. Reply: the early pathological process in sporadic Alzheimer's disease. Acta Neuropathol. 2013 Oct;126(4):615-8. PubMed.


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  1. We realize that our comment is long overdue, however, we believe it is still relevant. We are extremely gratified to see that the latest data from Braak and Del Tredici, derived from the analysis of uncountable numbers of specimens from Alzheimer’s disease (AD) patients (published in several recent papers [Braak and Del Treci, 2011; Braak and Del Treci, 2011; Braak and Del Treci, 2012; Braak and Del Treci, 2013; Braak and Del Treci, 2013; Braak et al., 2011] and the Advances in Anatomy, Embryology and Cell Biology), confirm a hypothesis we first proposed in 2006 (Muresan and Muresan, 2006): that AD pathology likely begins in the locus coeruleus (LC). Braak and Del Tredici arrived at this conclusion based on tau pathology. We formulated our hypothesis based on Aβ aggregates. Our hypothesis was entirely derived from studies with LC-derived neurons in culture. We identified peculiar features that only these neurons, not cortical or hippocampal neurons, manifested, namely a propensity to spontaneously produce and accumulate Aβ oligomers in the soma, and to transport the Aβ aggregates into cellular processes where they accumulate at axonal terminals and are eventually released into the surrounding space. In the brain, LC terminals end in most regions of the CNS, including those known to be vulnerable to AD pathology (Braak et al., 2011; Muresan and Muresan, 2006; Muresan and Muresan, 2008; Muresan and Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques).

    We stress that this role of the LC neurons in the initiation and propagation of AD pathology differs from ideas advanced earlier by several groups, that a deficiency of noradrenaline in LC neurons would facilitate Aβ pathology in vulnerable brain regions (Heneka et al., 2006; O’Neil et al., 2007). In our view, it is not the lack of noradrenaline that triggers the disease in the hippocampus and cortex, but Aβ oligomers and phosphorylated tau aggregates that first appear in LC neurons (Muresan and Muresan, 2008; Muresan and Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques). The dearth of noradrenaline in LC neurons could result from altered function. There are now numerous indications—not listed here—that the neurons in the LC are among the first to be affected by AD, and that they could provide the initial seeds of "bad" Aβ and “bad” tau required for nucleation—and large-scale spreading—of aggregated forms.

    We think that the AD research community should recognize that the LC could play a much more important role in the etiology of AD than previously thought, and urge more interest and resources for the study of this neglected, but intriguing possibility. As we say in the lab: “If you want to cure AD, aim to treat the LC.”

    Zoia Ladescu Muresan contributed to this comment.

    See also: Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. 


    . Alzheimer's pathogenesis: is there neuron-to-neuron propagation?. Acta Neuropathol. 2011 May;121(5):589-95. PubMed.

    . The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.

    . Where, when, and in what form does sporadic Alzheimer's disease begin?. Curr Opin Neurol. 2012 Dec;25(6):708-14. PubMed.

    . Reply: the early pathological process in sporadic Alzheimer's disease. Acta Neuropathol. 2013 Oct;126(4):615-8. PubMed.

    . Amyloid-β may be released from non-junctional varicosities of axons generated from abnormal tau-containing brainstem nuclei in sporadic Alzheimer's disease: a hypothesis. Acta Neuropathol. 2013 Aug;126(2):303-6. PubMed.

    . Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.

    . 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.

    . 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.

    . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.

    . Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice. J Chem Neuroanat. 2007 Nov;34(3-4):102-7. PubMed.

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