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

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.

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

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

Scrapie infection in lymphoreticular tissues in ARQ/ARQ Suffolk sheep. (a) PrP^d 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) PrP^d within TBMs is N terminally truncated whereas PrP^d 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 PrP^d deposition ((d), IHC for R145). (a)–(d) x20.

Figure 4

Pathogenesis of sheep scrapie. Permission was obtained for reproducing this figure originally published in [53]. For abbreviations see text.

Figure 5

Magnitude of PrP^d accumulation in LRS tissues of sheep as part of the blood transfusion experiment [95]. BSE donor sheep showed the highest levels of PrP^d 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 PrP^d. Graphic representation including scrapie data has been modified from [96, 97].

Figure 6

CVO involvement may contribute to the spread of infection into the brain parenchyma. Preclinically affected TSE sheep show mild early PrP^d accumulation in the median eminence (ME) (a; x4), or severe deposition in later stages (b; x4). Higher magnification is needed to detect mild PrP^d accumulation in the ME (c; x60). In later stages, preclinical sheep do show accumulation of PrP^d 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 PrP^d 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 PrP^d 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 PrP^d accumulation (h).

Figure 7

PrP^d 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

PrP^d accumulation in CVOs and in the porencephalic lesion. Sheep CVOs highlighted with an asterix in pictures (a–f) of low magnification showed consistent PrP^d deposition after intracerebral inoculation with BSE. Note that the porencephalic lesion which is surrounded by PrP^d 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

Schematic view of the neuroinvasion process involving the roles of the blood and the CVOs. For abbreviations see text and Figure 7 legend.