Morphogenesis of amyloid plaques in 87V murine scrapie†

Amyloid plaques of scrapie–infected mouse brains are composed of fibrillar forms of a host coded, cell surface sialoglycoprotein called PrP (prion protein). Serial ultrastructural immunogold staining was performed on plaques identified by light microscopic immunocytochemistry of brains of VM mice infected with the 8 7V strain of scrapie. Classical plaques, of a kuru–type morphology, were composed of a central core of bundles of amyloid fibrils. Amyloid fibrils of classical plaques were immunoreactive for PrP. In addition, PrP was also found at the plaque periphery, in the absence of fibrils, at the plasmalemma of cell processes and in the associated extracellular spaces. Frequent microglial cells and occasional astrocytes contained PrP within lysosomes. Other plaques with few or no recognizable amyloid fibrils were frequent and were termed primitive plaques. PrP could be demonstrated in a non–fibrillar form at the plasmalemma and in the extracellular spaces between neurites of such plaques. Many primitive plaques showed little or no sub–cellular pathology associated with the PrP accumulation. PrP was closely associated with the plasma–lemma of occasional dendrites passing towards the centre of primitive plaques. These results suggest that plaques are formed around one or more PrP releasing dendrites. PrP accumulates in the extracellular spaces adjacent to such processes prior to its spontaneous aggregation into fibrils. Lysosomal accumulation of PrP in microglia and astrocytes located at the periphery of plaques suggest that these cells are involved in the phagocytosis of excess or abnormal PrP.     

Prion protein expression in senile plaques in Alzheimer's disease

Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localises in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labelling immunohistochemistry. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-positive granules reminiscent of dystrophic neurites are observed in neuritic plaques. Finally, PrPC deposition also occurs as dense filamentous and amorphous precipitates in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrPC, betaA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochemistry, thus indicating no PrPC and betaA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrPC deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-associated protein, as already reported in other studies. Immunoprecipitation, electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and betaA4 do not co-precipitate with PrP. These results suggest that synaptophysin, APP and betaA4 are likely not bound to PrP. PrPC accumulation in betaA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrPC accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degradation of PrPC, resulting from or occurring in parallel to abnormal APP degradation, deserves further study.     

Transformation of degenerating neurofibrils into amyloid substance in Alzheimer's disease: histochemical and immunohistochemical studies

Degenerating neurofibrils (DNF), which are composed of paired helical filaments (PHF) and amyloid fibrils (AF), are the 2 characteristic pathological fibrillar deposits in Alzheimer cortex. These fibrils were simultaneously studied by 2 techniques: The immunolabelling with a specific antiserum raised against PHF and elective thioflavine S staining of AF. In neuronal perikaryons, neurofibrillary tangles (NFT) consist of 3 populations: firstly, strongly immunolabelled tangles were weakly thioflavine-stained. Secondly, less dense tangles were weakly immunolabelled but strongly thioflavine-stained. Thirdly, ghost tangles which correspond to extracellular NFT were exclusively thioflavine-stained. Thus, it is likely that NFT are degraded to form extracellular AF. Around neuritic plaques and some vessels with amyloid angiopathy, immunolabelled neurites, thioflavine-stained neurites and transition figures were also observed. On the other hand, the central core of plaques and pathological vessel walls were strongly thioflavine-stained but were never immunoreactive. In conclusion, these observations favour catabolism of PHF bundles found in NFT and in degenerating neurites into an amyloid substance. This amyloid substance seems different from other amyloid deposits found in the central core of neuritic plaques and vessel walls.     

Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain

Amyloid plaques, a well‐known hallmark of Alzheimer's disease (AD), are formed by aggregated β‐amyloid (Aβ). The cellular prion protein (PrPc) accumulates concomitantly with Aβ in amyloid plaques. One type of amyloid plaque, classified as a neuritic plaque, is composed of an amyloid core and surrounding dystrophic neurites. PrPc immunoreactivity reminiscent of dystrophic neurites is observed in neuritic plaques. Proteinase K treatment prior to immunohistochemistry removes PrPc immunoreactivity from amyloid plaques, whereas Aβ immunoreactivity is enhanced by this treatment. In the present study, we used a chemical pretreatment by a sarkosyl solution (0.1% sarkosyl, 75 mM NaOH, 2% NaCl), instead of proteinase K treatment, to evaluate PrPc accumulation within amyloid plaques. Since PrPc within amyloid plaques is removed by this chemical pretreatment, we can recognize that the PrP species deposits within amyloid plaques were PrPc. We could observe that PrPc accumulation in dystrophic neurites occurred differently compared with Aβ or hyperphosphorylated tau aggregation in the AD brain. These results could support the hypothesis that PrPc accumulation in dystrophic neurites reflects a response to impairments in cellular degradation, endocytosis, or transport mechanisms associated with AD rather than a non‐specific cross‐reactivity between PrPc and aggregated Aβ or tau.     

A special report I. Prion protein (PrP)--amyloid plaques in the transmissible spongiform encephalopathies, or prion diseases revisited

We present a retrospective analysis of PrP-amyloid plaques encountered in CJD and GSS. In human TSEs (kuru, CJD and GSS) several PrP-immunopositive plaques and plaque-like deposits were detected. In kuru, plaques were typical "kuru" plaques--stellate structures deposited mostly in the granular- and Purkinje-cell layer of the cerebellum. Many smaller or larger clusters were visible but, in contrast to GSS, they never merged together to form multicentric plaques. In all cases of GSS, plaques were localised in the granular- and Purkinje-cell layer and the molecular cell layer. There were many different forms of plaques: from kuru plaques (unicentric stellate plaques) to clusters of unicentric plaques, which by merging eventually formed "multicentric plaques". The latter are the hallmark of this disease. By electron microscopy, several types of amyloid plaques, which corresponded to those seen by PrP immunohistochemistry, were observed. The first type, unicentric "kuru" plaque, consisted of stellate arrangements (stars or cores) of amyloid bundles emanating from a densely interwoven centre. Amyloid stars were surrounded by astrocytic processes and invaded by microglial cells but dystrophic neurites were only rarely seen. In contrast, multicentric plaques were often surrounded by dystrophic neurites. The rarest type of plaque were neuritic plaques. In 263K- and 22C-H scrapie-infected hamster brains, by light microscopy and semi-thin (1 microm) sections, discrete PrP-immunopositive plaques were observed in the subependymal region but not in the deep brain neuroparenchyma. These plaques were not discernible by routine H & E staining. Ultrastructurally, plaques were recognised as areas of low electron density containing haphazardly-oriented fibrils and not as stellate compact structures typical of plaques in human cases of CJD and GSS. These plaques were located beneath the basal border of the ependymal cells and adjacent blood vessels. Occasional dystrophic neurites containing electron-dense inclusion bodies were seen within the plaque perimeter, which always remained PrP-negative.     

Ubiquitin-reactive axons have a widespread distribution and are unrelated to prion protein plaques in Creutzfeldt-Jakob disease

The amyloid plaques of Alzheimer disease (AD) are surrounded by dystrophic axons that contain ubiquitinated dense bodies. To investigate whether deposits of other types of amyloid cause axonal degeneration we studied 5 cases of Creutzfeldt-Jakob disease (CJD) with immunocytochemical methods using ubiquitin and prion protein (PrP) antisera. One of these cases contained PrP plaques in the cerebellum. In all cases dystrophic axons, which contain ubiquitinated dense bodies, were observed in neocortical and cerebellar grey matter, in absence of PrP-reactive amyloid deposits. Only a minority of PrP plaques present in the cerebellum was associated with ubiquitin positive neurites. The results indicate that, unlike in AD, the occurrence of ubiquitinated dystrophic axons is independent from amyloid deposition in CJD and is likely to be a primary phenomenon.     

The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition

The structural changes of Alzheimer's disease (AD) include a widespread alteration of neuronal cell processes in addition to senile plaques and neurofibrillary tangles. Since the antigenic characteristics of these abnormal neurites are similar to those of the abnormal neurites associated with the senile plaques, the question has been raised as to whether the widespread neuritic alteration is secondary to the deposition of amyloid. To answer this question, we examined brains from 2 subjects with a longer-lasting form of subacute sclerosing panencephalitis (SSPE) characterized by the presence of numerous neurofibrillary tangles but no senile plaques, 3 subjects with AD, and 2 age-matched controls. Light and electron immunocytochemical analyses revealed that abnormal neurites are present diffusely in SSPE cerebral cortex in the absence of amyloid deposits. These abnormal neurites were qualitatively identical to the widespread abnormal neurites of AD. The abnormal neurites, in contrast to the neurites of control brains, immunoreacted with antibodies to tau and ubiquitin. These distinctive antigenic features were due to the presence in these abnormal neurites of straight filaments, 14 to 16 nm in diameter, mixed with a few paired helical filaments. The spatial distribution of the widespread neuritic alteration correlated with that of neurofibrillary tangles in both conditions, but not with that of senile plaques in AD. The present findings demonstrate that a diffuse alteration of neurites similar to that present in AD takes place independently of the deposition of amyloid in SSPE, and they are consistent with the hypothesis that in AD, also, this alteration is not secondary to the deposition of amyloid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultrastructure of diffuse plaques in senile dementia of the Alzheimer type: comparison with primitive plaques

Summary We compared the ultrastructure between diffuse and primitive plaques in the brains of senile dementia, using pairs of routine electron microscopic ultrathin sections and adjacent semithin sections, which were immunolabeled for protein. In the frontal cortex, amyloid fibrils were rarely seen in a minority of diffuse plaques, suggesting an initial stage of the diffuse plaques. A majority of the diffuse plaques had electrondense material and/or amyloid fibrils between cell processes in part of but not the entire /A4-immunoreactive areas. Small degenerating neurites were often seen with apparent amyloid fibrils in the diffuse plaques, and these were considered to be in an advanced stage. The size and number of degenerating neurites were proportional to the amount of amyloid. Bundles of amyloid fibrils were occasionally surrounded by astroglial processes forming gap junctions. Neurons were found within some diffuse plaques, but capillaries were rarely seen. In contrast, in the temporal cortex, the diffuse plaques were smaller, and even these small ones had apparent amyloid fibrils. The amount of amyloid correlated significantly with plaque size in the temporal cortices, but not in the frontal cortices. Most of the diffuse plaques of the frontal lobe remained as advanced diffuse plaques (apparent amyloid with occasional astroglia and some degenerating neurites) for a long time, and did not transformed into primitive plaques, whereas the temporal diffuse plaques tended to transform into primitive plaques.Supported by the Grant-in-Aid for Scientific Research on Priority Areas No. 02240202 from the Ministry of Education, Science and Culture, Japan     

Ultrastructural abnormalities in the cerebral neocortex and hippocampus associated with Alzheimer's disease and aging

Summary Lesions of the frontal and temporal neocortices and hippocampus typically found in Alzheimer's disease were looked for with the electron microscope in 119 autopsy cases whose ages ranged from 24–93 years. By light microscopy 11 of the cases over the age of 60 had large numbers of plaques and neurofibrillary tangles, whereas the remaining cases had few or none. From the age frequency distribution of the electron microscopic lesions in these two categories of cases amyloid fibrils and abnormal neurites, both components of plaques, were first seen at approximately the same time. This suggests that amyloid is unlikely to precede the neurites in their formation. The abnormal neurites were thought, due to the small numbers of synapses in their walls, to be largely derived from degenerating neuronal processes and not synaptic boutons.     

Acetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation process

Acetylcholinesterase (AChE) triggers beta amyloid plaques formation and is associated with amyloid plaques in the brain. Recent studies have demonstrated that AChE promotes the aggregation of PrP106-126, a peptide deduced from the prion protein sequence. In the present study we show that AChE triggers also the fibrillization of the main component of the amyloid plaques -the peptide spanning residues 82-146 (PrP82-146)- found in patients with Gerstmann-Sträussler-Scheinker disease (GSS). The kinetics of PrP82-146 aggregate formation was directly correlated with AChE concentration and mature fibrils showed the tinctorial and optical properties of amyloid. Atomic force microscopy analysis showed that oligomer and amyloid fibril formation were significantly accelerated by AChE. This effect was mediated by the peripheral site of the enzyme since propidium iodide inhibited the fibrillization process. Present results strongly support the role of AChE in triggering amyloidogenesis and the potential therapeutic relevance of peripheral site blocker compounds.     

Dystrophic neurites of senile plaques in Alzheimer’s disease are deficient in cytochrome c oxidase

Double-labeling immunofluorescence and confocal microscopy have been used to learn about the local relationship between amyloid, mitochondria, and cytochrome c oxidase (COX) in dystrophic neurites of senile plaques in the frontal cortex in Alzheimer's disease (AD). Dystrophic neurites surrounding amyloid plaques are filled with mitochondrial porin-immunoreactive structures. In contrast with tangle-bearing and non-tangle-bearing neurons, which express mitochondrial porin and COX subunit 4, porin-immunoreactive neurites of senile plaques lack COX subunit 4. Parallel western blot studies in mitochondria-enriched fractions of the frontal cortex in the same cases disclosed reduced expression levels of COX, but not of prohibitin, in AD stages VB/C of Braak. Co-localization of porin and lysosomal associated protein 1, as revealed by double-labeling immunofluorescence and confocal microscopy, suggests that mitochondria may be engulfed by lysosomes in dystrophic neurites. These findings support a local link between amyloid deposition, abnormal mitochondria and impaired respiratory chain function (resulting from decrease of COX expression) in dystrophic neurites of senile plaques in AD.     

Heparan Sulfate Proteoglycan Is Associated with Amyloid Plaques and Neuroanatomically Targeted PrP Pathology throughout the Incubation Period of Scrapie-Infected Mice

Heparan sulfate proteoglycan (HSPG) has been found to be associated with amyloid deposits in a number of diseases including the cerebral amyloid plaques of Alzheimer's disease and the transmissible spongiform encephalopathies (TSEs). The role of HSPG in amyloid formation and the neurodegenerative pathology of these diseases have not been established. We have addressed these questions using a scrapie mouse model which exhibits both amyloid and nonamyloid deposition of abnormal PrP protein, the protein marker of TSE infection. The distribution of HSPG was examined throughout the course of the disease in the brains of experimentally infected mice and compared with the distribution of abnormal PrP. Abnormally high levels of HSPG were associated with most types of PrP pathology including all plaque types and diffuse neuroanatomically targeted forms. Scrapie-associated HSPG was present from 70 days after infection, the earliest time-point examined, in the same target areas as abnormal PrP. The association with amyloid plaques may indicate that HSPG is involved in amyloid plaque formation and/or persistence but involvement with early diffuse forms of PrP suggests a more fundamental role in scrapie pathogenesis.     

Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects

To clarify where and how beta-amyloid begins to deposit in senile plaques, we examined the ultrastructural localization of amyloid beta protein (Abeta) in diffuse plaques of brains with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Alzheimer disease (AD), and from nondemented aged subjects. Serial ultrathin sections of osmium-plastic blocks were immunogold-labeled for Abetax-42 (Abeta42), and sections on grids were observed under the electron microscope (EM) after observing the exact localization of the diffuse plaques in sections on glass slides by the reflection contrast microscope. Abeta42 deposition, which was decollated with gold particles, appeared in 3 forms in all subjects under the EM: 1) Scattered small bundles of amyloid fibrils between cell processes, frequently seen in the densely stained area of diffuse plaques. 2) Scattered small foci of nonfibrillar materials between cell processes as a relatively minor form. 3) Abeta42 on a part of the cell surface plasma membrane of normal appearing cell processes, a major form in weakly immunostained areas. The last form was not associated with degenerative neurites or reactive glia. Abeta42 deposition on the cell surface plasma membrane appears to be an initial event in diffuse plaques, and then it develops into amorphous/fibrillar amyloid between cell processes.     

Multiple transmitter systems contribute neurites to individual senile plaques

Senile plaques (SP), which consist largely of abnormal neuronal processes in proximity to deposits of amyloid, are a characteristic neuropathological feature of Alzheimer's disease. In lesser numbers, SP also occur in the brains of nondemented aged humans and nonhuman primates. To date, it is not known whether neurites in individual SP derive from neurons of one or several neurotransmitter systems. In aged monkeys, two strategies were used to test the hypothesis that individual SP can contain abnormal neurites arising from multiple neuronal systems. First, immunocytochemical methods were used to identify somatostatin-immunoreactive neurites in plaques, and these sections were subsequently stained with silver to visualize other neurites. Numerous plaques contained both somatostatin-positive and somatostatin-negative (i.e. argyrophilic only) neurites, suggesting that more than one transmitter system contributed neurites to each of these plaques. Second, two-color immunocytochemical techniques showed, in a small percentage of plaques, that cholinergic neurites coexist with neuropeptide Y (NPY)-containing neurites or catecholaminergic neurites. These results suggest that the formation of SP may result from events that involve abnormalities of neuronal processes arising from multiple transmitter systems.     

In vivo toxicity of prion protein in murine scrapie: ultrastructural and immunogold studies

Prion protein (PrP) is a cell surface, host coded, sialoglycoprotein which accumulates in excess in scrapie, Creutzfeldt‐Jakob disease, bovine spongiform encephalopathy and other transmissible spongiform encephalopathies. Infection of mice with the 87 V or ME7 scrapie strains results in distinctive and very different light microscopical patterns of vacuolation and disease specific PrP accumulation. In both of these scrapie strains immunogold electron microscopy was used to locate PrP to the plasmalemma of neurons from where it was released into the neuropil. Initial PrP accumulation around neurons and in early plaques lacking amyloid fibrils was generally not associated with morphological changes either of the neuron or dendrite releasing the PrP or in the adjacent neuropil in which excess PrP accumulated. However, accumulation of pre‐amyloid PrP in some brain areas was associated with specific degeneration of dendritic spines and axon terminals. Initial PrP aggregation into fibrils was also associated with tissue damage with both ME7 and 87 V plaques and diffuse accumulations. Tissue damage associated with fibrillogenesis was localized and would not be expected to have clinical significance. We conclude that pre‐amyloid PrP release and accumulation is not invariably toxic, either to the neuron releasing PrP or to the neuropil into which it is released. However, axon terminal degeneration and dendritic spine loss in some neuroanatomical areas may be indicative of specific PrP toxicity and may be the main cause of neurological dysfunction in murine scrapie.     

Ultrastructural Immuno-localization of Synthetic Prion Protein Peptide Antibodies in 87V Murine Scrapie

Disease specific forms of a host encoded cell surface sialoglycoprotein called prion protein (PrP) accumulate during the incubation period of the transmissible spongiform encephalopathies. A 33–35 kDa disease specific form of PrP is partially resistant to protease digestion whereas the normal form of PrP can be completely digested. Proteinase K digestion of the murine disease specific form of PrP produces diverse forms of low molecular weight PrP, some of which are N-terminally truncated at amino acid residue 49 or 57 within the octapeptide repeat segment. Amyloid plaques are a pathological feature of many of the transmissible spongiform encephalopathies and are composed of PrP. Using synthetic peptide antibodies to the N-terminus of PrP (which is not present in truncated disease specific PrP) and antibodies to the protease resistant fraction of PrP we have immunostained plaques and pre-amyloid deposits in the brains of mice, experimentally infected with the 87V strain of scrapie, for examination by light and electron microscopy. Classical fibrillar amyloid deposits in plaques as well as pre-amyloid deposits were both immunostained by antibodies to the N-terminus of PrP and to the protease resistant core of the PrP molecule. This suggests that both N-terminal and core amino acid residues are present in disease specific PrP released from scrapie infected cells in vivo. The results also suggest that N-terminal truncation of PrP may not be essential for formation of amyloid fibrils.     

Ultrastructural localization of argyrophilic substances in diffuse plaques of Alzheimer-type dementia demonstrated by methenamine silver staining

Summary The ultrastructure of argyrophilic substances in diffuse plaques of an Alzheimer-type dementia brain was examined using methenamine silver (MS) electron microscopy with the pre-embedding method. Electrondense substances, which were sparse aggregations of bundle-like structures with silver granules, were disseminated in the diffuse plaques. Comparison of serial MS and routine ultrathin sections revealed that diffuse plaques usually show scattered bundles of amyloid fibrils or amorphous materials, or both, between indistinct cell process membranes. Some of these processes were identified as astrocytic or dendritic in origin. A few degenerative neurites were frequently noted in large silver-positive areas but never in small areas. These findings suggest that the appearance of amyloid fibrils and amorphous materials between certain cell processes is a very morphological change in the process of senile plaque formation.     

Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases

Aims: TAR-DNA binding protein-43 (TDP-43) is the major ubiquitinated protein in the aggregates in frontotemporal dementia with ubiquitin-positive, tau-negative inclusions and motor neurone disease. Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism–dementia complex. We therefore aimed to determine whether there is TDP-43 pathology in human prion diseases, which are characterised by variable deposition of prion protein (PrP) aggregates in the brain as amyloid plaques or more diffuse deposits. Material and methods: TDP-43, ubiquitin and PrP were analysed by immunohistochemistry and double-labelling immunofluorescence, in sporadic, acquired and inherited forms of human prion disease. Results: Most PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin. No abnormal TDP-43 inclusions were identified in any type of prion disease case, and TDP-43 did not co-localize with ubiquitin-positive PrP plaques or with diffuse PrP aggregates. Conclusions: These data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.     

Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: a comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease

Background: Although the histological features of the amyloid plaques in variant Creutzfeldt–Jakob disease (vCJD) are distinct from those in other forms of prion disease [kuru, sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Sträussler–Scheinker disease (GSS)], their ultrastructural features have only been described in a single case report. Aims: To study vCJD plaques systematically and compare them with plaques in kuru, sCJD, GSS and Alzheimer disease (AD). Methods: Amyloid plaques were studied by transmission electron microscopy and image analysis in five cases of vCJD, three cases of GSS, two cases of sCJD, one case of kuru and five cases of AD. Immunohistochemistry was performed on paraffin sections from one case of vCJD, two cases of GSS, one case of kuru and two cases of sCJD. Results: The florid plaques in vCJD were either compact or more diffuse; in both forms, the radiating fibrils were organized into thick 'tongues', in contrast to kuru plaques. Dystrophic neurites (DNs) containing lysosomal electron-dense bodies or vesicles surrounded florid plaques. Microglial cells were found within florid plaques; occasional amyloid fibrils were identified in membrane-bound pockets of microglial cells. In vCJD, there was significant tau immunoreactivity in DNs around florid plaques while, in sCJD, GSS and kuru, minimal tau immunoreactivity was observed around plaques. Conclusions: The ultrastructure of the florid plaques and DNs in vCJD is more reminiscent of neuritic plaques in AD than kuru or multicentric plaques. These findings may reflect differences both in the strains of the transmissible agents responsible for these disorders and in host factors.     

AMYLOID PLAQUES IN THE BRAINS OF MICE INFECTED WITH SCRAPIE: MORPHOLOGICAL VARIATION AND STAINING PROPERTIES

Amyloid plaques in the brains of mice infected with scrapie: morphological variation and staining properties
Cerebral amyloid deposits predominantly in the form of plaques are associated with experimental scrapie produced by particular agents in inbred mice. In this paper the staining properties and variation in the morphology of these deposits are described. At the light microscope level a discretionary classification into six types is made: shadowy plaques; amorphous plaques; stellate plaques; giant plaques; diffuse amyloid deposits; and perivascular amyloid deposits. It is shown that Masson's trichrome technique provides the most efficient staining method for identifying cerebral amyloid of all these types. A preliminary ultrastructural examination of stellate plaques confirms the presence of amyloid on the basis of characteristic fibrils and demonstrates that microglia and distended neurites are involved in the structure of the plaques. The similarities and differences between cerebral amyloid in scrapie and other forms of amyloid deposits in the brain, particularly kuru plaques and senile plaques, are discussed.