Liu Y, Yoo MJ, 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 Dec 17;28(51):13805-14. PubMed.

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  1. This is an important and well-conducted study that may shed some light on the mechanisms that underlie the degeneration of the locus ceruleus (LC) in the course of Alzheimer disease (AD).

    LC degeneration is a very early and substantial feature of AD, as evidenced by studies from Grudzien et al., 2007 and many others. Importantly LC degeneration is greater than degeneration of the nucleus basalis Meynert in AD (Zarow et al., 2003). Before the loss of LC neurons, however, one could imagine a period of neuronal dysfunction and thus the starting point, its cause, nor the dynamics of LC degeneration in humans are known. In the present analysis, Liu and colleagues describe the degeneration of axons within LC projection areas at 12 months of age causing a significant 30-40 percent loss of norepinephrine (NE) levels in LC projection areas such as the cortex and hippocampus at 18 months of age. It is important to note that the LC itself is intact at 12 months and shows a 50 percent loss at 18 months of age. Given the massive deposition of β amyloid at this age in the APPswe/PS11d9 transgenic mouse model as well as the toxicity that has been attributed to the β amyloid oligomers and fibrils, it seems rather surprising that axonal and neuronal LC degeneration appears so late. In fact, this may point to the possibility that β amyloid itself is not the direct cause of the observed phenomenon but rather secondary mechanisms such as damage of synapses and axons through inflammatory mediators or excitotoxic stimuli. Furthermore, the tyrosine hydroxylase (TH) staining for LC axons and neurons could have been supported by additional immunostainings, e.g., against dopamine-β hydroxylase, in order to substantiate that induced neuronal loss, but not downregulation of TH itself is being observed.

    Since LC degeneration in AD is observed as early as in clinical pre-AD stages, e.g., in mild cognitive impairment (Grudzien et al., 2005), but is present only in late stages of the APPswe/PS11d9 transgenic mouse model, the authors’ conclusion, that this model recapitulates the progressive degeneration of monoaminergic nuclei in AD, seems a bit far-fetched and hypothetical. Of note, early LC degeneration is accompanied by neurofibrillary changes that have not been found in the present set of experiments. The study, however, nicely describes the fact that it may well be possible that LC neurons die by a retrograde mechanism initiated in its projection area. Given the neuroprotective and anti-inflammatory properties of NE, one can easily imagine how axonal loss, decreased NE, β amyloid deposition and neuroinflammation establish a vicious cycle that contributes to the progression of pathology and the clinical picture of AD.

    References:

    Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging. 2007 Mar;28(3):327-35. PubMed.

    Zarow C, Lyness SA, Mortimer JA, Chui HC. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol. 2003 Mar;60(3):337-41. PubMed.

    View all comments by Michael Heneka

  2. I really appreciate the positive comments regarding our present work on degeneration of monoaminergic neurons in APP/PS1 Tg model. I agree that defining the mechanism(s) by which these neurons degenerate will be important. However, it is also highly important that we finally have a robust system to study this aspect of AD in vivo. I also want to expand on a few of the comments in the overview.
    First, while the "overview" focuses on LC and NA neurons, I want to stress that we observe degeneration of multiple monoaminergic systems. In particular, degeneration of 5-HT system in both Tg model and in AD cases is very significant since this system can modulate memory, emotion, and BDNF signaling. It is possible that the degeneration of 5-HT system, as with the degeneration of LC neurons, contributes to the feed-forward nature of AD pathology.
    Second, given the 40-50 percent loss of fibers and significant neuronal atrophy at 12 months of age, it is likely that neurodegeneration starts well prior to 12 months of age (considered rather late by Michael Heneka). Consistent with this view, the loss of monoaminergic fibers is clearly apparent in the eight-month-old Tg mice, indicating that neurodegeneration starts much earlier than 12 months of age.

    View all comments by Michael K. Lee

  3. It was gratifying to read the paper by Liu et al. [1], at a time when our hypothesis on the possible role of brainstem neurons in Alzheimer disease (AD) pathobiology was posted on the SWAN Alzheimer Knowledge Base (hosted on the Alzheimer Research Forum website). [Editor's note: The SWAN database is under development.]

    In their paper, Liu et al. nicely describe the progressive neurodegeneration of neurons in the locus coeruleus (LC), in a mouse model of AD, and conclude that the LC neurons, which project into the brain regions affected by AD pathology, die by retrograde mechanisms. Abnormalities of LC neurons have been described in other mouse models of AD at early ages, several months before amyloid-β (Aβ) deposits are detected in the regions normally affected by plaque deposition (see [2], for example). As Dr. Heneka pointed out in his comment on the Liu et al. paper, degeneration of LC neurons is detected very early in the human disease too. Surprisingly, this significant degeneration occurs in the absence of Aβ pathology in the subcortical brain regions. Based on observations that degeneration appears to affect first the distal projections of the LC neurons, it was assumed that in AD, degeneration of LC neurons proceeds retrogradely, from the distal parts of the projections towards the cell bodies. The cause for this retrogradely advancing degeneration may not be the cortical Aβ deposits, since in most cases the deposits are largely absent at the time when the degeneration of LC neurons occurs.

    We have recently proposed that the LC neurons may actually play a role in triggering plaque formation by providing small seeds of aggregated Aβ that may accumulate—for a yet unknown reason—at the terminals of their projections, in the cortex [3]. Such accumulations may be small and scarce, and may easily go undetected in the mouse brain. In fact, Liu et al. note that they cannot exclude a possible presence of intracellular Aβ in the monoaminergic neurons, in the mouse model of AD they investigate. In another mouse model of AD (i.e., the PDAPP mouse), dystrophic TH-containing nerve terminals are found in locations that contain neuritic plaques [4]. We have proposed that, rather than being affected by the plaques, these terminals may actually participate in their initiation [3]. We note that our hypothesis does not contradict at all the idea that the LC neurons die by retrograde mechanisms, as suggested by Liu et al., and others. In cell culture, we detect Aβ accumulations at the terminals of CAD cells (a LC-derived neuronal cell line [5]) long before any signs of neurodegeneration can be detected [6]. Thus, it is possible that these neurons die—in the end—due to some pathological events at the terminals of their processes. Our model, which implicates LC neurons in facilitating the initiation of plaque pathology in AD, is in line with a study by Heneka et al. [7], which showed that degeneration of neurons in the LC can indeed promote AD pathology in the APP23 mouse (another model of AD). It appears that the neurons in the brainstem may play a more important role in the pathobiology of AD then previously thought, and the paper by Liu et al. provides further support to this less investigated aspect of AD.

    References:

    Liu Y, Yoo MJ, 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 Dec 17;28(51):13805-14. PubMed.

    Varvel NH, Bhaskar K, Patil AR, Pimplikar SW, Herrup K, Lamb BT. Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease. J Neurosci. 2008 Oct 22;28(43):10786-93. PubMed.

    Muresan Z, Muresan V. Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology. Neurodegener Dis. 2008;5(3-4):250-3. Epub 2008 Mar 6 PubMed.

    German DC, Nelson O, Liang F, Liang CL, Games D. The PDAPP mouse model of Alzheimer's disease: locus coeruleus neuronal shrinkage. J Comp Neurol. 2005 Nov 28;492(4):469-76. PubMed.

    Qi Y, Wang JK, McMillian M, Chikaraishi DM. Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation. J Neurosci. 1997 Feb 15;17(4):1217-25. PubMed.

    Muresan Z, Muresan V. Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. PubMed.

    Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, Sastre M, Galldiks N, Zimmer A, Hoehn M, Heiss WD, Klockgether T, Staufenbiel M. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.

    View all comments by Virgil Muresan

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