Apoptosis in relation to neuronal loss in experimental Creutzfeldt-Jakob disease in mice.

Apoptosis constitutes a genetically determined process to eliminate superfluous or damaged cells in tissues. Deficiencies in apoptosis regulation are involved in different pathologies including prion diseases. Some experimental studies show that neuronal loss--one of the hallmarks of prion diseases may be accomplished by apoptosis. We evaluated twenty five mice infected experimentally with the Fujisaki strains of CJD and sacrified sequentially in one week intervals. Apoptotic cells in various brain regions were detected by in situ end labelling (TUNEL) and electron microscopy in comparison with neuronal cell loss. The number of labelled cells per brain was very low--from a few labelled cells 6 weeks after inoculation to a maximum of 14 in the terminal stage. The number of neurones counted in 8 selected areas were considerably lower in terminally sick animals (20 and 21 week of incubation period) than in control mice. The mean value of loss of neuronal cells was 32%. The greatest loss (55%) of neurones was noted in the septal nuclei of the paraterminal body and the least lost (16%) in the hypothalamus. Compared to the extensive neuronal loss (30-50%), the number of apoptotic cells detected by in situ end labelling seems to be very low, and the process of neuronal death become more intensive during the progression of the disease.

Tropical spastic paraparesis.

Human T-cell lymphotropic virus type I (HTLV-I) is the cause of endemic tropical spastic paraparesis (TSP) or HTLV-I-associated myelopathy (HAM). Because TSP/HAM is not a fatal disease, the neuropathology of this disease, albeit relatively well understood, is based on the examination of just a few incidental cases. We summarise our experience with the neuropathology of tropical spastic paraparesis/HTLV-I associated myelopathy (TSP/HAM). We studied three cases of TSP/HAM from different parts of the world. We demonstrated peculiar lamellated structures, called "multilamellar bodies" (MLB). It is tempting to suggest that MLB may represent specific ultrastructural markers of TSP/HAM. The pathology of the anteriorand posterior horns was similar and comprised axonal degeneration, accompanied by extensive astrocytic gliosis. Lymphocytic infiltration, particularly observed as "cuffs" around blood vessels, was scattered among other cellular elements. Ultrastructurally, myelin sheaths were relatively well preserved, and some demyelinated but not remyelinated fibres were observed. Moreover, axons with abnormal accumulations of neurofilaments, suggestive of axonal degeneration, were detected. Several axons contained Hirano bodies. In many samples glial processes replaced most of the remaining neuropil.

Ultrastructural pathology of a Chilean case of tropical spastic paraparesis/human T-cell lymphotropic type I-associated myelopathy (TSP/HAM).

Human T-cell lymphotropic virus type I (HTLV-I), is the cause of endemic tropical spastic paraparesis (TSP) or HTLV-I-associated myelopathy (HAM). Because TSP/HAM is not a fatal disease, the neuropathology of this disease, albeit relatively well understood, is based on the examination of just a few incidental cases. Previously, we demonstrated peculiar lamellated structures, called "multilamellar bodies" (MLB). In this report, we present the ultrastructural neuropathology of a TSP/HAM case from Chile, with further detailed descriptions of MLB. It is tempting to suggest that MLB may represent specific ultrastructural markers of TSP/HAM. The pathology of the anterior and posterior horns was similar and was comprised of axonal degeneration, accompanied by extensive astrocytic gliosis. Lymphocytic infiltration, particularly observed as "cuffs" around blood vessels, was scattered among other cellular elements. Ultrastructurally, myelin sheaths were relatively well preserved, and some demyelinated but not remyelinated fibers were observed. Moreover, axons with abnormal accumulations of neurofilaments, suggestive of axonal degeneration, were detected. Several axons contained Hirano bodies. In many samples, glial processes replaced most of the remaining neuropil. In a few specimens of the anterior and posterior horns of the spinal cord, MLB were observed. These structures consisted of stacks of 30 to 40 electron-dense lamellae, which were interrupted by narrow electron-lucent spaces. All of the lamellae were immersed within an amorphous substance of intermediate density. Neurons of the dorsal root ganglia were basically normal except for increased lipofuscin accumulation. As in the spinal cord, myelinated axons were well preserved, but a few were demyelinated and surrounded by concentric arrays of Schwann cell membranes. Also, axons of the dorsal roots accumulated increased number of neurofilaments. Mast cells and Schwann cells were increased in number, the latter containing abundant pi granules and myelin fragments.

Neuronal loss and apoptosis in experimental Creutzfeldt-Jakob disease in mice.

One of the hallmarks of prion disease--neuronal cell loss, may be accomplished by apoptosis. The aim of this study was to estimate the neuronal cell loss in mice brains with experimental Creutzfeldt-Jakob disease (CJD) and control mice in the comparison with the apoptosis appeared by in situ end labelling (TUNEL) in function of time of post-incubation period and developing of the spongiform changes. The number of neurons was considerably lower in terminally sick animals (20-21 week of incubation period) than in control mice. The mean value of loss of neuronal cell was 32%. The greatest loss (55%) of neurons was noted in the septal nuclei of the paraterminal body and the least lost (16%) in the hypothalamus. We report here, that apoptotic cells are readily detectable in CJD-affected mice brains in time-dependt manner after infection of Fujisaki strain, but the number of apoptotic cells detected by in situ end labelling does not well correlate with the extensiveness of neuronal loss. The degree of apoptosis corresponds to the well developed spongiform changes.

Programmed cell death (apoptosis) in Alzheimer's disease and Creutzfeldt-Jakob disease.

The aim of our study was the estimation of the apoptosis process using in situ-end labelling of DNA breaks method on paraffin sections in 5 human cases of Alzheimer's disease (AD), 6 of Creutzfeldt-Jakob disease (CJD) and in 25 mice infected experimentally with the Fujisaki strain of CJD, killed sequentially at one-week intervals. The numbers of apoptotic cells in CJD-infected mice in the later stages of the disease and in terminally ill mice were progressively higher that at the early stage of the disease. Further, we found a correlation between the intensity of apoptosis and major lesions hallmark of disease--the intensity of spongiform changes in the cerebral cortex but not in the accumulation of PrP in CJD infected mice. The number of A beta-amyloid plaques in AD was not related to apoptotic index. Our study showed that apoptosis is a very important event in these neurodegenerative diseases and may become a basic mechanism in loss of neurons.