can stimulate the cAMP/CREB pathway, is also tightly regulated at synapses and can reverse Aβ-induced impairment in long-term potentiation (see Puzzo et al., 2005). LTP is a synaptic strengthening phenomenon that supports formation of new memories. Pangalos noted that cGMP levels are elevated in mice lacking phosphodiesterase 9 (PDE9) and that those animals have a lower threshold for long-term potentiation (LTP), supporting the idea that cGMP helps boost memory. Pfizer developed a selective PDE9 inhibitor, PF 0447943, and is currently recruiting for a Phase 2 clinical trial to test the safety and efficacy of the compound in patients with mild to moderate AD (see ClinicalTrials.gov). In humans, a single acute dose of the inhibitor leads to an increase in cGMP in the CSF, peaking at six hours and then gradually declining, Pangalos reported. Preclinical studies are encouraging. In rodents the compound improves performance in a novel object recognition test, even when the animals are struggling under the influence of scopolamine, which blocks memory. And when given for 30 days via osmotic pump to four-month-old APP transgenic mice, PF 0447943 attenuates synaptic loss.

A related program, pursued initially by Wyeth, centers on selective agonists of the β form of the estrogen receptor (ERβ), which can activate CREB. Pangalos reviewed some of the data supporting the role of estrogens in protecting against AD, including that they promote survival, axon sprouting and repair, LTP, and cognition. Estrogen depletion also exacerbates Aβ pathology in mouse models of AD (see Carroll et al., 2007), suggesting that estrogens may be protective against the disease. To test this hypothesis, Wyeth developed WAY-200070, a selective estrogen receptor modulator, or SERM. Because the compound selectively activates ERβ, which is not expressed in sex organs, it might prove a safer alternative to straight hormone replacement therapy, which has been linked to life-threatening side effects such as cancer (see ARF Live Discussion).

Pangalos and colleagues previously reported that this compound can increase levels of glutamate receptor subunits and post-synaptic density 95 (PSD95), a synaptic marker, in ovariectomized (OVX) mice. The compound also enhanced LTP and improved spatial memory in OVX rats (see ARF related news story). At Copper Mountain, Pangalos reported that WAY-200070 seems to increase the interaction between GluR1 glutamate receptor subunits and stargazin, a protein that helps anchor glutamate receptors to the synapse. How the compound does this is unclear. However, Pangalos also reported that the compound may boost protein translation, since it decreases phosphorylation of eukaryotic initiation factor 2α (Eif2α), which is required to initiate translation. Blocking Eif2a dephosphorylation with the phosphatase inhibitor salubrinal abolished the increases of GluR1 and PSD95 seen when rodents are treated with the ERβ agonist, supporting the idea that WAY-200070 exerts its influence by dephosphorylation of Eif2α, suggested Pangalos. Incidentally, work from Bob Vassar’s lab at Northwestern University, Chicago, suggests that phosphorylation of Eif2α may lead to preferential translation of certain mRNAs, including that of β-secretase (see ARF related news story), which loops the story right back to...yes, the peptide that dared not speak its name at this symposium. By reducing Eif2α phosphorylation, WAY-200070 may not only improve synaptic transmission, but reduce, shall we say, amyloidogenic APP processing.—Tom Fagan.

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References

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Paper Citations

Kida S, Josselyn SA, Peña de Ortiz S, Kogan JH, Chevere I, Masushige S, Silva AJ. CREB required for the stability of new and reactivated fear memories. Nat Neurosci. 2002 Apr;5(4):348-55. PubMed.
Han JH, Kushner SA, Yiu AP, Hsiang HL, Buch T, Waisman A, Bontempi B, Neve RL, Frankland PW, Josselyn SA. Selective erasure of a fear memory. Science. 2009 Mar 13;323(5920):1492-6. PubMed.
Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci. 2005 Jul 20;25(29):6887-97. PubMed.
Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, Laferla FM, Pike CJ. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007 Nov 28;27(48):13357-65. PubMed.

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Copper Mountain: Knight Vision—SIRT1 Aids ADAM10, Slays Aβ

01 Feb 2010

Unseasonably warm days gave way to some notable nights at this year’s Keystone Symposium, Alzheimer’s Disease Beyond Aβ, held 10-15 January at Copper Mountain, Colorado. One evening offering was a short talk from Gizem Donmez, a postdoctoral fellow in Leonard Guarente’s laboratory at MIT. Donmez reported that SIRT1, the histone deacetylase linked to longevity, might protect against AD by boosting ADAM10 (aka α-secretase) and promoting non-amyloidogenic processing of Aβ precursor protein (APP). If true, then you might want to eat more carrots because the effect seems to rely on SIRT1 playing vassal to the retinoic acid receptor.

SIRT1 is activated by caloric restriction, which protects against brain atrophy in primates (see ARF related news story). SIRT1 itself also protects against neurodegeneration in mouse models of AD (see Kim et al., 2007), and previous work from Giulio Pasinetti’s lab at Mount Sinai School of Medicine, New York, suggested that activation of α-secretase may be responsible (see ARF related news story on Qin et al., 2006). Pasinetti and colleagues attributed the increase in α-secretase to SIRT1 inhibition of the Rho kinase ROCK1, previously linked to suppression of the non-amyloidogenic secretase (see ARF related news story). But Donmez’s work suggests that there is more to the tale.

To explore the relationship between SIRT1 and AD, Donmez and colleagues made mice with either the SIRT1 gene knocked out or overexpressed. For knockouts, Donmez used the cre/lox system driven by a nestin promoter, limiting SIRT1 loss to neurons. For overexpression, she knocked the SIRT1 gene into the β actin locus, getting a mild, twofold overexpression. Donmez tested the effects of the SIRT1 mice on Aβ pathology by crossing them with APP/PS1 transgenic animals (APPSwe/PS1ΔE9).

Donmez reported that the APP/PS1/SIRT1 knockouts die earlier than control APP/PS1 animals, and that the knockouts have increased amyloid plaques and gliosis. The increased pathology in these mice was accompanied by a reduction in α-secretase activity. In contrast, APP/PS1 mice overexpressing SIRT1 had reduced levels of Aβ42 compared to controls and increased ADAM10 and ADAM10 mRNA. Levels of Notch intracellular domain, which is produced following α-secretase processing of the transmembrane receptor, were also increased when SIRT1 was overexpressed but not when it was knocked out. The results support the theory that SIRT1 can boost expression of the secretase.

Donmez jousted with the ADAM10 promoter using chromatin immunoprecipitation assays to determine exactly how SIRT1 might exert its influence. She reported that the deacetylase attaches to the promoter very close to a binding site for the retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer. Activation of the ADAM10 gene depended on SIRT1 deacetylase activity (an inactive mutant has no effect) and also the presence of retinoic acid. The evidence suggests that SIRT1 deacetylates RAR leading to increased expression of ADAM10, presumably by allowing RAR to bind more tightly to the promoter. In support of this, Donmez found that RARβ is deacetylated in the presence of SIRT1 and that RARβ acetylation is increased in SIRT1 knockout cells. Coming back full circle, she showed that she was able to reverse the reduced production of Aβ in SIRT1-overexpressing cells by knocking down ADAM10 transcripts with RNA interference.

Donmez concluded that SIRT1 activators might be worth pursuing as potential therapeutics for AD. Resveratrol, a SIRT1 activator found in miniscule quantities in red wine, is widely promoted in the popular press as an elixir of life. It has received serious attention from the scientific community as well, since it has been shown to mimic some of the effects of caloric restriction (see ARF related news story) though other research counters that blocking SIRT1 might actually improve cognition (see ARF related news story). Resveratrol, however, does not cross the blood-brain barrier very efficiently. Amongst all of this, vitamin A, which is metabolized to retinoic acid, might be worth a closer look, too. Recent findings suggest that all-trans retinoic acid can protect APP/PS double transgenic mice against Aβ pathology, reducing levels of the peptide without affecting APP expression (see ARF related news story on Ding et al., 2008), while acitretin, a vitamin A analog, was also shown to upregulate ADAM10 (see Tippmann et al., 2009). Because acitretin crosses the blood-brain barrier and has been approved for treating psoriasis since 1997, it would appear to be a candidate for exploratory clinical or preclinical studies.—Tom Fagan.

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Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169-79. PubMed.
Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Zhao W, Thiyagarajan M, MacGrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H, Pedrini S, Gandy S, Sauve AA, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Aug 4;281(31):21745-54. PubMed.
Ding Y, Qiao A, Wang Z, Goodwin JS, Lee ES, Block ML, Allsbrook M, McDonald MP, Fan GH. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model. J Neurosci. 2008 Nov 5;28(45):11622-34. PubMed.
Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F. Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 Jun;23(6):1643-54. PubMed.

Copper Mountain Brief: Rat-a-tat—New Model Comes a Knockin’

01 Feb 2010

Bigger, smarter, and more amenable than mice to the imaging techniques that are rapidly becoming indispensable in Alzheimer’s research, rats could be a valuable model for studying AD. The major downside of the sagacious creatures is that they are about five times more expensive to maintain than mice, but then again, maybe you get what you pay for. For all the research into mouse models, many still come up short, failing to recapitulate some of the most basic AD pathologies, such as neurofibrillary tangles and neuronal loss. What if you could have it all in one animal?

That could soon be possible, according to Terrence Town, Cedars-Sinai Medical Center, Los Angeles, California. At the recent Keystone Symposium, Alzheimer’s Disease Beyond Aβ, held 10-15 January 2010 at Copper Mountain, Colorado, Town debuted a new rat model at the end of a talk focusing on the role of the innate immune system in AD. The model is the result of collaboration with Robert M. Cohen and Robert Pechnick at the same institution. If the model characteristics Town presented turn out to be true, researchers may be salivating over more than their ratatouille.

The rats express both human APP with the Swedish mutation and human PS1 with the exon 9 deletion, a la David Borchelt’s APP/PS1 mouse (see Savonenko et al., 2005). The transgenes are driven by the hamster prion promoter, as in Karen Hsiao Ashe’s Tg2576 mice (see Hsiao et al., 1996). Town reported that the animals show reduced NeuN staining compared to controls (around 25 percent lower in the hippocampus and a slightly greater loss in the cingulate cortex), suggesting neuronal loss with age. The rats develop plaques that can be detected by FDDNP imaging; importantly, they also develop nearby tangles as seen by immunohistochemistry (using Cp13 and PHF1 antibodies to tau) and ultrastructural electron microscopy. FDDNP imaging discriminates transgenic animals from controls, which opens up the possibility of following pathology longitudinally in individual animals, Town reported. (FDDNP is thought to bind to both plaques and tangles). Caspase 3, a marker of cell death, is also elevated in the APP/PS1 rats compared to controls. Levels of the caspase increase with age, and the protein appears in the vicinity of plaques. Tunel staining of 16- and 27-month-old rat brain tissue suggests progressive cell loss in the cingulate and hippocampus, Town said.

Town believes his may be the first AD rat to have a chance of becoming widely used. He noted that he hopes to make it freely available to academic labs, though companies may have to deal with some red tape and pay a fee. He suggested these rats better mimic human AD pathology than do similar mouse models because the rat tau proteome is more akin to that of humans. For example, humans express six different tau isoforms that differ by the number (three or four) and type of repeat units and by the extent of inserts in the N-terminal of the protein (see Gustke et al., 1994). Whereas mice express a four-repeat tau exclusively in the brain, a recent study suggests that the rat brain boasts the full complement of six isoforms (see Hanes et al., 2009).

The transgenic rats also exhibit gliosis, another hallmark of AD, and interestingly, Town showed confocal microscopy data suggesting that activated microglia (as judged by IBA1 staining) seem to take up both Aβ (seen by ThioS or 4G8 staining) and are filled with tau (Cp13 staining). “This could be a unique form of microgliosis,” suggested Town.

This data all seems fairly hot of the press. Town showed no behavioral results, but in response to questions, he did say that the animals show a significant decline in hippocampal-based learning and memory that kicks in around 15 months of age when plaque deposition is evident. He concluded by suggesting that these animals may present a better platform for preclinical testing than the current crop of transgenic mice.

Other rat models that express human APP, PS1, or both have been produced in the past (see Vercauteren et al., 2004; Folkesson et al., 2007; Agca et al., 2008; Liu et al., 2008; Flood et al., 2009). It is not clear why these models have not been more widely used, but Town told ARF that some of them appear to be short-lived, making them less suitable for AD research, while others lack the extensive pathology. “One of the key features of our AD rat model is that it produces high levels of total Aβ with age (over 100 microgam/wet gram of brain tissue), and it has an almost 1:2 ratio of Aβ1-42:Aβ1-40,” Town told ARF via e-mail. “Perhaps other rat models have not attained the requisite levels/type of Aβ in order to precipitate the full amyloid cascade hypothesis,” he suggested.—Tom Fagan.

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References

Paper Citations

Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer's disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis. 2005 Apr;18(3):602-17. PubMed.
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Gustke N, Trinczek B, Biernat J, Mandelkow EM, Mandelkow E. Domains of tau protein and interactions with microtubules. Biochemistry. 1994 Aug 16;33(32):9511-22. PubMed.
Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M. Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem. 2009 Mar;108(5):1167-76. PubMed.
Vercauteren FG, Clerens S, Roy L, Hamel N, Arckens L, Vandesande F, Alhonen L, Janne J, Szyf M, Cuello AC. Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1. Brain Res Mol Brain Res. 2004 Dec 20;132(2):241-59. PubMed.
Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E. A transgenic rat expressing human APP with the Swedish Alzheimer's disease mutation. Biochem Biophys Res Commun. 2007 Jul 6;358(3):777-82. PubMed.
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Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K. A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis. 2008 Jul;31(1):46-57. PubMed.
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Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs?

03 Feb 2010

Updated 18 February 2010.

3 February 2010. Death and taxes are reputedly inevitable, though death and receptors may be more interesting to Alzforum readers. Both were in season at this month’s Keystone symposium, “Alzheimer’s Disease Beyond Aβ,” held 10-15 January 2010 at Copper Mountain, Colorado. Frank Longo, of Stanford University School of Medicine, California, reviewed evidence for the part the neurotrophin receptor p75 plays in amyloid-β toxicity, arguing that small-molecule p75 ligands may protect against AD. Marc Tessier-Lavigne of Genentech Inc., San Francisco, California, updated the audience on a topic that first made a splash at last year’s Keystone symposium (see ARF related news story). [January 3, 2024, Editor's note: This paper has been RETRACTED.] It is about a neurodegenerative cascade the N-terminal end of the amyloid precursor protein (N-APP) can touch off when it binds to death receptor 6 (DR6), a member of the tumor necrosis factor superfamily. The two stories are related because Tessier-Lavigne’s data suggest that N-APP may bind to p75 as well.

This neurotrophin receptor has been linked to AD for some time. For example, as Longo noted at Copper Mountain, p75, like its close relative DR6, is expressed in brain areas most vulnerable in AD, including the entorhinal cortex, hippocampus, and basal forebrain, and expression is elevated in patients with the disease. The receptor mediates Aβ-induced cell death according to data from Elizabeth Coulson’s group at the University of Queensland, Brisbane, Australia (see Sotthibundhu et al., 2008), and recently Longo and colleagues reported that p75 mediates Aβ-induced neuritic dystrophy, one of the key pathological findings in AD (see Knowles et al., 2009). However, other reports suggest p75 can also be protective in AD (see Bengoechea et al., 2009).

Much of the early work Longo described stemmed from the use of p75 knockout (KO) mice. Rather than having the full gene knocked out, these animals are missing the third exon and hence the majority of the receptor. Primary neurons from these knockouts survive in culture and resist Aβ42, showing less dystrophy when exposed to the peptide than do wild-type neurons. Neuritic dystrophy is milder in offspring from APP transgenic mice (with Swedish and London mutations) crossed with p75 KO mice. Those offspring also have fewer plaques than the parent human APP transgenic strain.

After summarizing some of his lab’s recent findings, Longo outlined a strategy to develop small-molecule p75 ligands to treat AD. The work is being done at Pharmatrophix, a startup company Longo co-founded. The company received initial support from the Alzheimer’s Drug Discovery Foundation (see marketwire story) and has since entered a partnership with Elan.

Longo and colleagues have developed small-molecule ligands that bind to p75, block Aβ-induced neurodegeneration, and prevent some of the downstream cascades associated with Aβ toxicity, such as activation of Cdk5, GSK3β, Jnk, tau phosphorylation, and inhibition of Akt (see Yang et al., 2008). Some of the molecules developed by Pharmatrophix are active in the picomolar range, Longo said, adding that he has begun testing them in both hippocampal slices and in vivo in mouse models of AD.

In cooperation with Mike Shelanski’s lab at Columbia University, New York, Longo found that the compounds can protect against Aβ-induced loss of dendritic spines in hippocampal slices. Together with Ottavio Arrancio, also at Columbia, the researchers found that the p75 ligands rescue LTP deficits in tissue from APP/PS1 mice. Several of these compounds get into the brain, Longo said. Though they do not affect plaques or the levels of Aβ as judged by ELISA, Longo reported that they do reduce neuritic dystrophy. The compounds rescue spine loss in pyramidal neurons, as well as deficits in novel object recognition and contextual fear conditioning exhibited by APP transgenic mice. In normal mice, the compounds also seem to have some benefit, Longo noted, preventing age-related loss of basal forebrain cholinergic neurons and shortening of neurite outgrowth.

Shortening and retraction of axons is also one of the consequences of activating DR6. When Tessier-Lavigne reported last year that N-APP activated the death receptor pathway, his data were limited to embryonic neurons deprived of growth factor support. Though the work introduced a potential new role for APP in neurodevelopment, its relevance to post-embryonic tissues, and to Alzheimer disease (AD) in particular, was unclear. Tessier-Lavigne’s group has since extended those studies to juvenile and adult neurons, and presented some of his newest data at the Copper Mountain conference. At present, the bottom line is that the N-APP/DR6 pathway may regulate synaptic structure and axon growth in adult tissue, but the question of whether it spells doom in the form of dementia remains open.

Using a transcranial window to examine neurons in 60-day-old mice, Tessier-Lavigne and Genentech colleagues Dara Kallop and Robby Weimer found that the density of dendritic spines is higher in DR6 KO animals than in DR6 heterozygotes. A similar phenotype was recently reported in APP knockout (KO) animals compared to APP heterozygotes by Jochen Herms and colleagues (Bittner et al., 2009). The apparent similarity in the phenotypes raises the possibility that N-APP’s activation of DR6 may help regulate synaptic structure and possibly plasticity.

Evidence that the signaling pathway controls axon growth and regeneration comes from both in vitro and in vivo work. Tessier-Lavigne showed that N-APP shortens axons in postnatal sensory and cortical neurons, and that this depends on activating DR6 (again the DR6.1 antibody or DR6 knockout blocked the effect). In these neurons, N-APP turned on caspase 6, which mediates DR6 signaling in embryos, suggesting that the same signaling pathways are at work in developing and developed neurons. To test if DR6 regulates axons in vivo, the scientists turned to an axon lesion paradigm where after transection, some axons regenerate but almost never extend through the lesion site. The scientists found more extensive regeneration in DR6 knockout animals. Six weeks after the injury, the DR6 KO animals had less dying back of axons than did control animals, and some of the regenerating axons actually crossed the lesion scar. Together, this evidence suggests that DR6 modulates axon growth in adult neurons, possibly through activation by APP, Tessier-Lavigne said.

How N-APP/DR6 relate to Alzheimer’s remains up for grabs; certainly there is no direct evidence yet that the death receptor pathway is causal or linked to AD. That said, Tessier-Lavigne cited some observations to support the idea that might be relevant to dementia. As far back as 1989, Greg Cole, then at the University of California, San Diego, with colleagues including the late Tsunao Saitoh, found that antibodies against the N-terminus of APP detected a unique peptide in the brain of AD patients and also a protein of 35 KDa (the size of the N-APP fragment) in soluble fractions from AD brain but not controls (Cole et al., 1989). The same scientists went on to show that antibodies against the APP N-terminus reacted with plaques (Cole et al., 1991). Those findings suggest that N-APP levels may be higher in AD brain. In addition, DR6 expression could help explain why neurodegeneration in AD is limited to specific regions of the brain despite the ubiquitous nature of APP. DR6 is highly expressed in areas where disease pathology is thought to occur earliest, such as the hippocampus and the entorhinal cortex, but sparsely expressed in areas spared in AD, such as the striatum. The gene for DR6 maps to a susceptibility locus for late-onset AD on chromosome 6, and it activates caspase 6, which occurs in plaques and tangles and is elevated in both general aging and in mild cognitive impairment. “It appears that in AD the ligand [N-APP] is there, the receptor is there, and the pathway might be active,” concluded Tessier-Lavigne.

There may also be more to the N-APP story than activation of DR6. Though the binding is less tight, Tessier-Lavigne and colleagues previously reported that N-APP does interact with the neurotrophin receptor p75, another member of the TNF superfamily, and Tessier-Lavigne thought this partnership might be physiologically relevant. He noted that N-APP can induce axon shortening in cerebellar neurons that do not express DR6 but do have p75, and the inhibition is relieved by interfering with p75. “It is possible that DR6 and p75 do a similar job,” he said. Whether Pharmatrophix’s p75 inhibitors might prevent N-APP-dependent neurodegeneration is an open question at this point.—Tom Fagan.

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References

Paper Citations

Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. Retraction Note: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2024 Jan;625(7993):204. PubMed. Retracted Paper.
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Copper Mountain: Fractious Receptors, Glia, and AD Pathology

15 Feb 2010

Circulating monocytes, macrophages, and brain-resident microglia have all been implicated as responders to Alzheimer disease pathology, but exactly how these cells affect disease progression and whether circulating cells can even gain entry into the brain has been controversial. At this year’s Keystone Symposium called Alzheimer’s Disease Beyond Aβ, held January 10-15 at Copper Mountain, Colorado, researchers tried to make sense of the different cells and chemokine signaling pathways that might make the difference between quietly clearing Aβ and setting off a pro-inflammatory cascade that exacerbates pathology (see also related Copper Mountain news). One of the fractious signaling pathways seems to begin with activation of the fractalkine receptor (CX3CR1).

Fractalkine, the ligand, is located on the surface of endothelial cells in the periphery and on neurons in the brain. It is released from these cells after cleavage by ADAM10, or α-secretase (see Hundhausen et al., 2003). CX3CR1 is a chemokine receptor that, in the central nervous system, seems to be exclusively located on microglia (see Harrison et al., 1998). Work from Richard Ransohoff’s lab at the Cleveland Clinic, Ohio, also suggests that this receptor always co-localized with glial markers, such as Iba. At Copper Mountain, Ransohoff reported on some of his studies with fractalkine receptor knockout mice. These animals, engineered at Howard Hughes Investigator Dan Littman’s lab at New York University, appeared to have normal monocyte responses to peritonitis, peripheral antigen challenge, and peripheral nerve injury (see Jung et al., 2000), but Ransohoff wondered if there might be consequences in the brain of deleting CX3CR1.

Ransohoff reported that CX3CR1-/- mice are more susceptible to neurotoxicity after various central nervous system insults (see Cardona et al., 2006). They develop greater neuronal damage when challenged with lipopolysaccharide, which causes an inflammatory immune response. They are more susceptible to Parkinsonism, losing three times more dopaminergic neurons in the substantia nigra brain region when exposed to the mitochondrial toxin MPTP. The loss of fractalkine signaling also exacerbated toxicity in a mouse model of amyotrophic lateral sclerosis. Transgenic mice expressing the G93A human superoxide dismutase 1 lost more spinal cord neurons as one or both fractalkine receptor genes were knocked out. Their muscles also weakened faster. In these scenarios, Ransohoff and colleagues saw minimal recruitment of monocytes from the periphery, suggesting that brain-resident microglia, the only CNS cells that express CX3CR1, are responsible for the effects. Adoptive transfer studies supported this hypothesis. The researchers stereotactically injected the brain of wild-type mice with activated microglia prepared from the brains of heterozygous or homozygous CX3CR1 knockout mice. Thirty six hours after this adoptive transfer, only mice that received the CX3CR1 knockout microglia exhibited signs of neurotoxicity. Overall, the findings suggest that CX3CR1 expression prevents brain microglia from mounting a toxic response.

But does activation of CX3CR1 play a role in Alzheimer disease? This is a separate question, and to address it, Ransohoff, together with Cleveland Clinic colleagues Bruce Lamb, Kiran Bhaskar and students Sungho Lee and Nick Varvel, crossed the fractalkine receptor knockout mice with transgenic animals expressing human APP and presenilin1 and also with mice expressing human tau. In the latter case, the loss of the CX3CR1 receptor seemed detrimental. The researchers found greater tau hyperphosphorylation and more neurofibrillary tangles (as judged by immunohistochemistry) in htau/CX3CR1 KO compared to htau controls. Silver staining also detected more tau aggregates in the receptor knockouts. Why tau is more hyperphosphorylated when CX3CR1 is missing is not yet clear, but Ransohoff reported that p38MAP kinase activity increases in the fractalkine receptor’s absence and that blocking the kinase prevented tau hyperphosphorylation in the crosses. To probe what might energize the kinase, he used a trans-well co-culture system to grow primary cortical neurons and glia in the same medium without having them physically touch each other. With that, he found that CX3CR1-/- glia induce p38MAPK activity in the neurons, suggesting that some soluble factor mediates the response. Ransohoff said his lab is currently trying to figure out what that factor might be. The answer could be important since this particular kinase is linked to AD pathology in multiple ways. It is more active in AD brains compared to controls (see Sheng et al., 2001). It mediates Aβ’s suppression of long-term potentiation, which is crucial for proper learning and memory (see ARF related news story). And the kinase also has a propensity to set off pro-inflammatory cytokines (see Munoz et al., 2007 [add citation]). All of this had led to active pursuit of p38MAPK inhibitors for the potential treatment of AD (for a review, see Munoz and Ammit, 2010).

Ransohoff’s data suggest that microglia with a competent fractalkine response can prevent tau turning toxic. So Ransohoff said he was surprised to find that the receptor seems to have the opposite effect on Aβ. APP/PS1 mice with only one copy of CX3CR1 had fewer plaques compared to APP/PS1 control mice, while CX3CR1-negative transgenic mice had even less. APP processing seems identical in the three different mice, suggesting that the difference between them may lie in Aβ clearance, said Ransohoff. Interestingly, he reported finding fewer microglia surrounding plaques in wild-type mice compared to the chemokine receptor knockouts, which may indicate that CX3CR1 mutant microglia more actively clear plaques, he suggested.

What do the apparently opposing effects of CX3CR1 signaling on Aβ and tau pathology mean for Alzheimer disease? Some clues came from a talk by Joseph El Khoury, Massachusetts General Hospital, Charlestown. El Khoury has tried the same approach crossing APP/PS1 mice with CX3CR1 knockouts, and in support of Ransohoff’s findings, he reported that mice lacking the receptor had less soluble Aβ as detected by ELISA, and reduced Aβ deposition as judged by immunohistochemistry. The APP/PS1/CX3CR1-negative animals also performed significantly better than controls in the Barnes maze test of spatial learning and memory. Interestingly, fewer microglia surround plaques in these crosses.

All told, the data suggest that the role played by the fractalkine receptor in AD may be more complex than in PD and ALS, where it seems wholly protective. While it may protect against tau toxicity htau mice, the chemokine pathway seems to exacerbate plaque pathology (though Ransohoff cautions that both tau and Aβ effects have not been seen in the same mouse model). Why knocking out the receptor and reducing microglia activation, as reported by El Khoury, protects against plaques and improves memory is not clear, but El Khoury thinks it may be related to monocytes that phagocytose Aβ in vivo. He showed a video taken via a two-photon microscope trained on a transcranial window. In the video, GFP-labeled monocytes could be seen hovering around and plucking up Aβ deposits. Whether those monocytes could be persuaded to do the same thing in Alzheimer disease, for example by blocking fractalkine signaling, might be worth exploring.—Tom Fagan.

Part 1 of a two-part series. See Part 2.

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References

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Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen KJ, Rose-John S, Ludwig A. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood. 2003 Aug 15;102(4):1186-95. PubMed.
Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10896-901. PubMed.
Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol. 2000 Jun;20(11):4106-14. PubMed.
Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006 Jul;9(7):917-24. PubMed.
Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, Mrak RE, Griffin WS. Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int. 2001 Nov-Dec;39(5-6):341-8. PubMed.
Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology. 2010 Mar;58(3):561-8. PubMed.

Copper Mountain: Origins and Actions of Glial Cells in AD

15 Feb 2010

There’s more to the brain than neurons. Astrocytes and microglia play crucial roles in the development and maintenance of a healthy brain, and both have been studied for their potential protective and deleterious roles in Alzheimer disease. The field grapples with two fundamental questions: What do these cells do, and where do they come from? At Alzheimer’s Disease Beyond Aβ, this year’s Keystone Symposium held January 10-15 at Copper Mountain, Colorado, presenters tried to answer both. The general impression is that researchers are finally getting some traction in understanding the role of these cells and whether or not peripheral phagocytic monocytes can infiltrate the brain and influence pathological cascades (see part 1.[link to part 1 or first story])

One cell type that has been implicated in neurodegeneration is the astrocyte. Less involved in immune responses than microglia, astrocytes lend important trophic support to neurons and protect them from excitotoxicity (see ARF related news story). But they may also be involved in glial activation, and one of the proteins they release, the calcium-binding protein S100B, appears to be upregulated in AD (see Mrak and Griffinbc, 2001). S100B also surfaces around amyloid plaques in APP transgenic mice (see Sheng et al., 2000). To probe the role of the protein in AD, researchers led by Terrence Town, Cedars Sinai Medical Center, Los Angeles, and Takashi Mori at Saitama University, Kawagoe, Japan, crossed Tg2576 APP transgenic mice with animals that overexpress human S100B. At Copper Mountain, Town reported that at 15 and 19 months of age, the double-transgenic animals have deposited more and larger Aβ plaques in the cingulate cortex, hippocampus, and entorhinal cortex compared to Tg2576 controls. Blood vessels in the double- transgenic animals also contain numerous Aβ deposits ,and the mice have higher levels of soluble Aβ and of C-99, and sAPP-β fragments of APP generated by β-secretase (BACE) cleavage. The researchers confirmed elevated BACE activity when they measured it directly.

In addition to more amyloidogenic processing of APP, microgliosis (judged by Iba1 staining) and astrogliosis (judged by GFAP staining) emerged in the double transgenic mice by 19 months of age. But at 9 months, before the emergence of any Aβ pathology, proinflammatory cytokines, including tumor necrosis factor α, interleukin 1b (IL-1b), IL-6 and even mouse S100B were up. This work just appeared in the February Glia (see Mori et al., 2010). The timing of events, with inflammatory signals going off before Aβ begins to accumulate, suggests that brain inflammatory processes are not simply a consequence of plaques but may even drive cerebral β-amyloidosis, suggested Town.

Town also reviewed some of his recent work on TGF-β signaling, which suggests that blocking this pathway can bias peripheral mononuclear phagocytes toward non-inflammatory responses in AD models. The cells’ inflammatory tendencies are can be appeased by shunting TGFβ signaling away from the downstream transcription factors Smad2 and Smad3, and toward Smads 1, 5, and 8 (see ARF related news story). Together, the TGF-β and the S100B data demonstrate a delicate balance when microglia or macrophages come into contact with Aβ, suggested Town. He believes the balance might be struck to enable Aβ clearance without setting off an inflammatory cascade by blocking TGFβ signaling and is currently searching for small-molecule inhibitors that might be suitable for preclinical work. To this end, he has entered into a partnership with Novartis Inc, and with a medicinal chemistry lab at Yale University, Town told ARF.

Town’s data suggest that dialing down TGF-β signaling in peripheral mononuclear phagocytes may open the door for these cells to enter the brain and scavenge Aβ. The role of peripheral macrophages in the brain remains somewhat controversial, however, and its study has been hampered by technical challenges. For one thing, distinguishing brain-resident microglia from infiltrating circulatory macrophages is quite difficult because, when activated, the former express similar markers to the latter. One technique that has been used to explore the role of myeloid cells in the brain is to ablate myeloid-generating bone marrow by irradiation and then transplant new, traceable cells from another animal. In this way, researchers, including Josef Priller, Charité Universitätsmedizin Berlin, Germany, reported that only circulating monocytes expressing the chemokine receptor CCR2 and high levels of the cell surface marker Ly-6C are able to infiltrate the brain (see ARF related news story and Mildner et al., 2009). But questions remain as to whether circulating monocytes enter the brain because the blood brain barrier gets damaged by irradiation, as some researchers suspect, and whether those infiltrating cells have any impact on AD pathology. At Copper Mountain, Priller had some answers.

Priller has tested how bone marrow-derived cells infiltrate the brain using AD mouse models. He irradiated of APP/PS1 and APP23 transgenic mice, then transplanted bone marrow cells. He reported that four months later, bone marrow-derived cells only infiltrated the brain if the transplant was CCR2-positive. But he also found that the even these cells do not enter the brain if it was shielded from the radiation. In this brain-protected setting, plaque morphology was also different—many more microglia were seen to gather around plaques but the plaque load in both cortices and hippocampus was the same. When the whole body was irradiated, microglia appeared to be more distant from plaques and the total amount of Aβ in the brain was reduced, though there was no change in APP processing. The finding suggests that the whole-body radiation itself may leave the brain susceptible to infiltrating cells, perhaps through damage to the vasculature, and it suggests caution in interpreting results obtained with whole-body irradiation. But another interpretation is that the irradiation acts as a wake-up call, sensitizing the brain to microglia. In this regard, Town wondered if the microglia seemed more distant from plaques after total body irradiation because the plaques were being digested by the cells. “I think there could be something profound going on there. Perhaps the injury from irradiation is providing a secondary stimulus to mobilize plaque-clearing mononuclear phagocytes,” he told ARF.

One way to circumvent radiation damage when measuring infiltration of cells into the brain is to use parabiosis, where animals share each other’s circulatory systems (see ARF related news story). Fabio Rossi and colleagues at the University of British Columbia, Vancouver, conjoined a normal mouse to one with green fluorescent protein (GFP)-expressing bone marrow cells. In this scenario, the researchers found no GFP-labeled cells in normal mouse’s brain, suggesting that circulating monocytes rarely cross the blood-brain barrier (see ARF related news story on Ajami et al., 2007). Joseph El Khoury, and colleagues at Massachusetts General Hospital, Charlestown, have used parabiosis with AD transgenic mice. The researchers hooked up female APP/PS1 mice to mice that have their CX3CR1 gene replaced with GFP. At Copper Mountain, El Khoury reported infiltration of green cells into the brain of 6 month-old APP/PS1 animals. El Khoury is not sure why, but when the researchers tried the same approach with regular CX3CR1/GFP knockins, they saw no infiltration into the brain. “We don’t yet know why that is. Nonetheless, the work shows that bone marrow cells can get into the brain without there being any irradiation damage,” he said. Whether APP/PS1 transgenic mice already have some damage to the vasculature that makes them susceptible to infiltration is unclear, but the fact that the researchers did not see any infiltration in regular CX3CR1 KO mice suggests that there is something specific to the APP/PS1 transgenic mice that facilitates infiltration of circulating cells. What imbues that susceptibility remains to be seen.—Tom Fagan.

Part 2 of a two-part series. See also Part 1.

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References

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Mrak RE, Griffinbc WS. The role of activated astrocytes and of the neurotrophic cytokine S100B in the pathogenesis of Alzheimer's disease. Neurobiol Aging. 2001 Nov-Dec;22(6):915-22. PubMed.
Sheng JG, Mrak RE, Bales KR, Cordell B, Paul SM, Jones RA, Woodward S, Zhou XQ, McGinness JM, Griffin WS. Overexpression of the neuritotrophic cytokine S100beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice. J Neurochem. 2000 Jan;74(1):295-301. PubMed.
Mori T, Koyama N, Arendash GW, Horikoshi-Sakuraba Y, Tan J, Town T. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. Glia. 2010 Feb;58(3):300-14. PubMed.
Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain. 2009 Sep;132(Pt 9):2487-500. PubMed.
Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci. 2007 Dec;10(12):1538-43. PubMed.

Copper Mountain: Can CREB Save Memory?

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Copper Mountain: Knight Vision—SIRT1 Aids ADAM10, Slays Aβ

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Copper Mountain Brief: Rat-a-tat—New Model Comes a Knockin’

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Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs?

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Copper Mountain: Fractious Receptors, Glia, and AD Pathology

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Copper Mountain: Origins and Actions of Glial Cells in AD

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