J. W. Boellaard

Neuronal autophagy in experimental scrapie

SummaryIn this study we report the formation of giant autophagic vacuoles (AV) in neurons in experimental scrapie in hamsters. Autophagy is an important step in the cellular turnover of proteins and organelles. It is known to occur in neurons under physiological as under pathological conditions. Giant AV, however, are seen very rarely only in pathological states. In our model AV are much more numerous after intracerebral (i.c.) transmission of the scrapie agent than after the transmission via the intraperitoneal route which points to a correlation between the intensity of the process and the period of incubation. As the appearance of the AV in our model is correlated chronologically with that of scrapie-associated fibrils, at least after i.c. transmission, the process may be related to a disturbance of cellular protein metabolism and, thus, to the processing of prion protein.

Microglia is a component of the prion protein amyloid plaque in the Gerstmann-Sträussler-Scheinker syndrome

SummaryThe microglial cell has been demonstrated as component of the cerebral amyloid plaque of Alzheimers disease. Involvement of microglia in plaques of another cerebral amyloidosis, the Gerstmann-Sträussler-Scheinker syndrome (GSS), has found little attention. We examine here the presence of microglia in GSS plaques by immunohistochemistry and transmission electron microscopy. Paraffin sections from five brains of patients with GSS were immunolabelled with antibodies against prion protein, A4/β amyloid protein, ferritin, leukocyte common antigen, HLA-DR, CD 68, and the MAC387 epitope for microglia and monocytes/macrophages; microglia was also labelled with the Ricinus communis agglutinin-1 lectin. Such (immuno)labelling demonstrated many delicate cell processes and occasional somata within and around prion protein plaques in all GSS brains. Microglial immunoreactivity was strongest with anti-ferritin and variable with anti-macrophage antibodies. Ultrastructural examination of brain tissue from one autopsy and one biopsy of GSS identified microglial cells in close proximity of amyloid plaque fibrils. Our observations demonstrate microglia as an important component of the amyloid plaque in GSS and suggest a major role for microglia in processing and deposition, or at least organization, of prion protein amyloid. Thus, plaques in both transmissible and nontransmissible cerebral amyloidoses seem to develop via similar pathogenetic mechanisms, irrespective of differences in etiology and molecular composition of the amyloid.

Experimental transmission of human subacute spongiform encephalopathy to small rodents

SummarySpongiform encephalopathy was transmitted to mice from a patient belonging to the “Sch” family with Gerstmann-Sträussler-Scheinkers disease (GSS). Incubation periods in the first passage were much shorter than those in mice infected with Creutzfeldt-Jakob disease. Clinical and pathologic findings of mice infected with both disease were almost identical. This is the first successful transmission from a typical GSS case without severe spongiform change which suggests the possible transmissible nature of this disorder.

Neuronal autophagy in experimental Creutzfeldt-Jakob's disease

SummaryWe report an experimental model of Creutzfeldt-Jakobs disease (CJD) in mice leading to the formation of giant autophagic vacuoles (AV) in neurons of the cerebral cortex. These AV appear at the end of the incubation period (4–6 months post-inoculation), together with spongy changes and clinical symptoms. Autophagy, a process of intracellular digestion of cell constituents by the lysosomal compartment, is known in many cell types, where it plays a role both in the physiological turnover and in pathological processes and is involved in protein metabolism. The same also occurs in neurons. Here autophagy is known to occur in the normal state and leads to residual bodies called lipofuscin granules. An increase in lipofuscin is known to occur in human and experimental CJD. Therefore, an increase in autophagy and in AV can be expected. In our experimental model, the activation of neuronal autophagy may be related to an alteration in neuronal protein metabolism.

Gerstmann-Sträussler-Scheinker's disease

SummaryLight and electron microscopic observations are reported on a brain biopsy of a man of 59 with a rare familial disease of the CNS and a 5-year clinical course. Electron micrographs of the frontal biopsy reveal plaque-like deposits composed of amyloid cores, often multicentric in the cortex and subcortical white matter. They are localized between enlarged astrocytic processes. In the neuropil they are sometimes associated with abnormal neuritic processes, in the white matter with processes of fibrous astroglia and basement membranes. There are no signs of primary neuritic or synaptic involvement in the plaque formation which is more obviously associated with altered astrocytic processes. Moreover, degenerative alterations in the cortical vessels and slight astroglial spongiform changes as well as oligodendroglial proliferation can be found. Plaques are considered to be mainly of the kuru type; the relationship with transmissible spongiform encephalopathies is discussed.

Subakute spongiforme Encephalopathie mit multiformer Plaquebildung

SummaryReport of two unrelated cases of a rare familiar disease of degenerative nature, from a clinical point of view belonging to the spinocerebellar atrophies, combined with dementia. According to the pedigrees, the disease can be followed up to 3–4 generations.Microscopic study reveals glioneuronal dystrophy with spongiform changes together with kuru plaques and atypical plaque-like formations, hitherto only described in this disease. Nosological aspects of these findings are discussed.Report of two unrelated cases of a rare familiar disease of degenerative nature, from a clinical point of view belonging to the spinocerebellar atrophies, combined with dementia. According to the pedigrees, the disease can be followed up to 3--4 generations. Microscopic study reveals glioneuronal dystrophy with spongiform changes together with kuru plaques and atypical plaque-like formations, hitherto only described in this disease. Nosological aspects of these findings are discussed.

Ultrastructural heterogeneity of neuronal lipofuscin in the normal human cerebral cortex

SummaryThe ultrastructure of the age pigment in neurons of the normal human isocortex was investigated in seven autopsies and two biopsies. In the autopsies four cortical areas of Brodmann viz. 6, 7, 11 and 17 were studied. The lipofuscin granules appear as complexes composed of lipid and pigment. These are characterized by (1) their shape, (2) frequency per neuron, (3) the relative amount of pigment and lipid in the complexes, and (4) the structure of the matrix. The neurons contain numerous varieties of lipopigment, six of which occur with great frequency and are designated as varieties 1–6. Variety 1 is found in pyramidal neurons and seems to be characteristic of long loop projectory neuronal systems. 2, is found in large non-pyramidal neurons. 3 is found in pyramidal and non-pyramidal neurons. 4, 5 and 6 are found in non-pyramidal neurons. The pigment matrix is linear in all six varieties of lipopigment. Short linear elements are present in varieties 1, 2 and 5. Long linear elements are found in varieties 3, 4, and 6. Circular whorled arrangements are found in 4. We think that these varietics of lipofuscin may signify metabolic and/or functional differences of the different types of neurons and may contribute to the biochemical classification of cortical neurons.

Morbus Gerstmann-Sträussler-Scheinker

SummaryThe clinical symptoms from three cases and histological findings from two patients suffering from morbus Gerstmann-Sträussler-Scheinker (M-GSS) are reported. This disease belongs to the group of subacute spongiform encephalopathies. It is extremely rare and so far has only been observed in 52 members of four large families, in which the symptoms begin between the age of 35 and 50 and lead to death in 4–5 years. In the family reported here, cerebellar symptoms including myoclonia and later dementia, bulbar, and pyramidal symptoms were typical; two patients also had deterioration of vision and hearing. CSF and other biochemical data were normal. The EEGs showed progressive general slowing without periodic dysrhythmia. Evoked potential gave no evidence of demyelinization. The disease may safely be distinguished from morbus Creutzfeldt-Jakob (M-CJ) and Alzheimers disease by histology, which reveals kuru plaques in most cases and invariably multicentric plaques as well as cortical spongiform changes of varying degree with loss of nerve cells and glial proliferation; however, only minor degenerative alterations in the cortical vessels are seen. The transmission to monkeys and histological similarities to M-CJ and kuru suggest a slow virus related to that causing scrapie. Alternatively, the genetically determined susceptibility of the patient may decide the type of reaction to the slow virus. The disposition to M-GSS is autosomally dominant.ZusammenfassungBefunde von drei Patienten aus einer Familie mit einem Morbus Gerstmann-Sträussler-Scheinker (M-GSS) werden mitgeteilt. Die Diagnose wurde zweimal autoptisch gesichert. Klinisch und morphologisch handelt es sich um eine seltene familiäre subakute spongiöse Encephalopathie mit besonderem Befall des Kleinhirns, deren Vorkommen bisher nur in vier Familien mit insgesamt 52 Kranken gesichert ist. In der hier untersuchten Familie begann die Erkrankung durchschnittlich im fünften Dezennium und führte innerhalb von fünf Jahren zum Tode. Cerebellare Funktionsstörungen, später Demenz, bulbäre und Pyramidenbahn-Symptome sowie Hör- und Sehminderung bei zwei Patienten, charakterisierten das klinische Bild. Die biochemischen Befunde, einschließlich deren des Liquors, waren unauffällig. Neurophysiologisch zeigte sich mit fortschreitender Erkrankung eine Allgemeinveränderung im EEG ohne periodische paroxysmale Abläufe. Für eine Demyelinisierung ergaben die evozierten Potentiale keinen Hinweis. Nur durch die histologischen Befunde mit den nicht immer nachweisbaren Kuru-Plaques, aber stets unterschiedlich ausgeprägten multizentrischen Plaques, spongiösen Ver↭derungen wechselnder Ausprägung war die Erkrankung sicher vom M. Alzheimer und M. Creutzfeldt-Jakob (M-CJ) abzugrenzen. Nach ersten positiven Übertragungsversuchen auf Primaten und ähnlichen histologischen Veränderungen beim M-CJ und Kuru wird eine slow-virus-Infektion durch ein nichtkonventionelles, möglicherweise dem M-CJ-, Kuru- und Scrapie-Virus verwandtes Virus diskutiert. Die unterschiedliche Manifestation der beim Menschen beobachteten Erkrankungen könnte auch durch verschiedene dispositionelle Faktoren beim Wirt erklärt werden, die nach den bisherigen humangenetischen Befunden beim M-GSS autosomal dominant weitergegeben werden.

Creutzfeldt-Jakob disease with amyloid angiopathy: diagnosis by immunological analyses and transmission experiments*

SummaryIt was difficult to make a definite pathological diagnosis in a 73-year-old man with Creutzfeldt-Jakob disease (CJD) due to extensive amyloid angiopathy which lacked any severe spongiform changes. Immunostaining using anti-prion protein (PrP) antibody revealed fine granular deposits in the gray matter, after hydrolytic autoclaving pretreatment on tissue sections. Western blotting also revealed an abnormal isoform of PrP, but PrP gene analysis did not show any abnormalities. The primary transmission experiments were repeated three times and induced spongiform encephalopathy in a few mice after a long incubation period.

Acid phosphatase activity in human neuronal and glial lipofuscin.

SummaryThe ultrastructural demonstration of acid phosphatase activity in neuronal and glial lipofuscin of the aged human brain indicates lysosomal activity. Contrary to the constantly high enzyme activity of astroglial lipofuscin and low activity of oligodendroglial lipofuscin, the enzyme activity of neuronal pigment differs in different locations, i.e., in different neuronal populations. The activity is probably based on the importation of lysosomal enzymes into the pigment component of lipofuscin. These facts indicate the possibility of a continuous autophagosomal function of lipofuscin in neuronal and glial cell physiology. Therefore, the findings are arguments against the view that lipofuscin is a wear-and-tear material only and claim for it an active role in cell metabolism.