Boosting neurotransmitter signaling to compensate for sagging synapses and neuron loss in Alzheimer disease has met with skepticism, based partly on the notion that you can’t fix what’s gone. However, new work by researchers at Stanford University Medical School, Palo Alto, California, offers a measure of hope to therapeutic approaches that prop up the norepinephrine system, which has thus far languished beneath the travails of the cholinergic pathway, the target of most approved drugs for AD. Using drugs to revive norepinephrine transmission in the brain, the scientists were able to restore contextual memory in a mouse model for Down syndrome at a stage when the mice already had neurodegeneration and behavioral defects. Tampering with failing neurotransmitter circuits in people is tricky, but given the links between Down syndrome and dementia, experts say the new data suggest norepinephrine-based strategies could hold promise in AD. The study appeared online in the November 18 Science Translational Medicine. This interdisciplinary journal was launched last month by the American Association for the Advancement of Science (AAAS), which publishes the journal Science.

Ties between Down syndrome (DS) and AD exist on several levels. Epidemiological studies find a higher incidence of dementia among seniors with DS (56 percent) compared with age-matched adults in the general population (6 percent) (see, e.g., Janicki et al., 2000). Neuropathologically, the brains of middle-aged DS patients look strikingly similar to those of AD patients, filled with amyloid plaques and neurofibrillary tangles and showing neuronal atrophy patterns characteristic of AD (see review, Mann, 1988). And several years ago, first author Ahmad Salehi, who is now at the Veterans Affairs Palo Alto Health Care System, and colleagues showed that basal forebrain cholinergic neurons fizzle in the Ts65Dn Down syndrome model. These mice are trisomic for a chromosome 16 fragment that includes a quarter of some 400 genes triplicated in DS. Amyloid precursor protein (APP) is among the trisomic genes in Ts65Dn animals, and in the earlier study, Salehi’s team blamed the observed cholinergic deficits on disrupted transport of nerve growth factor caused by excess APP (Salehi et al., 2006 and ARF related news story).

In the new work, Salehi and colleagues analyzed the same mice for defects in neurotransmission mediated by a different transmitter, norepinephrine. The hippocampus gets its supply of this neurotransmitter almost exclusively from neurons in a brain stem region called the locus coeruleus (LC). Selectively killing LC neurons intensifies pathogenesis in APP-overexpressing AD mice (Heneka et al., 2006; Kalinin et al., 2006). Furthermore, researchers have reported LC degeneration in people with early AD and even mild cognitive impairment (MCI) (Grudzien et al., 2007), suggesting that norepinephrine deficiency develops early in the course of disease (see also Weinshenker, 2008 review).

Given norepinephrine’s role in helping the hippocampus integrate different types of information, Salehi and colleagues put the mice through two behavioral tests. One used nesting behavior as a readout for hippocampal-based cognition, which is compromised in DS patients. The other used tones and shocks to produce fear-based responses that were measured as episodes of freezing. The fear-conditioning test distinguishes contextual learning, which relies on the hippocampus, from cue-based recall, which depends on the amygdala and stays somewhat intact in DS.

At six months of age, the Ts65Dn mice did fine with cue-based tasks but showed significant disabilities in contextual learning and nesting behavior. “This fit with the function of the locus coeruleus,” said Salehi, noting that contextual learning requires the LC (Murchison et al., 2004). He and coworkers then wondered if they could reverse the learning deficits in the Ts65Dn mice—a prospect they thought unlikely given that the animals already had reduced amounts of norepinephrine and LC degeneration at the time of testing. However, the researchers found that hippocampal neurons, the downstream targets of LC cells, could still respond to norepinephrine, as revealed by their ability to fire when treated with a β1- and β2-adrenergic receptor agonist (isoproterenol). “The machinery was still there,” Salehi said.

This suggested that a norepinephrine boost might actually help the Ts65Dn mice. The researchers injected six-month-old animals subcutaneously with brain-penetrant norepinephrine precursors (L-threo-3,4-dihydroxyphenylserine, aka L-DOPS), along with carbidopa, which inhibits the conversion of L-DOPS to norepinephrine. Because carbidopa does not cross the blood-brain barrier, only the L-DOPS that reaches the brain gets converted to norepinephrine. This combination strategy thereby avoids norepinephrine’s peripheral side effects.

Since norepinephrine concentrations in the brain seemed to max out five hours post-treatment, the researchers did the behavioral tests at this timepoint, and found that L-DOPS/carbidopa restored Ts65Dn deficits in contextual memory and nesting behavior.

Doug Feinstein of the University of Illinois, Chicago, questioned whether the treatment regimen used in the current study would be relevant for AD. “They give one injection and look at behavior five hours later. It’s a single, short-term, acute treatment,” he told ARF. “It does not address the cause of pathology or means to halt or prevent further disease progression.” Salehi agreed that the treatment was acute and its effects short-lived. Indeed, nesting benefits disappeared two weeks after treatment was stopped.

Nonetheless, strategies that boost norepinephrine signaling appear promising in other disease scenarios. Feinstein said he has a paper in press in the Journal of Neuroimmune Pharmacology showing that treatment with L-DOPS and noradrenaline reuptake inhibitors (NARIs) improves symptoms in a mouse model of multiple sclerosis. His lab is also treating APP mice with L-DOPS on a chronic basis, and has seen encouraging results in Morris water maze testing. “Overall I think it has a lot of value,” he said. “It should be tested in AD patients.” In August, Feinstein submitted a proposal to the Alzheimer’s Disease Cooperative Study to test L-DOPS/carbidopa, along with a NARI, in MCI patients.

If the drug shows efficacy, it could enjoy a fast track to approval because prior studies have already shown it is safe. L-DOPS is currently marketed in Japan and southeast Asia under the brand name Droxidopa for neurogenic orthostatic hypotension (a condition marked by norepinephrine deficiency), and is in Phase 3 testing in the U.S.

But increasing norepinephrine as a therapeutic strategy for AD could prove complicated, suggested David Weinshenker of Emory University in Atlanta, Georgia, in an interview with ARF. Though LC neurons die in AD, the survivors try to compensate by shooting out new dendrites and axons (Szot et al., 2006). Thus, even though AD patients have fewer LC neurons, they actually have increased norepinephrine release (Raskind et al., 1984; Raskind et al., 1999). As such, treating AD patients with drugs that enhance norepinephrine transmission has been linked with increased agitation (Peskind et al., 1995), and blocking norepinephrine receptors can reduce these symptoms (Wang et al., 2009). “Increasing norepinephrine could alleviate cognitive problems but at the same time exacerbate some of the behavioral symptoms,” Weinshenker said, noting that the key may be early intervention. “If you could identify people with MCI before they progress to full-blown AD and start developing some of these behavioral abnormalities...maybe you'd get the benefit but not the side effects,” he said.

Salehi agreed that achieving the risk-benefit balance will be tough. “To treat or restore cognition in AD or DS, you need to have a multisystem approach,” he told ARF. This idea came out in the team’s final set of experiments, which explored the genetic basis of the LC degeneration and cognitive dysfunction seen in the DS mice. By analyzing Ts65Dn mice with either two or three copies of APP, they discovered that animals lacking the third copy of APP had intact LC neurons but still did not build nests properly. “This finding suggests that although increased APP gene dose alone can account for the degenerative changes in LC cell body size and number, this is not the case for the defects in contextual learning,” the authors write. “The most plausible conclusion is that other genes combine with APP to affect the degeneration of LC neurons.”—Esther Landhuis.

References:
Salehi A, Faizi M, Colas D, Valletta J, Laguna J, Takimoto-Kimura R, Kleschevnikov A, Wagner SL, Aisen P, Shamloo M, Mobley WC. Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. Abstract

Wiseman FK. Cognitive Enhancement Therapy for a Model of Down Syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ps9. Abstract

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  1. Trisomy Trouble: Neurotrophin Signaling Defective in Down Syndrome

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External Citations

  1. Phase 3 testing

Further Reading

Papers

  1. . Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.
  2. . Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging. 2007 Aug;28(8):1206-14. PubMed.
  3. . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.
  4. . Functional consequences of locus coeruleus degeneration in Alzheimer's disease. Curr Alzheimer Res. 2008 Jun;5(3):342-5. PubMed.
  5. . Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. PubMed.
  6. . Cognitive enhancement therapy for a model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ps9. PubMed.

Primary Papers

  1. . Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. PubMed.
  2. . Cognitive enhancement therapy for a model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ps9. PubMed.