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

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  1. In this paper, Braak and Del Tredici propose that the Alzheimer’s disease (AD) process may not begin in the cerebral cortex, but rather in the locus ceruleus (LC). This hypothesis is in part based on their recently published data that AD-associated tau pathology regularly occurs in the LC of young adults and children (1).

    Several years ago, we proposed a similar hypothesis stating that the neuropathology of AD may actually begin in subcortical regions of the brain—specifically in the LC—and then spread to the cortex and hippocampus. We communicated our findings at two meetings (Annual Meeting of the Society for Neuroscience, Atlanta, Georgia, 14-18 October 2006, and 8th International Conference on Alzheimer’s Disease/Parkinson’s Disease, Salzburg, Austria, 14-18 March 2007), and in a published paper (2). In a subsequent paper (3), and an AlzSWAN hypothesis (4), both published in 2008, we discussed in much detail our novel hypothesis and its implications for the pathogenic process and the treatment of AD. Unlike Braak and Del Tredici, who developed their hypothesis focusing on tau pathology, we focused on amyloid-β (Aβ) pathology. However, both Braak/Del Tredici and our group reached the conclusion that the production and dissemination of the typical pathogenic species in AD could start in the LC.

    Based on the specific characteristics of LC-derived neurons, we envisioned a model where the pathogenic, oligomeric Aβ species are first produced within the soma of LC neurons in the brainstem, and then accumulate at the terminals of their projections in the cortex and hippocampus. We also proposed that, in a second step, these toxic Aβ species are released from the terminals of the projections of LC neurons in the extracellular space, where they become nucleation sites for the assembly of neuritic plaques, and also exert other detrimental effects on neurons in these AD-vulnerable brain regions. We described this mechanism as “seeding neuritic plaques from the distance” (3,4). As our model envisions for Aβ, the Braak-Del Tredici model assumes that misfolded, abnormally phosphorylated tau appears first in LC neurons, and is then transported along the LC projections, accumulating at their terminals in cortical brain regions. As we proposed for Aβ (2-4), Braak-Del Tredici envision that the misfolded tau is then released into the extracellular space, and serves as seed for abnormal phosphorylation and aggregation of tau present in the cortical neurons. This assumes that the tau aggregates originating in LC neurons are somehow taken up by the local neurons. In terms of mechanism of dissemination of pathogenic aggregates from subcortical to cortical brain regions, the Braak-Del Tredici model and ours are similar.

    Other groups, in particular those represented by the speakers and panelists at the Webinar hosted by Alzforum in December 2010, also published extensively in support of a role of the LC in initiating—in various ways—the AD pathology. Now is the time that the AD scientific community re-examines the role of the LC in the pathogenic mechanisms of AD. In their current paper, Braak and Del Tredici propose that the presently accepted neuropathological stages for AD (5) should be reconsidered to include an initial stage of subcortical pathology. We have no doubt that these efforts will lead to the development of new strategies for treating the LC very early in the disease, thus eliminating the subsequent development of cortico-hippocampal pathology altogether.

    References:
    See also Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. AlzSWAN Knowledge Base. Alzheimer Research Forum. 2008.

    References:

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

    . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.