One of the shortcomings of most mouse models of Alzheimer disease is that they fail to recapitulate the rampant neurodegeneration that is seen in mid- to late stages of the disease in humans. This has led to the idea that in mice at least, Aβ alone is not sufficiently toxic to cause neuron loss—additional factors, such as tau pathology or even beyond tau, may be a co-requisite. In this week’s Journal of Neuroscience, researchers led by Michael Lee at Johns Hopkins University, Baltimore, Maryland, offer a slightly different view. They report that in PS/APP double transgenic mice, there is significant neuron loss—of brainstem monoaminergic neurons, that is, which project into the forebrain from the locus ceruleus (LC). Because LC neurons that do not project to the cortex are unaffected, one explanation is that pathology in the cortex—be it Aβ deposition, inflammation, or some other unknown entity unleashed in this model—leads to degeneration of the brainstem monoaminergic neurons that project into the cortex. The findings suggest that at least some mouse neurons are susceptible to robust and progressive neurodegeneration in the absence of tau pathology.
Loss of monoaminergic neurons—serotonergic neurons in the raphe nuclei and noradrenergic neurons in the LC—has been well documented in AD patients and may even occur early in the disease (see Grudzien et al., 2007). Some LC noradrenergic neurons are also lost in both humans (see Marien et al., 2004) and mice (see Leslie et al., 1985; Sturrock et al., 1985) during normal aging, but whether these neurons are affected in AD mouse models has been more controversial. One study suggests minimal effect on LC neurons in single transgenic (V717F APP) mice (see German et al., 2005), but more recent studies suggest significant loss of tyrosine hydroxylase (TH), a marker of noradrenergic neurons, in the LC of APP/PS1 double transgenic mice (see O’Neil et al., 2007) and even in single transgenic Tg2576 mice by as early as eight months (see Guerin et al., 2007). In showing a temporal loss of both TH and LC cell bodies, this new paper by Lee and colleagues seems to confirm that LC neurons are vulnerable in an AD-like setting.
Lead author Ying Liu and colleagues first examined four- to 18-month-old APP/PS1 transgenic mice for tyrosine hydroxylase. They found that in the cortex and hippocampus there was progressive loss of TH-positive afferent axons. Four-month-old TG mice appeared normal, but in 12-month-old animals there was significant TH loss in the motor and barrel cortices, and in the CA1 and dentate gyri of the hippocampus. The amygdala, which is spared Aβ deposition until much later in these animals, had normal TH levels even in 18-month-old mice. In single APP or single PS1 transgenic animals, the researchers found no loss of TH, even in 18-month-old mice.
To test if frank neuronal loss accompanied this TH loss, the authors used stereomicroscopy to examine neurons in the LC and the dorsal raphe nuclei. In 12-month-old animals the numbers of neurons were similar to those in wild-type animals, but by18 months there was a 50 percent reduction—only in the LC. The results support the idea of a progressive neurodegenerative process that starts in the NA axons that innervate the cortex and hippocampus, and eventually leads to loss of NA neurons in the LC. “The results of the present study demonstrate that the APPswe/PS1ΔE9 mouse model of AD recapitulates the progressive degeneration of MAergic neurons occurring in AD,” write the authors.
“This is an elegant study that clearly shows damage to noradrenergic afferents in the cortex, which is consistent with previous work,” said Doug Feinstein, University of Illinois Chicago, in an interview with ARF. Feinstein was not involved in this work but has studied noradrenergic loss in AD. One thing he questioned is whether the timing accurately mimics what is seen in AD patients, which can have noradrenergic loss very early in the disease (see Grudizen et al., 2007). “One important question is when does loss of, or damage to, these neurons happen?” asked Feinstein. He said that since NA neuron loss has been documented in very mild AD, it suggests that what goes on in these older double transgenic mice, which already have rampant Aβ deposits, could be different. “That, or there could be more subtle damage occurring earlier that they didn’t see,” he suggested.
Michael Heneka, University of Bonn, Germany, agrees. “It’s a bit surprising that the LC degeneration appears so late,” he told ARF (and see also comment below). This raises the possibility that the direct cause of the damage might not be Aβ, but some secondary mechanisms, such as damage of synapses and axons through inflammatory mediators or excitotoxic stimuli, he suggested.
Both Feinstein and Heneka agreed that how and why noradrenergic axons are damaged requires further study. Why do these neurons in particular degenerate, when other cortical and hippocampal neurons are relatively preserved in these transgenic mice despite the abundance of Aβ? Liu and colleagues ruled out the direct involvement of Aβ in the LC by immunostaining for both Aβ deposits (4G8 antibody) and soluble Aβ (Aβ42-specific antibody). Likewise, they found no evidence of phosphorylated tau (AT8 and PHF1 immunoreactivity) within NA cell bodies, suggesting that toxic tau also has no or limited role in noradrenergic loss.
Feinstein said that the LC neurons are notoriously sensitive. Studies have shown that upon injection of the neurotoxin DSP4, the LC NA neurons are damaged or die but other NA neurons are spared. “So there may be selective vulnerability,” he said. The authors agree. “The lack of Ach neuron loss in Tg mice may reflect species difference in cellular vulnerability,” they write. They also propose that axon length may be a factor. “Alternatively, longer cortical afferents on MAergic neurons, compared with the Ach neurons, may increase vulnerability of MAergic neurons to defects in retrograde support,” they write. Feinstein expressed a similar sentiment. He suggested that loss of trophic support due to damage to glia and neurons in the cortex and hippocampus might play a role. “NA afferents can pick up neurotrophic factors, which, if not being produced, could cause damage in other brain regions,” he said.
One other aspect of AD attributable that may be linked to noradrenergic loss is heightened anxiety. Liu and colleagues found that loss of noradrenergic LC neurons precedes increased anxiety in these mice, as judged in an open field test, which lends some support to that hypothesis.—Tom Fagan.
Liu Y, Yoo M-J, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK. Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. 2008, December 17; 28:13805-13814.
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