Focus on the Locus! (Ceruleus, That Is, in Alzheimer’s Disease)
This Webinar recapped the latest research in this area. Michael Heneka of the University of Bonn, Germany, and Doug Feinstein of the University of Illinois, Chicago, gave presentations, and were joined in a panel discussion by Virgil Muresan, New Jersey Medical School, Newark; Murray Raskind, University of Washington, Seattle; Ahmad Salehi, Stanford University School of Medicine, Palo Alto, California; and David Weinshenker, Emory University, Atlanta, Georgia.
With their indispensable role in learning and memory, the hippocampus and cortex have grabbed the lion’s share of attention in Alzheimer’s disease, leaving other brain areas—such as that bluish spot in the brain stem called the locus ceruleus—in relative obscurity. In recent years, though, this hub of noradrenaline-producing neurons has been raising Michael Heneka’s and Douglas Feinstein’s eyebrows, as their data suggest that shortage of this neurotransmitter accelerates AD pathogenesis. In multiple AD mouse strains, damage to the locus ceruleus drives up amyloid pathology and hastens memory loss. Conversely, restoring noradrenaline by way of synthetic precursors can rescue these problems. What causes the locus ceruleus to degenerate in the first place? Does this happen in human AD, too? Might this brain area be a viable target for therapies replenishing noradrenaline and/or noradrenergic cells?
By Esther Landhuis
That there is damage to a cluster of noradrenergic brainstem neurons known as the locus ceruleus (LC) has been recognized for decades as a mark of Alzheimer’s disease (Mann et al., 1980; Bondareff et al., 1982; Haglund et al., 2006). Tau pathology also occurs in LC neurons of people with early AD or mild cognitive impairment (Grudzien et al., 2007), and there is evidence of reduced levels of the noradrenaline transporter as well (see Gulyas et al., 2010). The LC is compromised in transgenic APP mice (see German et al., 2005) and in dogs with spontaneous dementia (Insua et al., 2010). Furthermore, recent work by Zoia Muresan and Virgil Muresan, New Jersey Medical School, Newark, supports the intriguing notion that buildup of intracellular, neuritic Aβ in brainstem neurons could initiate plaque formation in AD (Muresan and Muresan, 2008). However, as reviewed by David Weinshenker, Emory University, Atlanta, Georgia, (Weinshenker, 2008), only in the last few years have researchers begun to make headway investigating how LC degeneration affects AD pathogenesis. Michael Heneka of the University of Bonn, Germany, and Douglas Feinstein of the University of Illinois, Chicago, have been the LC’s most active protagonists for some years, but more scientists are beginning to give heed to this nucleus embedded deep in the base of the brain.
Treating mice with the neurotoxic compound N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4) selectively kills about two-thirds of LC neurons, allowing scientists to study the effects of noradrenaline deficiency in AD models. Feinstein, Heneka, and others have induced LC degeneration in APP23 and H6 (Mucke et al., 2000) strains of transgenic mice overexpressing mutant amyloid precursor protein. Compared to littermates whose LC is intact, DSP4-treated AD mice rack up more brain amyloid and do worse on memory tests (Kalinin et al., 2007; Heneka et al., 2006). More recently, Heneka and colleagues showed that APP/PS1 mice lose their sense of smell in response to DSP4, suggesting that LC degeneration may contribute to the olfactory deficits observed in AD (Rey et al., in press at Neurobiology of Aging). Rats may be less susceptible to DSP4. Researchers led by Murray Raskind at the University of Washington, Seattle, recently reported little loss of noradrenergic neurons in rats treated with the toxin (Szot et al., 2010).
Noradrenaline-deficient AD mice also have worse glial inflammation, which turns out to be a key factor underlying their intensified Aβ pathology. Aβ typically spurs microglia to unleash a slew of harmful cytokines and chemokines, but Heneka’s lab reported earlier this year that noradrenaline supplied by the LC dampens this process, thereby curbing neuroinflammation. In addition, the scientists found that when noradrenaline was scarce, microglia were slower to move toward amyloid plaques and chew them up (Heneka et al., 2010 and ARF related news story). A more recent report helps flesh out this picture by proposing two ways in which noradrenaline helps microglia clear Aβ. Led by Yingying Le, Chinese Academy of Sciences, Shanghai, researchers showed that LC-supplied catecholamine activates glial expression of an Aβ receptor, and helps the phagocytes make more of an Aβ-degrading enzyme (Kong et al., 2010 and ARF related news story). Based on these studies, noradrenaline released from the locus ceruleus seems to work in two ways—it tones down microglial inflammatory responses while also making them better at degrading Aβ.
A growing body of data suggests that boosting the brain’s noradrenaline supply could help fight neurological disease. Feinstein and colleagues used a synthetic noradrenaline precursor (L-threo-3,4-dihydroxyphenylserine, aka L-DOPS or droxidopa) to slow disease progression in a mouse model of multiple sclerosis (Simonini et al., 2010). Similarly, Ahmad Salehi, Veterans Affairs Palo Alto Health Care System, and colleagues at Stanford University, were able to restore contextual memory in APP-overexpressing Down’s syndrome mice (Ts65Dn) even at a stage with considerable neuron loss and behavioral deficits (Salehi et al., 2009 and ARF related news story). And Feinstein’s team has unpublished data suggesting that L-DOPS reduces plaques and inflammation, and seems to provide some cognitive benefit, in 5XFAD-APP/PS1 AD transgenic mice (Oakley et al., 2006).
More recently, Heneka and colleagues have created two new genetic models that require no toxic agent to induce noradrenaline deficiency. For the first model, the scientists crossed APP/PS1 mice with dopamine-β-hydroxylate knockout mice to generate animals devoid of noradrenaline. (This enzyme catalyzes the conversion of dopamine to noradrenaline.) The second strain was made by breeding APP/PS1 mice onto a background lacking Ear2, an orphan nuclear receptor that regulates development of LC neurons. Compared with single mutant mice, both these new double mutant strains have more severe deficits in spatial memory and hippocampal long-term potentiation. Again, L-DOPS rescues some of these defects (unpublished data).
Together, these studies provide a basis for further testing to revive cognition in AD patients by preventing the loss of the locus ceruleus, or somehow restoring its function. What should be done next? A panel discussion explored these issues and more:
- The basis of LC degeneration: Why, when, how does it begin?
- Targeting the LC: Can tissue transplants or viral approaches that stimulate noradrenaline-generating cells provide benefit? What would work in humans?
- How do we differentiate noradrenaline’s effects on glial and neuronal cells?
- Is LC degeneration to blame for the degeneration of cholinergic neurons in the nucleus basalis of Meynert?
I think the locus ceruleus is definitely implicated in Alzheimer’s disease, perhaps in some way mediating synaptic plasticity, which is an early casualty in the Alzheimer’s disease war on the brain.
I had treated a number of mice and rats in the early 1980s with DSP-4, thinking it would be a good candidate for an animal model of AD, but the mice and rats did not exhibit AD pathology such as plaques and tangles, so I did not end up publishing the data.
The animals did become very jumpy, jumping like springs, which I thought was probably a form of myoclonus. Also, many of the animals developed a tumor that had viral-like inclusions on electron microscopic examination; however, we were not sure what to make of the tumors and never did publish the information.