Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.

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  1. The paper by Eisele et al. (1) convincingly shows that minute amounts of Aβ-containing brain extracts injected into the brains of a transgenic mouse expressing APP with Swedish mutation can induce formation of Aβ deposits in many brain regions. Two observations are notable: 1) strong congophilic amyloidosis only develops in regions that normally show extensive Aβ deposition, such as the hippocampus and the entorhinal cortex, indicating that intrinsic conditions within the different brain areas play a role in the development of amyloidosis, and 2) trace amounts of amyloidogenic factors can trigger potent induction of amyloidosis, when in contact with the brain tissue, which is consistent with a seeding mechanism (2). Although the nature of the “seed” in these experiments is not clear, the extracts used for induction contained Aβ monomers and oligomers, the latter being the likely culprits. The true nature of the seeds in the human brain and how they develop at the onset of AD are not known.

    Recently, we proposed that such seeds could be provided by Aβ oligomers that accumulate at the terminals of projections of locus coeruleus neurons (3,4). In culture, CAD cells (a cell line derived from the locus coeruleus) (5,6) occasionally spontaneously develop Aβ accumulations at the terminals of their processes, through mechanisms that remain to be explained (4,7). Importantly, the processes of the locus coeruleus neurons extend throughout the brain, with their terminals reaching the cortex and hippocampus (8). Based on our results obtained with cell culture (7), we hypothesized that Aβ accumulations could form, under AD conditions, within the terminals of the processes of certain brainstem neurons (3,4). One can easily envision mechanisms by which these minute amounts of oligomeric Aβ, present at the terminals of processes, may become extracellular, and induce Aβ deposition as described in the paper by Eisele et al. (1). Although the locus coeruleus neurons project throughout the brain, it is within the lesion prone regions, such as the hippocampus and the cortex, where the neuritic Aβ accumulations trigger the formation of plaques, due to the intrinsic properties of these brain regions, which favor Aβ deposition. The paper by Eisele et al. (1) provides further support for the hypothesis that Aβ deposition in AD could be initiated by seeds of oligomeric Aβ that develop in specific brain regions that are somehow predisposed to amyloidogenesis.

    See also:

    Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum. 2008. Abstract

    Muresan, Z. and V. Muresan, CAD cells are a useful model for studies of APP cell biology and Alzheimer’s disease pathology, including accumulation of Aβ within neurites. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum. 2009. Abstract

    References:

    Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC, Jucker M. Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.

    Harper JD, Lansbury PT. Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem. 1997;66:385-407. 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.

    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.

    Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci. 2005;28:403-50. PubMed.

    View all comments by Virgil Muresan

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