Lesions of the brain stem in sporadic CJD were histopathologically and immunohistochemically investigated using an anti‐PrP antibody on ten consecutive autopsy cases. Three major histopathological ...changes, spongiform changes, neuronal loss and hypertrophic astrocytosis, were employed as parameters of the alterations. The quadrigeminal plate and pontine nuclei were the most severely and consistently affected structures, and immunoreactivity against PrP was seen in these structures. There existed some discrepancies between the severity of the lesions and the intensity of the immunoreactivity against PrP. The medulla oblongata essentially remained normal on histopathological examination, but the inferior olivary nucleus showed prominent PrP deposition. Although the general view that pathological alterations in the brain stem are relatively mild in sporadic CJD was confirmed in this study, lesions of variable degrees which might influence a patient's clinical course were still observed in many structures in the brain stem.
1. As an extension of our previous study of quinacrine and its derivatives, chelating chemicals were screened to obtain more effective, better brain-permeable antiprion compounds using either ...prion-infected neuroblastoma cells or brain capillary endothelial cells.2. Eleven chemicals were found to have antiprion activity. Most of them shared a common structure consisting of benzene or naphthalene at either end of an azo bond. Structure-activity data suggest that chelating activity is not necessary but might contribute to the antiprion action.3. Chrysoidine, a representative compound found here, was about 27 times more effective in the antiprion activity and five times more efficiently permeable through the brain capillary endothelial cells than quinacrine was.4. These chemicals might be useful as compounds for development of therapeutics for prion diseases.
•Immune system roles in the anti-prion action of cellulose ether (CE) are unknown.•CE effect is impaired by pre T-cell antigen receptor α deficiency or thymectomy.•CE effect is also impaired by TCRδ ...deficiency or lytic granule dysfunction.•The αβ T-cell lineage, B cells or TLR4 signaling pathway do not affect CE effect.•Interaction between NKT and γδ T cells may be involved in the action of CE.
The anti-prion activity of cellulose ether (CE) has been reported in rodents, but the mechanism of action is not well understood. As defects in early T-cell development have been reported in Tga20 mice which show only a slight effect of CE administration, we investigated the involvement of immune functions in the CE action. We confirmed an insertion of the prion protein transgene into the pre T-cell antigen receptor α gene of Tga20 mice, and its impaired expression in the thymus and other tissues. The influence of immune suppression on the CE effect was then examined in high CE-responder mice treated with immunosuppressive agents or neonatal thymectomy. As neonatal thymectomy significantly reduced the CE effect, we compared the influence of various T-cell defects in mice with similar genetic backgrounds. The CE effect was increased or unchanged in mice with defects in the αβ T-cell lineage, whereas it was abolished in T-cell receptor δ deficient mice. Further, when other immune defects were examined, the CE effect was reduced in mice with lysosomal trafficking dysfunction, but was unchanged in mice deficient in B-cell differentiation or toll-like receptor 4 signaling. These findings collectively suggest that the mechanism of CE action may involve γδ T cells and lytic granule function, as well as immune factors like natural killer T cells which are lacking in pre T-cell antigen receptor α deficient mice and neonatally thymectomized mice.
Purpose
In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no ...non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain.
Methods
The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Sträussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent
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CBF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer’s disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention.
Results
Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain.
Conclusion
Although
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CBF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs.
Anti-prion effects of cellulose ether (CE) are reported in rodents, but the molecular mechanism is fully unknown. Here, we investigated the genetic background of CE effectiveness by proteomic and ...genetic analysis in mice. Proteomic analysis in the two mouse lines showing a dramatic difference in CE effectiveness revealed a distinct polymorphism in the glia maturation factor β gene. This polymorphism was significantly associated with the CE effectiveness in various prion-infected mouse lines. Sequencing of this gene and its vicinity genes also revealed several other polymorphisms that were significantly related to the CE effectiveness. These polymorphisms are useful as genetic markers for finding more suitable mouse lines and exploring the genetic factors of CE effectiveness.
•Anti-prion effects of cellulose ether vary among mouse lines.•Cox proportional hazards model is useful for evaluating the effects.•Glia maturation factor β polymorphisms significantly correlate with the effects.•The polymorphisms are genetic markers of cellulose ether effectiveness in mice.
Structural modification of the 9-substituted amino side chain of quinacrine resulted in compounds with better potencies and selectivities than quinacrine.
A library of functionalized ...6-chloro-2-methoxy-(
N
9-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-
N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (
15) which had submicromolar EC
50 values (0.1–0.7
μM) on all cell models, was able to clear PrP
Sc at non-toxic concentrations of 1.2–2.5
μM, and was more active than quinacrine in terms of EC
50 values. Other promising compounds were
14 (a regioisomer of
15) and
17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of
14,
15, and
17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
A 9‐year‐old Japanese girl received a cadaveric dura mater graft during surgery following a head injury with brain contusion. She continued to do well, but when she became 19‐years‐old, she gradually ...showed a violent character and was treated in a psychiatric hospital. Another 6 years later, 200 months after the procedure, she developed a progressive gait ataxia, which subsequently led to her death within 10 months of onset. An autopsy showed she had CJD. This patient represents an atypical case of dura‐associated CJD (dCJD) with unusual clinicopathological features including the late occurrence of myoclonus, an absence of periodic synchronous discharges in the electroencephalogram, and the presence of widespread florid plaques. However, our detection of an asymmetrical increase in the MRI‐derived images of pulvinar nuclei has not been previously observed in other atypical cases of dCJD. Because atypical dCJD cases share several clinicopathological features with those of vCJD, and because asymmetrical hyperintense signals in the pulvinar have been observed in some neuropathologically confirmed vCJD cases, we had some difficulty in a differential diagnosis between atypical dCJD and vCJD. This is the first atypical dCJD case showing a pulvinar high signal compared with all other basal ganglia on MRI.
Diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders. A thioflavin derivative, 2-4'-(methylamino)phenyl benzothiazole (BTA-1) ...and a Congo red derivative, (trans, trans),-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) are representative chemicals of these probes. In this report, the two chemicals were studied in transmissible spongiform encephalopathies (TSE). Both BTA-1 and BSB selectively bound to compact plaques of prion protein (PrP), not only in the brain specimens of certain types of human TSE, but also in the brains of TSE-infected mice when the probes were injected intravenously. The chemicals bound to plaques in the brains were stable and could be detected for more than 42 h post-injection. In addition, the chemicals inhibited abnormal PrP formation in a cellular model of TSE with IC(50) values of 4 nM for BTA-1 and 1.4 micro M for BSB. In an experimental mouse model, the intravenous injection of 1 mg BSB prolonged the incubation period by 14 %. This efficacy was only observed against the RML strain and not the other strains examined. These observations suggest that these chemicals bind directly to PrP aggregates and inhibit new formation of abnormal PrP in a strain-dependent manner. Both BTA-1 and BSB can be expected to be lead chemicals not only for imaging probes but also for therapeutic drugs for TSEs caused by certain strains.
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