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PubMed1996

Monoclonal antibodies against the human metalloprotease EC 3.4.24.15 label neurofibrillary tangles in Alzheimer's disease brain.

Alzheimer's disease is characterized neuropathologically by the presence of neuritic and amyloid plaques, vascular amyloid, and neurofibrillary tangles in specific brain areas. The main constituent of amyloid deposits is amyloid beta protein, a 40-42 amino acid proteolytic product of the amyloid beta-precursor protein. In our search for proteases that can generate the N-terminus of amyloid beta protein (beta-secretases), we discovered a thiol-dependent metalloprotease that was identified, by peptide sequencing, as metalloendopeptidase EC 3.4.24.15. In vitro, the metalloprotease cleaves the methionine-aspartic acid bond in a 10 amino acid synthetic peptide, indicating that it could generate the N-terminus of amyloid beta protein, and generates amyloidogenic fragments from full-length recombinant amyloid beta-precursor protein. Mouse monoclonal antibodies produced against a unique synthetic peptide from the metalloprotease labeled various monkey tissues as detected by western blots and immunohistochemistry. Unexpectedly, two monoclonal antibodies, IVD6 and IIIF3, immunolabeled strongly intracellular neurofibrillary tangles, neurites of senile plaques, and neuropil threads, but not "ghost" tangles or amyloid in sections taken from Alzheimer's disease brain. This finding provides further evidence for the metalloprotease's relevance to Alzheimer's disease pathology, although the connection between tangle staining and the formation of amyloid beta protein remains to be elucidated.

Alzheimer Disease↗
PubMed1990

Antigenic profile of plaques and neurofibrillary tangles in the amygdala in Down's syndrome: a comparison with Alzheimer's disease.

Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity.

Niemann-Pick type C disease is a neurovisceral storage disorder. Neurofibrillary tangles similar to those in Alzheimer's disease have been reported in most juvenile/adult patients without amyloid beta protein (Abeta) deposits. Recently, we found deposits of Abeta in the form of diffuse plaques in three (31- and 32-year-old sisters and a 37-year-old man) of nine Niemann-Pick type C disease patients, who presented with most severe tauopathy and with numerous neurofibrillary tangles. Abeta deposits were not detected in any of the control brains of patients younger than age 42 years. These three patients with Abeta deposit all were homozygotes of apolipoprotein E epsilon 4. Our study suggested that NPC1 gene mutations combined with homozygosity of apolipoprotein E epsilon 4 alleles could manifest neuropathology similar to that of Alzheimer's disease. Investigation of these patients may provide an important clue for understanding the pathogenesis of Alzheimer's disease.

Adult↗
PubMed1990

Cognitive impairment in Parkinson's disease: amyloid plaques, neurofibrillary tangles, and neuropil threads in the cerebral cortex.

Sensitive silver methods for extracellular amyloid and intraneuronal cytoskeleton abnormalities (neurofibrillary tangles and neuropil threads) were employed to examine the cortical pathology in Parkinson's disease. In cases with cognitive impairment many plaque-like amyloid deposits were found in the cerebral cortex. Neuritic plaques were rare or absent. Neither the Ammon's horn nor the isocortex revealed a sufficiently large number of tangles to permit the diagnosis of a coexisting fully developed Alzheimer's disease. Large numbers of neurofibrillary tangles and neuropil threads were only found in layer Pre-alpha of the entorhinal cortex. This layer gives rise to major portions of the perforant tract, a pathway which serves as a link in the transmission of data from isocortical association areas to the hippocampal formation. During the course of Parkinson's disease the hippocampal formation is thus endangered to become disrupted from isocortical influences. It is concluded that the cognitive impairment shown by many individuals suffering from Parkinson's disease may partly be caused by cortical lesions.

Aged↗
PubMed1989

The reinterpretation of the immunochemical study of Alzheimer neurofibrillary tangles.

Many studies have been done on neurofibrillary tangles occurring in Alzheimer's disease using antibodies, but without agreement on the interpretation of the results. Immunochemical studies using antibodies to neurofilament and tau and the antibody, Alz50, were carried out to estaslish a common view. The results suggest that: 1) antibodies to neurofilament recognizing tangles react with the phosphorylated epitope of tau in paired helical filaments; 2) Alz50 reacts with abnormal tau, which has slower electrophoretic mobility than normal tau; and 3) a certain part of tau has the protease-resistant property in brains affected by the disease.

Alzheimer Disease↗
PubMed1992

Ultrastructural localization of acetylcholinesterase in neurofibrillary tangles, neuropil threads and senile plaques in aged and Alzheimer's brain.

Acetylcholinesterase (AChE) histochemistry was used to evaluate the accumulation of this enzyme in senile plaques, neurofibrillary tangles and neuropil threads using light and electron microscopy in Alzheimer's disease as well as non-demented aged brains. Under the electron microscope, a crystalline-like AChE precipitate was localized over paired helical filaments and straight filaments in both neurofibrillary tangles and neuropil threads. AChE reaction product also decorated the amyloid fibrils in diffuse plaques as well as the halo and the heavy accumulation of amyloid which forms the core of classical plaques. In both diffuse plaques and the halo of classical plaques, we found AChE-positive structures resembling cell processes, which in some cases appeared to contain amyloid fibrils. The possible origin and significance of AChE localized over paired helical filaments, straight filaments and amyloid is discussed.

Acetylcholinesterase↗
PubMed1982

Immunostaining of neurofibrillary tangles in Alzheimer's senile dementia with a neurofilament antiserum.

Using anti-chicken brain neurofilament antisera, Alzheimer's neurofibrillary tangles from two patients with senile dementia were stained by immunofluorescence and by the peroxidase-antiperoxidase procedure in cryostat sections of hippocampus and frontal cortex. In sections of cerebellum obtained from the same patients, the distribution of immunostaining was the same as that observed in experimental animals: Purkinje cell baskets and nerve fibers in the inner half of the molecular layer were demonstrated selectively. The immunostaining of the tangles was abolished when the antisera were absorbed by their own antigen, by bovine brain filament preparations, or by the fraction of bovine brain filament preparations nonabsorbed on anti-glial fibrillary acidic (GFA) protein immunoaffinity columns. Absorption with a bovine microtubule preparation isolated by two cycles of the assembly-disassembly procedure did not abolish the staining. Immunostaining experiments conducted on bovine brain filament preparations resolved on sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the antisera staining the tangles reacted with the 200,000-, 150,000-, and 70,000-dalton neurofilament polypeptides. Antisera raised to the 150,000- dalton bovine neurofilament polypeptide isolated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis stained the tangle much less intensely, although Purkinje cell baskets in the cerebellum appeared well stained. No staining of neurofibrillary tangles was observed with antisera to other classes of 10-nm filament proteins (GFA protein, vimentin, and desmin).

Aged↗
PubMed1991

Microglia are associated with the extracellular neurofibrillary tangles of Alzheimer disease.

When neurons die, the filaments of neurofibrillary tangles (NFT) undergo structural and antigenic modifications. The exact mechanism of this modification is unknown, but glial cells could play an important role. Previous studies have shown that astroglial processes infiltrate extracellular NFT. In this study we use double immunolabelling to show that microglia also infiltrate extracellular NFT. Therefore, along with the previously identified astroglia, the microglia could be responsible for the modification of extracellular NFT.

Aged↗
PubMed1994

Morphological investigation of neurofibrillary tangles in Alzheimer's disease.

There are two types of neurofibrillary tangles, namely, a twisted tubule and a straight or uniform tubule in the same cell in the brain with Alzheimer's disease. However, in some parts of the same fibril, both the twisted and straight tubules clearly could be seen as a continuation of each other. This finding suggests that both of the tubules have a deep relation to each other, especially at the molecular level. This might also suggest the possibility of both tubules which mutually transform into each other.

Aged↗
PubMed2002

The subthalamic nucleus has neurofibrillary tangles in argyrophilic grain disease and advanced Alzheimer's disease.

Neurofibrillary tangles (NFT) are present in the subthalamic nucleus (STN) of progressive supranuclear palsy and corticobasal degeneration, two sporadic tauopathies with preferential accumulation of tau with four repeats in the microtubule binding domain (4R tau). Since recent evidence suggests that argyrophilic grain disease (AGD) is also a 4R tauopathy, we hypothesized that the STN may also be affected in AGD. Tau immunostaining was used to evaluate NFT in the STN in 18 cases of AGD compared with 18 non-AGD cases matched for age, sex and Braak stage. AGD cases had significantly more NFT in the STN than non-AGD cases (P=0.008) with no relationship between NFT score and Braak stage. Surprisingly, NFT were also found in the STN of some non-AGD cases, notably in cases with advanced Braak stage (i.e. Alzheimer's disease). When AGD and non-AGD were considered as a whole there was a correlation between neurofibrillary degeneration in the STN and Braak stage. This study demonstrates that neurofibrillary degeneration is frequent in the STN in AGD, but also detected in non-AGD cases with advanced Braak stage.

Aged↗
PubMed2001

Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease.

Although evidence suggests that neurofibrillary tangles (NFTs) and neuronal cell loss are prominent features of Alzheimer's disease (AD), the relationship between the two remains unknown. In the present study, the relationship between the activation of apoptotic mechanisms and NFT formation in AD was investigated using a caspase-cleavage site-directed antibody to fodrin, an abundant neuronal cytoskeleton protein. This antibody recognized cleavage products of fodrin after digestion by caspase-3, but did not recognize full-length fodrin. In vitro analysis of this fodrin caspase-cleavage product (CCP) antibody demonstrates that it is a specific probe for the detection of apoptotic but not necrotic pathways in cultured neurons. To determine whether caspases cleave fodrin in vivo, tissue sections from controls and AD were immunostained for fodrin (CCPs). Although no staining was observed in control cases, labeling of neurons was observed in the hippocampus of all AD cases, which increased as a function of disease progression. To determine a possible relationship between caspase activation and NFT formation, double-labeling experiments with fodrin CCP and PHF-1 were performed. Co-localization of these markers was observed in many neurons, and quantitative analysis showed that as the extent of NFT formation increased, there was a significant corresponding increase in fodrin CCP immunolabeling (r = 0.84). Taken together, these results provide evidence for the activation of apoptotic mechanisms in neurons in the AD brain and suggest that there is an association between NFT formation and the activation of apoptotic pathways in AD.

Adult↗
PubMed1980

Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia.

The degree of neurofibrillary tangle formation, granulovascuolar degeneration, and nerve cell loss was quantified in serial sections of the hippocampal formation from the brains of 5 adults dying with Down syndrome (monogolism). These morphometric results were compared with values obtained from a series of mentally normal elderly patients reported previously. Granulovacuolar change appeared to be related as much to patient age as to the existence of monogolism. By contrast, the number of Alzheimer neurofibrillary tangles and loss of pyramidal neurons from the hippocampus exceeded levels found in considerably older subjects and fell into the same range of severity as was noted in 8 patients with Alzheimer dementia. The neuron population in the hippocampus of Down syndrome patients may be only half the expected normal number for their decade. These quantitative similarities stimulate the search for a common pathogenetic mechanism underlying cerebral changes in monogolism and senile dementia of the Alzheimer type.

Adult↗
PubMed1988

Partial sequence of MAP2 in the region of a shared epitope with Alzheimer neurofibrillary tangles.

A 3.3-kilobase DNA complementary to human microtubule-associated protein 2 (MAP2) was sequenced by the dideoxy method. The 3' end terminates at an internal EcoRI site before the polyA tail. Due to the arrangement of the cDNA insert in the lambda gt11 vector, the MAP2 fragment is not fused to beta-galactosidase when expressed. The Chou Fasman algorithm for the initial 58 amino acids from the first in-frame methionine predicts an alpha helix. Beyond this point, a series of turns is predicted until amino acid 160. The frequent presence of basic residues in proximity to serines or threonines is consistent with multiple phosphorylation sites. The minimum specificity determinant for Ca2+/calmodulin-dependent kinase is repeated 13 times. The sequence of a region containing a MAP2 epitope that is shared with the Alzheimer neurofibrillary tangle was determined by DNase treatment of the cDNA and antibody selecting the small resultant clones in a lambda gt11 sublibrary. Likewise, a MAP2 epitope that is not shared with the neurofibrillary tangle also has been located. Both epitopes are in the projection portion of the molecule. A bovine MAP2 cyanogen bromide fragment, which contains the epitope shared with the neurofibrillary tangle, is partially insoluble under aqueous conditions, probably due to the aggregation of oppositely charged residues. Thus, rapid cleavage of MAP2 to small peptides is probably necessary in vivo to prevent the aggregation of larger cleavage fragments.

Alzheimer Disease↗
PubMedDate not supplied

A beta-associated cerebral angiopathy and senile plaques with neurofibrillary tangles and cerebral hemorrhage in an aged wolverine (Gulo gulo).

In this study of an aged wolverine (Gulo gulo), we document neuropathologic lesions (cerebral amyloid angiopathy (CAA), neuritic plaques (NPs), neurofibrillary tangles (NFTs), and granulovacuolar degeneration strikingly similar to those present in aging and Alzheimer's disease (AD), with the additional finding of concurrent cerebral hemorrhage. A beta immunoreactive cerebral amyloid angiopathy and senile plaques (neuritic and diffuse) were present throughout the cerebral cortex and hippocampus. Ubiquitin immunoreactivity was noted in peripheral portions of some of the plaques. Argyrophilic intracellular neurofibrillary tangles containing abnormally phosphorylated (Ser 202) tau protein were present within cortical and hippocampal neurons. The wolverine should be added to the list of nonhuman species (dogs, nonhuman primates, polar bears) with amyloid deposits similar to those in aged humans and in humans with AD. The aged wolverine appears to be distinct from other nonhuman species in possessing plaques and NFTs, as well as other histologic cerebral lesions frequently associated with AD.

Aging↗
PubMed1993

Neuritic plaques in Alzheimer disease originate from neurofibrillary tangles.

Amyloid beta-protein is a major focus in efforts to understand the etiology of Alzheimer disease yet there is little known about the mechanism of its deposition in plaques. I propose deposition of amyloid in neuritic plaques depends on the remains of neurofibrillary tangles after neuronal death. The interaction of these two lesions means neuritic plaques are not only dependent on neurofibrillary tangles and neuronal death but also dependent on their concurrence.

Alzheimer Disease↗
PubMed1998

Bcl-2 and Bax protein expression in neurofibrillary tangles in progressive supranuclear palsy.

Double-labeling immunohistochemistry to Bcl-2 and Bax and to tau protein was examined in the brains of patients with progressive supranuclear palsy (PSP) to study the possible relationship between the expression of Bax and Bcl-2 proteins and neurofibrillary tangle formation. No differences between Bcl-2 and Bax immunoreactivity in neurons of the brain stem were observed in PSP patients and controls. Moreover, the intensity of Bcl-2 and Bax immunoreactivity was similar in tangle-bearing and non-tangle-bearing neurons in PSP patients. These results suggest that Bcl-2 and Bax are probably not implicated in neurofibrillary tangle formation in PSP.

Case-Control Studies↗
PubMedDate not supplied

Ultrastructure of neurofibrillary tangles in the cerebral cortex of sheep.

Recently, we reported that neurofibrillary tangles (NFTs) of the Alzheimer type develop in the cerebral cortex of aged sheep (Ovis aries). In the current study, we utilized light and electron microscopic immunocytochemistry to describe in greater detail the characteristics of sheep NFTs during early stages of neurofibrillary degeneration. We investigated neurons that were stained using the monoclonal antibody Alz-50 and that contained relatively small numbers of paired helical filaments (PHFs). Serially cut ultrathin sections were evaluated to take maximal advantage of ultrastructural resolution. At the light microscope level, we observed preferential localization of Alz-50 immunoreactive accumulations at dendritic branch points in early NFTs. A similar staining pattern was observed using the monoclonal antibody AT8 which recognizes a phosphorylated epitope on tau. Ultrastructurally, we found that Alz-50 staining at dendritic branch points was associated with clusters of ribosomes. The focal deposition of phosphorylated tau proteins at dendritic branch points may indicate a link between the initial stages of neurofibrillary pathology and specific cytoskeletal alterations that involve dendritic remodeling. Neurons that contained relatively small numbers of PHFs appeared otherwise healthy with regard to their cytoskeleton and organelles.

Aging↗