Gerstmann-Sträussler-Scheinker disease showing beta-protein type cerebellar and cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is observed in several brain degenerative disorders, but this pathological condition has received little attention in Gerstmann-Sträussler-Scheinker disease (GSS). We report a 69-year-old man who showed the cardinal features of GSS together with typical and extensive congophilic angiopathy. Immunohistochemical studies revealed that the vast majority of the amyloid plaques present in the brain of this patient were consistently labeled by anti-prion protein (PrP) antibody. Double immunostaining disclosed many additional beta-protein immunoreactive plaque-like lesions, including a special type of "hybrid" plaque with colocalization of PrP and beta-protein (beta-PrP). The vascular amyloid deposits seen in both the cerebellum and cerebrum were immunoreactive only to anti-beta-protein antibody. It seems likely that the extensive deposition of beta-protein amyloid (including brain vascular amyloidosis) seen in this and other similar cases is part of pathology of GSS, although the possibility that this finding is due to ageing or concomitant Alzheimer's disease cannot be completely ruled out.

Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein.

A histopathological study was carried out on the brains of eight ex-boxers (ages 56 to 83) using conventional histological staining methods and immunocytochemistry with antibodies to amyloid beta-protein and the PHF-related tau protein. All cases showed a large number of tau-immunoreactive neurofibrillary tangles and also beta-protein immunoreactive senile plaques in the cortex. In the areas with many neurofibrillary tangles, neuropil threads with tau-immunoreactivity were also observed, and some of the senile plaque lesions were surrounded by abnormal neurites with tau-immunoreactivity. Moreover, three cases revealed beta-protein-type cerebrovascular amyloid deposits on both leptomeningeal and cortical blood vessels. The present observations indicate that the cerebral pathology of dementia pugilistica is very similar to that of Alzheimer's disease and suggest that these two disorders share some common etiological and pathogenic mechanisms.

Early senile plaques in Alzheimer's disease demonstrated by histochemistry, immunocytochemistry, and electron microscopy.

To clarify early pathologic changes in Alzheimer's disease, the brains from two cases from a single family with this disease were examined. A mother who died at age 75 with severe dementia showed an abundance of typical senile plaques, neurofibrillary tangles, and cerebrovascular amyloidosis. The senile plaque and cerebrovascular amyloid were strongly immunoreactive to anti-beta protein antibody. Her son manifested erratic and bizarre behavior, and was suspected of having committed suicide at age 52. His brain weight and macroscopic observations were normal; however, Bielschowsky's silver impregnation and methenamine silver stains showed numerous argyrophilic plaque-like lesions in the neocortex. They were weakly immunolabeled by anti-beta protein antibody, but lacked any abnormal neurites of Congophilic amyloid deposits. These lesions resembled the "type 3" immunoreactive lesions (previously reported by us in Alzheimer's disease and Down's syndrome) which seem to be an early stage of senile plaque formation. These putative early plaque lesions were also examined by methenamine silver electron microscopy, and were seen to consist of loose aggregations of irregular spindle-shaped structures with a heavy deposition of silver grains, with genuine amyloid fibrils not being apparent. It is believed that the accumulation of beta-protein immunoreactive material without amyloid fibril formation might be an initial step in the development of the senile plaque, and that the son, having extensive cortical involvement with type 3 plaque lesions, demonstrated clinical manifestations of less completely developed Alzheimer's disease.

Amyloidosis of the nervous system.

Various types of amyloid fibril deposits occur in the nervous system with unique clinical characteristics and pathogeneses. Genetic mutations cause the familial amyloidotic polyneuropathies and acquired polyneuropathies occurring particularly in patients suffering from hypernephromas and myelomas also result from the production of abnormal proteins. Amyloid fibril deposits in cerebral plaques and vessels consisting of beta-protein are seen in acquired and familial Alzheimer's disease and in Down's syndrome individuals over 40 years of age. This amyloid fibril deposition could result from a mutational, transcriptional or post-translational alteration in these pathologic processes with most evidence supporting the latter. Other diseases including hereditary cerebral hemorrhage of the Dutch type and Batten's disease involve beta-amyloid deposition. The features of the familial and transmissible forms of the spongiform encephalopathies are associated with the prion protein which comprises the amyloid fibril deposits in these conditions. This wide variety of nervous system disorders having amyloid deposits as their primary or subsidiary characteristic make studies of these conditions intriguing models for research workers in clinical, pathologic and molecular biologic fields.

Evidence of amyloid beta-protein immunoreactive early plaque lesions in Down's syndrome brains.

An immunohistochemical study was carried out on the brains of 12 cases with Down's syndrome (ages 18 to 62) using a monoclonal antibody to amyloid beta-protein with formic acid pretreatment of the sections. Localized ill-defined, weakly immunostained areas with a reticulogranular appearance were the only neocortical lesions observed in two cases aged 31 years. The presence of similar immunoreactive areas with larger size were the predominant cerebral lesions seen in 3 cases who died at the ages of 37 or 38 years. These resembled the "type 3" immunoreactive lesions (lacking any obvious amyloid deposits or abnormal neurites) that were observed previously by us in Alzheimer's disease. In addition to these lesions, older cases of Down's syndrome over 50 years of age showed discrete senile plaques with substantial deposits of amyloid (the number of these lesions increased with age), and many neurofibrillary tangles and cerebrovascular amyloid deposits were also found in these cases. The present observations support the theory that the type 3 lesions are an early stage in senile plaque formation, and suggest that an extensive appearance of type 3 lesions easily detected by immunostaining with formic acid pretreatment is an early neuropathologic change in Alzheimer's disease.

Antibodies specific for the pancreatic islet amyloid polypeptide associated with type 2 diabetes mellitus.

Antibodies raised to a lysine solubilized peptide composed of residues 20-29 of the pancreatic islet amyloid polypeptide react selectively and specifically with this polypeptide and with islet amyloid deposits in Type 2 diabetes mellitus. These antibodies may prove useful in studies employing radioimmunoassay of body fluids and islet cell cultures in order to define if a pathogenic relationship exists between the islet amyloid polypeptide and Type 2 diabetes mellitus.

Evidence for the derivation of a peptide ligand from the amyloid beta-protein precursor of Alzheimer's disease.

A monoclonal antibody to a synthetic peptide consisting of residues 8-17 of amyloid beta-protein was used in immunohistochemical studies to reveal binding sites for this peptide in cytoplasmic vesicles in cells of the adrenal zona reticularis and the islets of Langerhans of the pancreas. These binding sites showed some specificity for this peptide and so may represent a membrane receptor. These results suggest that the membrane bound beta-protein precursor may be processed by limited extracellular proteolysis to release a peptide ligand containing the 8-17 sequence. It has been reported recently that the core protein of a heparin sulphate proteoglycan (HSPG) secreted by PC12 cells shows some homology with the beta-protein precursor. This suggests that the binding sites might be due to the presence of a HSPG core protein receptor. Further studies should be carried out to find out if receptors to beta-protein peptides are present in brain tissue, since these might play a role in the catabolism of the beta-protein precursor, and in the formation of cerebral amyloid in Alzheimer's disease (AD).

A study of the morphology and distribution of amyloid beta protein immunoreactive plaque and related lesions in the brains of Alzheimer's disease and adult Down's syndrome.

An immunohistochemical study was carried out on the brains of 20 cases with Alzheimer's disease and the same number of non-Alzheimer's controls using a monoclonal antibody to amyloid beta protein. The morphology and distribution of immunoreactive plaque-like lesions and the sensitivity of immunostaining were assessed both with and without formic acid pretreatment of the sections, and these results were compared with those obtained from conventional Congo red and silver impregnation staining methods. The brains of 8 cases with Down's syndrome (ages 18 to 62) were also studied using similar staining techniques. In the cases with Alzheimer's disease Congo red and immunostaining without formic acid pretreatment mainly stained the core deposits of amyloid in compact plaques, whereas the silver stain could also detect numerous diffuse plaques. Immunostaining with formic acid pretreatment was the most sensitive technique, and this showed many additional immunoreactive lesions of faint granular staining with little evidence of amyloid deposition or degenerating neurites. Similar ill-defined, faintly immunoreactive areas were the only neocortical lesions observed in the two cases aged 31 and 38 years respectively, and in addition to these lesions, older cases of Down's syndrome revealed extensive and numerous discrete senile plaques with amyloid deposition. Far fewer immunoreactive lesions were observed in the non-Alzheimer's controls. The ill-defined, beta protein immunoreactive regions mentioned above, therefore, are presumed to be very early stages in senile plaque development, and it is concluded that an extensive appearance of beta protein immunoreactive plaque lesions throughout the cortex and subcortical gray matter structures is typical of Alzheimer's disease.

The pathobiology of Alzheimer's disease.

The discovery of beta protein, the major component of the amyloid fibrils of the plaques and cerebral vessels and of the paired helical filaments of the neurofibrillary tangles, has provided a means to decipher the pathogenesis of Alzheimer's disease. The same lesions in aged Down's syndrome individuals have also been shown to be composed of beta protein. Gene probes localize the gene for beta protein, as well as that for familial Alzheimer's disease, to chromosome 21, but these genes are not linked. A study of posttranslational modifications of the 695-amino-acid beta-protein gene precursor, with specific reference to abnormal proteolysis, may provide insights into the cause of the amyloidotic lesions of Alzheimer's disease and the means of arresting them.

Amyloid beta protein and the basis for Alzheimer's disease.

The amyloid fibril protein isolated from the cerebrovascular amyloid deposits seen in 92% of cases of Alzheimer's disease and 100% of cases of Down's syndrome over the age of 40 has been shown to have a previously unknown amino acid sequence. This protein has been designated beta protein (beta P) and the type amyloid fibrils, ACv beta. Polyclonal and monoclonal antibodies raised to a synthetic peptide comprising the first 10 amino acids of beta P localized both to cerebrovascular amyloid deposits as well as to the amyloid cores of all "senile" plaques. An amino acid sequence analysis based on that of the beta P has been reported indicating that the plaque amyloid fibril deposits are also composed of beta P. These deposits must cause severe disruption of neuronal fibers. Thus beta P in the form of amyloid deposits seems intrinsic to the destruction of neuronal competence and thus to the ensuing dementia of Alzheimer's disease. Since proteolysis converts the beta P precursor (Pre beta P) into amyloid fibrils, it is possible that 1) an abnormality in synthesis of the Pre beta P, perhaps during post-transitional events, or 2) an abnormality in proteolytic processing occurs to afford beta P deposits and the pathologic changes in Alzheimer's disease. Regardless of the processing abnormality, beta P represents a major component in the pathogenesis of Alzheimer's disease.

Morphology and distribution of plaque and related deposits in the brains of Alzheimer's disease and control cases. An immunohistochemical study using amyloid beta-protein antibody.

A monoclonal antibody (4D12/2/6) to a synthetic peptide consisting of residues 8-17 of the amyloid beta-protein of Alzheimer's disease was used in an immunohistochemical study to investigate the localization of beta-protein immunoreactivity in neuritic plaques in the brains of 20 cases with Alzheimer's disease and a similar number of nonAlzheimer controls. The morphology and distribution of immunoreactive plaque-like lesions and the sensitivity of immunostaining were assessed both with and without formic acid pretreatment of the sections, and these results were compared with those obtained using conventional Congo red and silver impregnation staining methods. Congo red and immunostaining without formic acid pretreatment mainly stained the core deposits of amyloid in compact plaques, whereas the silver stain could also detect numerous diffuse plaques. Immunostaining with formic acid pretreatment was the most sensitive technique, and this revealed many additional immunoreactive lesions which were impossible or difficult to detect with the other staining methods. These additional lesions included variable sized areas of faint granular staining with little evidence of amyloid deposition or degenerating neurites that are presumed to be very early stages in plaque development. Far fewer immunoreactive lesions were observed in the nonAlzheimer controls. It is concluded that an abundant presence of anti-beta-protein immunoreactive plaque lesions throughout the cortex and subcortical gray matter structures is typical of Alzheimer's disease even when only moderate numbers of plaques can be detected by Congo red or silver stain. This immunostaining procedure with a specific monoclonal antibody for beta-protein may be very useful for the postmortem diagnosis of Alzheimer's disease.

Cerebrovascular amyloid in scrapie-affected sheep reacts with antibodies to prion protein.

In an immunohistochemical study of naturally-occurring and experimental scrapie in sheep, deposits of cerebrovascular amyloid were found to react with antibodies to hamster scrapie prion protein (PrP 27-30), but not with antibodies to the amyloid beta-protein of Alzheimer's disease. It is concluded that this vascular amyloid is formed from PrP and is therefore closely associated with scrapie infection. It is likely that this amyloid is formed from a host precursor protein as a specific pathological consequence of invasion by the scrapie agent.

Amyloid fibrils formed from a segment of the pancreatic islet amyloid protein.

A synthetic peptide formed from residues 20-29 of the pancreatic islet amyloid protein has the confirmation of a twisted beta-pleated sheet protein suggesting it is a potential contributor toward amyloid fibril formation in the islets of Langerhans in Type 2 diabetes mellitus.

Differences between vascular and plaque core amyloid in Alzheimer's disease.

The predominant protein of cerebrovascular and plaque core amyloid in Alzheimer's disease, Down's syndrome, hereditary hemorrhage with amyloidosis--Dutch type, sporadic cerebral amyloid angiopathy, and age-related amyloidosis is a unique polypeptide, called beta protein. The length of the plaque amyloid protein was reported to be 42-43 residues, but the complete length of the cerebral vascular amyloid is not known. To clarify this issue, amyloid fibrils from the leptomeninges of an Alzheimer's disease patient were isolated and the primary structure determined. The complete sequence of cerebrovascular beta-amyloid protein, although homologous to the plaque core amyloid protein previously reported, has 39 residues instead of 42. Amino terminal heterogeneity is present but minimal, and it is three residues shorter at the carboxy terminus. These differences are similar to those found in two cases of hereditary hemorrhage with amyloidosis--Dutch type. The differences between vascular and plaque beta-amyloid may reflect diverse processing of the beta protein precursor in the vessel wall and brain parenchyma due to tissue-specific endopeptidases.

Immunohistochemical evidence for the derivation of a peptide ligand from the amyloid beta-protein precursor of Alzheimer disease.

A monoclonal antibody to a synthetic peptide consisting of residues 8-17 of the amyloid beta protein of Alzheimer disease was used in immunohistochemical studies to reveal binding sites for this peptide in vesicular elements in the islets of Langerhans of the pancreas and the zona reticularis of the adrenal gland. These binding sites may represent a specific membrane receptor. These results, together with similarities in structural features between the precursors for epidermal growth factor and beta protein, suggest that the beta-protein precursor may be processed to release an active peptide ligand rather than acting as a membrane receptor. In Alzheimer disease, abnormal processing of this active peptide precursor may result in the deposition of beta-protein amyloid fibrils in the brain.