Neuronal and astrocytic responses involving the serotonergic system in human spongiform encephalopathies

Abstract

The relationships between the degree of cortical prion protein (PrP) deposition, tissue vacuolation and astrocytosis were studied in the frontal cortex of 27 cases of human spongiform encephalopathy, encompassing 13 cases of sporadic Creutzfeldt-Jakob disease (sCJD), four cases of familial CJD (fCJD) (one owing to E200K mutation, one owing to 144 bp insertion, one owing to P102L mutation and one owing to A117V mutation), five cases of iatrogenic CJD (iCJD) owing to growth hormone therapy and five cases of variant CJD (vCJD). The size and number of tryptophan hydroxylase (TPH) positive cells in the dorsal raphe were determined as an index of the function of the brain's serotonergic system. The amount of PrP deposited in frontal cortex in vCJD was significantly greater than that in both sCJD and iCJD, which did not differ significantly from each other. The extent of grey matter deposition of PrP correlated with that of white matter deposition. Deposition of PrP as plaques was greater in cases of sCJD bearing valine at codon 129 of PrP gene, especially when homozygous. However, all cases of vCJD displayed florid plaque formation yet these were homozygous for methionine at codon 129. Prion protein deposition as plaques was greater in cases of sCJD with 2A PrP isotype than those with 1 PrP isotype, similar to that seen in cases of vCJD all of which are 2B PrP isotype. There were no significant differences in the extent of astrocytosis between the different aetiological groups, in either grey or white matter, as visualized with glial fibrillary acidic protein (GFAP) or 5HT-2A receptor (5HT-2AR) immunostaining, although there was a strong correlation between the severity of 5HT-2AR and GFAP reactions within both grey and white matter. The extent of PrP deposition within the grey, but not white, matter correlated with the degree of astrocytosis for both GFAP and 5HT-2AR and the extent of tissue vacuolation in grey and white matter, although the latter did not correlate with degree of astrocytosis for either GFAP or 5HT-2AR. Astrocytes may be responding directly to the presence of PrP within the tissue, rather than the vacuolar damage to neurones. Although S100beta immunoreactivity was present in astrocytes in control cases, no S100beta staining was seen in astrocytes in either grey or white matter in most CJD cases. There were no differences in the number of TPH-positive cells between CJD and control cases, although the mean TPH-positive cell size was significantly greater, and cells were more intensely stained, in CJD compared to controls, suggesting a pathological overactivity of the brain's serotonergic system in CJD. This may result in excessive release of 5HT within the brain triggering increased 5HT-2AR expression within activated astrocytes leading to release and depletion of S100beta protein from such cells. The clinical symptoms of fluctuating attention and arousal could be mediated, at least in part, by such alterations in function of the serotonergic system.

Cerebral White Matter Disruption in Creutzfeldt-Jakob Disease

“…However, human WM findings are scarce in sporadic CJD, the most common sporadic type. [35][36][37] It is plausible, thus, that white matter pathways between the injured gray matter sites are affected in CJD, but robust evidence has been lacking until now. The current study provides such evidence through DTI-derived indices: FA, MD, RD, and AD.…”

Experimental transmission of atypical scrapie to sheep

“…This may also account for the apparent absence of disease-related PrP Sc in lymphoid tissues. It is interesting to note that in familial CJD (E200K mutation) also, PrP labelling was seen as a uniformly fine deposit throughout all cortical layers [ 25 ].…”

Does the Use of Antidepressants Accelerate the Disease Progress in Creutzfeldt–Jakob Disease Patients With Depression? A Case Report and A Systematic Review

“…One reason may be the pathological overactivity of the brain’s serotonergic system in this disease. This hypothesis is supported by the evidence that the mean tryptophan hydroxylase (TPH)-positive cell size was significantly greater and cells were more intensely stained in CJD compared to controls (55). This may result in an increase in release of 5-HT.…”