Relationship of amyloid β/A4 protein to the neurofibrillary tangles in Guamanian parkinsonism-dementia

The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), wich clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immuno-histochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its -amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thiolavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as tangle-associated amyloid deposits. Such BAP deposits have previously eeen described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.     

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

Summary 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 -protein and the PHF-related tau protein. All cases showed a large number of tau-immunoreactive neurofibrillary tangles and also -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 -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.Supported by grants from the Intractable Disease Division, Ministry of Health and Welfare, Primary Amyloidosis Research Committee and Kanae Foundation of New Medicine, and a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture, Japan     

Similar topographical distribution of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism–dementia complex in people living in the Kii peninsula of Japan suggests a single tauopathy

The presence of many neurofibrillary tangles (NFTs) in the central nervous system is a hallmark of amyotrophic lateral sclerosis (ALS) and parkinsonism–dementia complex (PDC) in people living in the Kii peninsula of Japan and in the island of Guam. To determine whether or not ALS and PDC are on a spectrum of a single tauopathy, we investigated the topography of NFTs semiquantitatively in two patients with ALS, three with PDC, and two with “PDC plus ALS” (PDC followed by ALS) on the basis of clinical symptoms. NFTs were counted under ×100 magnification of Gallyas-Braak stained preparations and were plotted on brain maps of the hemisphere, brainstem, and the spinal cord. In all cases, the hippocampus, particularly in the CA1 field, the parahippocampal gyrus, amygdaloid nucleus, and the temporal poles were most severely affected. In the neocortex, layers II–III were more severely affected by NFTs than layers V–VI. In the spinal cord, a few NFTs were revealed in the intermediate gray. NFTs were dense in all cases of PDC and “PDC plus ALS” and variable in density in ALS cases, although the topography was similar between them. We conclude that similar topographical distribution of NFTs in ALS and PDC in people living in the Kii peninsula of Japan suggests a single tauopathy.     

Combined analysis of CSF βA42 peptide and tau protein and serum antibodies to glycosaminoglycans in Alzheimer's disease: preliminary data

Summary. Neuropathological hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, containing βA₄₂ peptide and tau protein, respectively. Amyloid plaques contain also glycosaminoglycans (GAGs). Whereas cerebrospinal fluid (CSF) levels of βA₄₂ peptide and tau protein have been demonstrated as potential markers of Alzheimer's disease (AD), no data are available for GAGs. We determined (Elisa) tau and βA₄₂ CSF levels, as well as serum antibodies to GAGs in 9 AD patients, and the values were analyzed in relation to age and severity of the disease. Beta-A42 and tau CSF levels were significantly reduced and increased, respectively, in AD patients when compared to controls, but they did not correlate with the severity of the disease. Despite their role in amyloidogenesis, we did not find evidence for the use of GAGs as diagnostic marker of AD. Received September 4, 2001; accepted November 5, 2001     

Ultrastructural localization of Alzheimer amyloid β/A4 protein precursor in the cytoplasm of neurons and senile plaque-associated astrocytes

Summary The ultrastructural localization of amyloid /A4 protein precursor (APP) in the brains of control and Alzheimer's disease patients was examined immunohistochemically using antisera against the N and C termini of APP. In both control and Alzheimer brains, immunoreaction for APP was seen in the cytoplasm of most neurons, on plasma membranes, outer membrane of mitochondria, granular substance and neurofilaments. Cell bodies and foot processes of astrocytes, containing glial filaments, were also labeled. In primitive and classic type senile plaques, APP immunoreaction products were localized in the astroglial processes that surrounded the amyloid mass of the senile plaques. Swollen degenerating neurites in the senile plaques were also labeled. Amyloid fibrils were negative with APP antisera.Supported by Grant-in-Aid for Scientific Research on Priority Area 02240105 from the Ministry of Education, Science, and Culture, Japan     

A point mutation in the EGF-4 domain of β(3) integrin is responsible for the formation of the Sec(a) platelet alloantigen and affects receptor function

Neonatal alloimmune thrombocytopenia (NAIT) is caused by fetomaternal platelet incompatibility with maternal antibodies crossing the placenta and destroying fetal platelets. Antibodies against human platelet antigen-1a (HPA-1a) and HPA-5b are responsible for the majority of NAIT cases. We observed a suspected NAIT in a newborn with a platelet count of 25 G/l and petechial haemorrhages. Serological analysis of maternal serum revealed an immunisation against αIIbβ3 on paternal platelets only, indicating the presence of an antibody against a new rare alloantigen (Sec(a)) residing on αIIbβ3. The location of Sec(a) on αIIbβ3 was confirmed by immunoprecipitation. Nucleotide sequence analysis of paternal β3 revealed a single nucleotide exchange (G(1818)T) in exon 11 of the β3 gene (ITGB3), changing Lys(580) (wild-type) to Asn(580) (Sec(a)). Two additional members of the family Sec were typed Sec(a) positive, but none of 300 blood donors. Chinese hamster ovary cells expressing Asn(580), but not Lys(580) αIIbβ3, bound anti-Sec(a), which was corroborated by immunoprecipitation. Adhesion of transfected cells onto immobilised fibrinogen showed reduced binding of the Asn(580) variant compared to wild-type αIIbβ3. Analysis of transfected cells with anti-LIBS and PAC-1 antibody showed reduced binding when compared to the wild-type. No such effects were observed with Sec(a) positive platelets, which, however, are heterozygous for the Lys(580)Asn mutation. In this study, we describe a NAIT case caused by maternal alloimmunisation against a new antigen on αIIbβ3. Analysis with mutant transfected cells showed that the Lys(580)Asn mutation responsible for the formation of the Sec(a) antigenic determinant affects αIIbβ3 receptor function.