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. 2010:2010:747892.
doi: 10.1155/2010/747892. Epub 2010 Jun 23.

Neuroinvasion in prion diseases: the roles of ascending neural infection and blood dissemination

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Neuroinvasion in prion diseases: the roles of ascending neural infection and blood dissemination

Sílvia Sisó et al. Interdiscip Perspect Infect Dis. 2010.

Abstract

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system.

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Figures

Figure 1
Figure 1
Schematic representation of the most generally accepted hypothesis of the routes of neuroinvasion in TSEs. Permission was obtained for reproducing this figure originally published in [22]. DRG, dorsal root ganglia; NG, nodose ganglion; CMGC, celiac and mesenteric ganglion complex; GI tract, gastrointestinal tract.
Figure 2
Figure 2
Diagrammatic representation of the possible pathways of absorption of TSE agents from the gut lumen and their transport to the ENS. Permission was obtained for reproducing this figure originally published in [26].
Figure 3
Figure 3
Scrapie infection in lymphoreticular tissues in ARQ/ARQ Suffolk sheep. (a) PrPd accumulation is associated with both FDC and macrophages in clinically affected sheep as shown by single IHC for PrP antibody R145. Peyer's patches of the distal ileum. (b) PrPd within TBMs is N terminally truncated whereas PrPd associated with FDC is not [52]. TBM and FDC can be distinguished in tissue sections by using N or C terminal PrP antibodies. FDCs (brown), labelled by the N terminal antibody FH11, are in light zone whereas TBMs (purple), labelled by the C terminal antibody R145, are both in dark and light zones of secondary lymphoid follicles: double IHC for FH11 (brown, DAB substrate) and R145 (purple, VIP substrate). In spleen, nerve endings located in the marginal zone ((c), IHC for PgP9.5) do not colocalised with PrPd deposition ((d), IHC for R145). (a)–(d) x20.
Figure 4
Figure 4
Pathogenesis of sheep scrapie. Permission was obtained for reproducing this figure originally published in [53]. For abbreviations see text.
Figure 5
Figure 5
Magnitude of PrPd accumulation in LRS tissues of sheep as part of the blood transfusion experiment [95]. BSE donor sheep showed the highest levels of PrPd accumulation in palatine tonsil and mesenteric lymph node (MsLN) but the lowest in the spleen. In contrast, the spleen in BSE-transfused sheep showed significant higher magnitudes of PrPd. Graphic representation including scrapie data has been modified from [96, 97].
Figure 6
Figure 6
CVO involvement may contribute to the spread of infection into the brain parenchyma. Preclinically affected TSE sheep show mild early PrPd accumulation in the median eminence (ME) (a; x4), or severe deposition in later stages (b; x4). Higher magnification is needed to detect mild PrPd accumulation in the ME (c; x60). In later stages, preclinical sheep do show accumulation of PrPd in those brain areas with established connections with the CVOs. A sagittal section of the diencephalon (d; x1) has been produced from the area compressed in the white rectangle in the macroscopic sagittal view of the brain highlighting some of the neural structures. Thus, the involvement of the ME correlates with PrPd accumulation in the arcuate nucleus (ARQ) (a,b,e), and that of the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO) correlates with PrPd in several nuclei: preoptic (PON) (f, x1), suprachiasmatic (SQN) (g; x4), supraoptic (SOP) (e, x1), paraventricular (PVN) (d, e), bed nucleus of the stria terminalis (BNST) (d) and perifornical (PFN) (f). Such correlations are difficult in the vagal complex because of the widespread severe PrPd accumulation (h).
Figure 7
Figure 7
PrPd accumulation within CVOs in clinically affected animals with different TSE strains. AP, area postrema; PG, pineal gland; ME, median eminence; SCO, subcommisural organ; OVLT, organum vasculosum of lamina terminalis; SFO, subfornical organ; NH, neurophypophysis.
Figure 8
Figure 8
PrPd accumulation in CVOs and in the porencephalic lesion. Sheep CVOs highlighted with an asterix in pictures (a–f) of low magnification showed consistent PrPd deposition after intracerebral inoculation with BSE. Note that the porencephalic lesion which is surrounded by PrPd accumulations (g; x10) has abundant proliferation of newly formed vessels as revealed by a Van-Gieson staining (h; x20). CVOs: AP, area postrema; PG, pineal gland; ME, median eminence; SCO, subcommisural organ; OVLT, organum vasculosum of the lamina terminalis; SFO, subfornical organ. Brain structures: DMNV, dorsal nucleus of the vagus nerve; IV, fourth ventricle; Saq, Silvios' acqueduct; ON, optic chiasm; III, third ventricle; AWC, anterior white commisure. The figure is modified from (Sisó et al. [98]).
Figure 9
Figure 9
Schematic view of the neuroinvasion process involving the roles of the blood and the CVOs. For abbreviations see text and Figure 7 legend.

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References

    1. Fraser H. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway. Nature. 1982;295(5845):149–150. - PubMed
    1. Scott JR, Fraser H. Transport and targeting of scrapie infectivity and pathology in the optic nerve projections following intraocular infection. Progress in Clinical and Biological Research. 1989;317:645–652. - PubMed
    1. Bartz JC, Kincaid AE, Bessen RA. Rapid prion neuroinvasion following tongue infection. Journal of Virology. 2003;77(1):583–591. - PMC - PubMed
    1. Kincaid AE, Bartz JC. The nasal cavity is a route for prion infection in hamsters. Journal of Virology. 2007;81(9):4482–4491. - PMC - PubMed
    1. Sbriccoli M, Cardone F, Valanzano A, et al. Neuroinvasion of the 263 K scrapie strain after intranasal administration occurs through olfactory-unrelated pathways. Acta Neuropathologica. 2009;117(2):175–184. - PubMed

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