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PubMed2004

Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease.

Previously, we have shown that caspase-6 but not caspase-3 is activated by serum deprivation and induces a protracted cell death in primary cultures of human neurons (LeBlanc AC, Liu H, Goodyer C, Bergeron C, Hammond J: Caspase-6 role in apoptosis of human neurons, amyloidogenesis and Alzheimer's disease. J Biol Chem 1999, 274:23426-23436 and Zhang Y, Goodyer C, LeBlanc A: Selective and protracted apoptosis in human primary neurons microinjected with active caspase-3, -6, -7, and -8. J Neurosci 2000, 20:8384-8389). Here, we show with neoepitope antibodies that the p20 subunit of active caspase-6 increases twofold to threefold in the affected temporal and frontal cortex but not in the unaffected cerebellum of Alzheimer's disease brains and is present in neurofibrillary tangles, neuropil threads, and the neuritic plaques. Furthermore, a neoepitope antibody to caspase-6-cleaved Tau strongly detects intracellular tangles, extracellular tangles, pretangles, neuropil threads, and neuritic plaques. Immunoreactivity with both antibodies in pretangles indicates that the caspase-6 is active early in the pathogenesis of Alzheimer's disease. In contrast to the nuclear and cytosolic localization of active caspase-6 in apoptotic neurons of fetal and adult ischemic brains, the active caspase-6 in Alzheimer's disease brains is sequestered into the tangles or neurites. The localization of active caspase-6 may strongly jeopardize the structural integrity of the neuronal cytoskeletal system leading to inescapable neuronal dysfunction and eventual cell death in Alzheimer's disease neurons. Our results suggest that active caspase-6 is strongly implicated in human neuronal degeneration and apoptosis.

Aged↗

PubMed1990

Alzheimer's neurofibrillary tangles and paired helical filaments in the pheochromocytoma cells of the adrenal medulla--electron microscopic and immunoelectron microscopic observations.

Alzheimer's neurofibrillary tangles (NFT) and paired helical filaments (PHF) were found in the pheochromocytoma cells of the adrenal gland removed from a 54-year-old female. By electron microscopy they were identical to those found in the brains affected by dementia of Alzheimer type. In the tumor cells, most of the PHF were found dispersed loosely in the cytoplasm, while typical NFT were infrequent. By immunoelectron microscopy using peroxidase-antiperoxidase method, both NFT and dispersed PHF were stained positively with a polyclonal antiserum to human tau protein. This is the first observation of NFT and PHF in paraneuronal tumor cells. The patient has no obvious Alzheimer's disease.

Adrenal Gland Neoplasms↗

PubMedDate not supplied

The topographic distribution of senile plaques and neurofibrillary tangles in the brains of non-demented persons of different ages.

The incidence and severity of senile plaques (SP) and neurofibrillary tangles (NFT) were examined in six areas of brain in 60 non-demented patients of age range 6-84 years. Thirty-two patients showed neither SP nor NFT in any region (30 of these were under 65 years of age), 15 patients showed both SP and NFT in one or more regions (14 were over 60 years of age), 11 patients aged 21-84 years showed NFT only in one or more areas and two patients showed SP alone and only in the amygdala. Overall comparison of number and severity showed the greatest severity of SP within the amygdala in most instances, whereas NFT were found in most instances and at greatest severity within the hippocampus. The reason for this apparent vulnerability of these areas of brain to SP and NFT formation may lie with their connections with the outside world via the olfactory bulbs and tract. This pathway may thus provide an entry point to the brain for pathogenic agent(s) that may induce, either directly or indirectly, pathological processes that ultimately lead to SP and NFT formation.

Adolescent↗

PubMed1993

Altered phosphorylation of growth-associated protein B50/GAP-43 in Alzheimer disease with high neurofibrillary tangle density.

The growth-associated phosphoprotein B50/GAP-43, associated with axonal proliferation and regeneration, was isolated from superior temporal gyrus (area 22) of seven control and eight Alzheimer disease (AD) postmortem human brains. Membrane and cytoplasmic proteins were fractionated and B50/GAP-43 was isolated by reverse-phase HPLC and gel electrophoresis. B50/GAP-43 was identified with rabbit polyclonal antibodies 4P3 (generated against the calmodulin binding domain of B50/GAP-43) and 1B5 (generated against whole bovine B50/GAP-43). B50/GAP-43 protein was further separated into phosphorylated and dephosphorylated species by calmodulin-Sepharose chromatography. The amounts of phosphorylated and dephosphorylated B50/GAP-43 forms were determined by electrophoresis, protein staining, and densitometry. Data on the relative phosphorylation of B50/GAP-43 protein in membrane and cytoplasmic fractions show a 10-fold difference in the ratio of cytoplasmic/membrane phosphorylation of B50/GAP-43 in AD brains with high neurofibrillary tangle (NFT) density compared to AD brains with low NFT density. This difference is due to a decreased percentage of phosphorylated B50/GAP-43 in the membrane fraction relative to that in the cytosolic fraction from high NFT density. No analogous relationship was found between the phosphorylation of B50/GAP-43 and the density of neuritic plaques in the brains examined. These data indicate differential distribution of phosphorylated and dephosphorylated B50/GAP-43 in normal and AD brains is related to NFT density but not to neuritic plaque density.

Aged↗

PubMed1999

Variant Gerstmann-Sträussler syndrome with the P105L prion gene mutation: an unusual case with nigral degeneration and widespread neurofibrillary tangles.

We present here a case of variant Gerstmann-Sträussler syndrome (GSS) with a codon 105 mutation of the prion protein gene. A 57-year-old woman developed dementia and gait disturbance dissimilar to the spastic paraparesis that is observed in most cases with codon 105 mutation. The clinical course of the disease in this case was 12 years. The brain weighed 900 g, and the frontal lobe, pallidum and thalamus were markedly atrophic. Severe neuronal loss was observed in the deep layer of the frontal and temporal cortices, and fibrillary gliosis and a marked loss of neurons was observed in the globus pallidus, thalamus and substantia nigra. Many amyloid plaques and some ballooned neurons were present in the frontal, temporal and parietal cortices. However, no spongiform changes were seen. The cerebellum was relatively well preserved. Numerous neurofibrillary tangles (NFTs) were recognized in the cerebral cortices, and scattered NFTs were observed in the basal nucleus of Meynert, thalamus, substantia nigra, periaqueductal gray matter, raphe nuclei and locus ceruleus. The case presented here indicates the presence of variations in the pathological findings of cases with codon 105 mutation, and that the formation of cortical and brain stem NFTs might have something to do with the duration of illness and/or the degree of brain tissue destruction that had occurred.

Brain↗

PubMed1995

Decreased activity of hippocampal neurons in Alzheimer's disease is not related to the presence of neurofibrillary tangles.

Numerous studies have established the key role of the Golgi apparatus (GA) in post-translational processing, transport and targeting of proteins destined for secretion, lysosomes and plasma membranes. Moreover, several studies performed in our laboratories have shown that the size of the immunocytochemically detected neuronal GA is a reliable index of neuronal activity in aging, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. It has been suggested that in AD there is decreased neuronal activity, e.g. in terms of glucose metabolism and protein synthetic capability. To further explore the hypothesis of decreased neuronal activity in AD, in this study the size of the GA was measured in pyramidal neurons of the CA1 area of the hippocampus of non-demented controls and AD patients. The size of the GA was measured separately in neurons with and without neurofibrillary tangles (NFT). Moreover, in order to establish a correlation between the density of NFT and the size of the GA, the density of extraneuronal NFT was determined around each neuron and related to the size of its GA. The results, quantified by image analysis, indicate that there is a significant reduction in GA size in the neurons of the CA1 area of the hippocampus of AD patients. However, there was no significant relationship between the size of the GA and the presence or absence of intracellular NFT. In addition, there was no correlation between the density of extracellular NFT and GA size of adjacent neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2000

Dual enhancement of double immunofluorescent signals by CARD: participation of ubiquitin during formation of neurofibrillary tangles.

Amplification with catalyzed reporter deposition (CARD) greatly enhances peroxidase signals, which has been utilized to amplify immunohistochemical labelings including fluorochromes. Here we describe a strategy to amplify each of two immunofluorescent signals without crosstalk on double-stained histological sections from human autopsied brains with Alzheimer's disease (AD). One of the two primary antibodies (anti-Abeta or anti-PHF-tau) was probed by a species-specific secondary antibody conjugated with horseradish peroxidase (HRP), which was visualized by FITC-labeled tyramide. After inactivation of HRP, the other primary antibody was probed by another species-specific secondary antibody conjugated with HRP. Amplification with biotinylated tyramide was followed by streptavidin-conjugated Cy-5, which specifically labeled the latter epitope. It was found that Abeta and PHF-tau were localized to senile plaques and neurofibrillary tangles (NFTs), respectively, which verified lack of crosstalk on the double-stained section. Localization of ubiquitin and PHF-tau was looked for at higher magnification in NFT-bearing neurons. Although these two epitopes were colocalized in some neurons, ubiquitin was not always present in PHF-tau positive NFTs. Discrepancy between PFH-tau and ubiquitin, verified inter- and intracellularly, may represent different stages of NFT formation. This is the first report of successful CARD amplification of two different fluorescent signals on double-labeling immunohistochemistry, which is now proved to be powerful in detecting epitopes in relation to AD-related lesions. Improved intensity over tenfold of the two fluorescent signals without crosstalk will expand the application of the multilabeling method with fluorochromes.

Alzheimer Disease↗

PubMed1998

A protein kinase, PKN, accumulates in Alzheimer neurofibrillary tangles and associated endoplasmic reticulum-derived vesicles and phosphorylates tau protein.

A possible role for a protein kinase, PKN, a fatty acid-activated serine/threonine kinase with a catalytic domain homologous to the protein kinase C family and a direct target for Rho, was investigated in the pathology of Alzheimer's disease (AD) using a sensitive immunocytochemistry on postmortem human brain tissues and a kinase assay for human tau protein. The present study provides evidences by light, electron, and confocal laser microscopy that in control human brains, PKN is enriched in neurons, where the kinase is concentrated in a subset of endoplasmic reticulum (ER) and ER-derived vesicles localized to the apical compartment of juxtanuclear cytoplasm, as well as late endosomes, multivesicular bodies, Golgi bodies, secretary vesicles, and nuclei. In AD-affected neurons, PKN was redistributed to the cortical cytoplasm and neurites and was closely associated with neurofibrillary tangles (NFTs) and their major constituent, abnormally modified tau. PKN was also found in degenerative neurites within senile plaques. In addition, we report that human tau protein is directly phosphorylated by PKN both in vitro and in vivo. Thus, our results suggest a specific role for PKN in NFT formation and neurodegeneration in AD damaged neurons.

Aged↗

PubMed2002

Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain.

Recent studies have confirmed the role of reactive oxygen species in the pathogenesis of Alzheimer's disease (AD). 8-Oxo-2'-deoxyguanosine accumulation in AD brain has been discussed, but few studies of DNA repair enzymes in AD brain have been done. Further, a relationship between mitochondrial function and oxidative stress has been noticed. In this study, to evaluate the repair mechanism for oxidative DNA damage in AD brain, we investigated brain tissues from autopsy cases of AD and control cases using an antibody against the mitochondrial form of 8-oxoguanine DNA glycosylase (hOGG1-2a), an enzyme that repairs 8-oxo-2'-deoxyguanosine. hOGGI-2a is expressed mainly in the neuronal cytoplasm in both AD and control cases in regionally different manners. Expression of hOGG1-2a is decreased in the orbitofrontal gyrus and entorhinal cortex in AD compared to that in control cases. Immunoreactivity to hOGG1-2a is associated with neurofibrillary tangles, dystrophic neurites and reactive astrocytes in AD. Our results indicate that the repair enzyme for oxidative damage in mitochondrial DNA may not function appropriately in AD, and thus oxidative DNA damage in mitochondria may be involved in the pathomechanism of AD.

Aged↗

PubMed2001

The relationship between alphaB-crystallin and neurofibrillary tangles in Alzheimer's disease.

AlphaB-crystallin is known as a small heat shock protein with a cytoprotective function. This study was undertaken to investigate the relationship between alphaB-crystallin and changes seen in Alzheimer's disease. The distribution and immunohistochemical characteristics of alphaB-crystallin positive neurones in the cerebral cortices of 4 patients with Alzheimer's disease were examined. AlphaB-crystallin positive neurones were mainly distributed in the limbic and paralimbic regions, namely parahippocampal gyrus, fusiform gyrus, cingulate cortex, middle and superior frontal gyrus, and insular cortex, which corresponded to commonly affected regions in Alzheimer's disease. Moreover, such neurones were present predominantly in the III or V layer of the cerebral cortex. The number of alphaB-crystallin positive neurones increased in parallel with the neuronal loss. Logistic regression analysis revealed a significant relation between the density of alphaB-crystallin positive neurones and that of extracellular neurofibrillary tangles (NFTs), with a correlation coefficient (r) of 0.57 and P < 0.0001 in 14 regions of the cerebral cortex. In contrast, the relation was not statistically significant between the density of alphaB-crystallin positive neurones and that of classical senile plaques, diffuse plaques or intracellular NFTs. Modified Gallyas-Braak (GB) staining on alphaB-crystallin positive neurone demonstrated several patterns of the structures: faint GB positive structures in the swollen perikaryon with straight neurites, fine granules compressed and contorted into fuzzy bundles, intensely GB positive filamentous structures together with fine granules and very intensely GB positive ring-like NFTs in a swollen perikaryon with curved neurites. In positive neurones, the density of ring-like NFTs correlated with that of atrophic perikaryon, or bent neurites and a decrease in the immunoreactivity of alphaB-crystallin. These data suggest that a close relationship exists between the appearance of alphaB-crystallin in neurones, extracellular NFTs, and neurofibrillary formation in alphaB-crystallin positive neurones in Alzheimer brain.

Aged↗

PubMed1996

Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II.

Using immunohistochemistry, we examined the localization of four types of proline-directed kinases in the brains of control rats and in the brains of non-demented aged human subjects, subjects with Alzheimer's disease and those with Down's syndrome. The four kinases were: cyclin-dependent kinase (cdk) 5, a component of tau protein kinase (TPK) II; TPK I/glycogen synthase kinase (GSK)-3 beta; GSK-3 alpha; and mitogen-activated protein kinase (MAPK/ERK2). Each of these kinases has been reported to promote the hyperphosphorylation of tau protein in vitro. The kinases were located essentially in neurons, although the intensity and distribution of labeling varied. Antiserum for cdk5 showed the most preferential and consistent labeling of intraneuronal neurofibrillary tangles (NFT). Antiserum for TPK I/GSK-3 beta also labeled intraneuronal NFT. Double immunolabeling for TPK I/GSK-3 beta and tau 1 showed that TPK I/GSK-3 beta was closely associated with NFT. Antiserum for GSK-3 alpha labeled neurons weakly, and the intensity of labeling did not differ between neurons with and without NFT. Antiserum for MAPK labeled neurons in superficial cortical layers, but NFT appeared in both superficial and deep cortical layers. These findings suggest that cdk5 and TPK I/GSK-3 beta are the critically important kinases for the generation in vivo of hyperphosphorylated tau, the main component of the paired helical filaments in NFT.

Aged↗

PubMed2005

Transgenic mice expressing mutant (N279K) human tau show mutation dependent cognitive deficits without neurofibrillary tangle formation.

Mutations in the tau gene, which is located on chromosome 17, were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To determine if cognitive deficits could be caused by tau mutations, two transgenic mouse lines were generated expressing a four-repeat isoform of human tau or its mutant, containing one of the FTDP-17 mutations (WILD mice and N279K mice). In open field test, N279K mice showed hyperactivity in locomotion and rearing. In prepulse inhibition test, N279K mice but not Wild mice showed significant deficits. Both transgenic mice, especially N279K mice, showed impairment in acquisition of spatial learning in Morris water maze. Although both N279K mice and Wild mice acquired passive avoidance as well as non-transgenic mice, N279K mice but not Wild mice showed severe deficits in acquisition of active avoidance. Histological analysis of the present mutant mice did not show any signs of neurofibrillary tangle formations in the brain, and cognitive dysfunction seemed to precede such neuropathological changes or occur independently from them. The behavioral phenotype of N279K mice mimics features of human FTDP-17 and provides a basic model for elucidating mechanisms underlying cognitive deficits in not only FTDP-17, but also diverse tauopathies.

Alzheimer Disease↗

PubMed1999

beta-amyloid deposition and neurofibrillary tangle formation in the olfactory bulb in ageing and Alzheimer's disease.

Impaired olfaction, hyposmia or anosmia are part of the clinical phenotype in neurodegenerative disorders including Alzheimer's disease (AD). It has been proposed that the most severely affected areas are interconnected with the central olfactory system in contrast to the relative sparing of other sensory areas which lack olfactory connections. The pathology of the first synaptic relay in the olfactory pathway, the olfactory bulb (OB), has been studied in AD, but the results have been inconsistent. In order to define more fully the pathology of the OB, we analysed 15 AD and 15 control cases, using amyloid and tau immunohistochemistry on serial sections. This study demonstrates for the first time that all layers of the OB are severely affected in AD and in normal ageing. The principal effector cells of the OB, the mitral cells, developed neurofibrillary tangles (NFTs) both in AD and in controls. All the cases, with the exception of two of the controls, contained NFTs. Amyloid immunoreactivity was detected in diffuse, primitive, classical and compact deposits in AD, while five control cases contained mainly diffuse deposits. We did not find a correlation between amyloid deposition and NFT formation. Among the control cases, two contained neither amyloid nor NFTs, eight had NFTs but no amyloid and only five had both NFTs and amyloid. All the AD cases had NFT and amyloid deposition. Our data suggest that the earlier pathology in the OB is NFT formation and more than ten NFTs/section is compatible with 93.3% diagnostic accuracy for AD.

Aged↗

PubMed2001

Hyperphosphorylation of RNA polymerase II and reduced neuronal RNA levels precede neurofibrillary tangles in Alzheimer disease.

Affected neurons of Alzheimer disease (AD) brain are distinguished by the presence of the cell cycle cdc2 kinase and mitotic phosphoepitopes. A significant body of previous data has documented a decrease in neuronal RNA levels and nucleolar volume in AD brain. Here we present evidence that integrates these seemingly distinct findings and offers an explanation for the degenerative outcome of the disease. During mitosis cdc2 phosphorylates and inhibits the major transcriptional regulator RNA polymerase II (RNAP II). We therefore investigated cdc2 phosphorylation of RNAP II in AD brain. Using the H5 and H14 monoclonal antibodies specific for the cdc2-phosphorylated sites in RNAP II, we found that the polymerase is highly phosphorylated in AD. Moreover, RNAP II in AD translocates from its normally nuclear compartment to the cytoplasm of affected neurons, where it colocalizes with cdc2. These M phase-like changes in RNAP II correlate with decreased levels of poly-A RNA in affected neurons. Significantly, they precede tau phosphorylation and neurofibrillary tangle formation. Our data support the hypothesis that inappropriate activation of the cell cycle cdc2 kinase in differentiated neurons contributes to neuronal dysfunction and degeneration in part by inhibiting RNAP II and cellular processes dependent on transcription.

Adult↗

PubMed2006

Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain.

Thrombin is a serine protease that is generated by proteolytic cleavage of its precursor, prothrombin. We previously showed that thrombin proteolyses the microtubule-associated protein tau and that phosphorylation of tau inhibits this process. To characterize further the role of thrombin in the brain, we investigated prothrombin and thrombin expression in cultured brain cells and in brains of control, Alzheimer disease (AD) and parkinsonism-dementia complex of Guam (PDCG). We show by reverse transcriptase-polymerase chain reaction that prothrombin mRNA is expressed in brain tissues, neuroblastoma cells, and cultured human astrocytes, oligodendrocytes, and microglial cells. We also show by immunohistochemistry that the proteins prothrombin and thrombin are present in brain using specific monoclonal and polyclonal antibodies for both proteins. All antibodies stained residual serum in blood vessels, as well as normal pyramidal neurons and their processes, and some astrocytes. Additionally, in AD and PDCG cases, all antibodies stained extra- and intracellular neurofibrillary tangles (NFTs), senile plaques, and reactive microglial cells. The ubiquitous expression of prothrombin and thrombin in brain cells suggests that thrombin plays an important physiological role in normal brain. The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases.

Aged↗

PubMed2004

Cross-linking of ubiquitin, HSP27, parkin, and alpha-synuclein by gamma-glutamyl-epsilon-lysine bonds in Alzheimer's neurofibrillary tangles.

The accumulation of misfolded proteins in intracellular inclusions is a generic feature of neurodegenerative disorders. Although heavily ubiquitylated, the aggregated proteins are not degraded by the proteasomes. A possible reason for this phenomenon may be a modification of deposited proteins by transglutaminases forming gamma-glutamyl-epsilon-lysine (GGEL) cross-links between distinct proteins. Here, we show that the frequency of GGEL cross-links is an order of magnitude higher in Alzheimer's brain cortex than in age-matched or younger controls. This difference is due to the accumulation of GGEL cross-links in ubiquitin-immunopositive protein particles present in both Alzheimer's brains and those from aged individuals. The highly cross-linked protein aggregates show immunoreactivity to antibodies against tau and neurofilament proteins, and partially also to alpha-synuclein, indicating that these structures are inherent in Alzheimer's neurofibrillary tangles and Lewy bodies. Using mass sequence analysis, we identified the same six pairs of peptide sequences cross-linked in both senile and Alzheimer's specimens: Gln31 and Gln190 of HSP27 protein are cross-linked with Lys29 and Lys48 of ubiquitin and HSP27 therefore may cross-link two (poly)ubiquitin chains. One lysine residue of parkin and one of alpha-synuclein were also found to be cross-linked. The data suggest that cross-linking of (poly)ubiquitin moieties via HSP27 may have a role in the stabilization of the intraneuronal protein aggregates by interference with the proteasomal elimination of unfolded proteins.

Adult↗

PubMed2005

Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L).

Here, we describe the generation of a novel transgenic mouse model of human tauopathy. The rTg(tau(P301L))4510 mouse expresses the P301L mutation in tau (4R0N) associated with frontotemporal dementia and parkinsonism linked to chromosome 17. Transgene expression was driven by a forebrain-specific Ca(2+) calmodulin kinase II promoter system resulting in high levels of expression in the hippocampus and neocortex. Importantly, transgene expression in this model is induced via the tetracycline-operon responsive element and is suppressed after treatment with doxycycline. Continued transgene expression in rTg(tau(P301L))4510 mice results in age-dependent development of many salient characteristics of hereditary human dementia. From an early age, immunohistochemical studies demonstrated abnormal biochemical processing of tau and the presence of pathological conformation- and phosphorylation-dependent epitopes. Neurofibrillary tangle (NFT) pathology was first observed in the neocortex and progressed into the hippocampus and limbic structures with increasing age. Consistent with the formation of NFTs, immunoblots indicated an age-dependent transition of accumulating tau species from Sarkosyl soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. Ultrastructural analysis revealed the presence of straight tau filaments. Furthermore, the effects of tau(P301L) expression on spatial reference memory were longitudinally tested using the Morris water maze. Compared with nontransgenic age-matched control littermates, rTg(tau(P301L))4510 mice developed significant cognitive impairments from 4 months of age. Memory deficits were accompanied by gross forebrain atrophy and a prominent loss of neurons, most strikingly in hippocampal subdivision CA1. Collectively, these data describe a novel transgenic mouse that closely mimics human tauopathy and may represent an important model for the future study of tau-related neurodegenerative disease.

Aging↗

PubMed1990

Comparison of three silver stains for demonstrating neurofibrillary tangles and neuritic plaques in brain tissue stored for long periods.

Three methods were compared to find a reliable method for demonstrating neurofibrillary tangles (NFTs) and neuritic plaques (NPs) in brain tissue stored for long periods in formalin or as paraffin blocks. The short-term fixation of tissue, e.g. up to 6 months in formalin does not usually present a problem using any of the three methods tried, e.g. Gallyas, modified Palmgren, or modified Bielschowsky, but once the time lengthens to 6 years or more the demonstration of NFTs and NPs is not so reliable using the first two methods. The modified Bielschowsky method, however, demonstrates well both NFTs and NPs in material stored in formalin or as paraffin blocks for long periods, e.g. 7 years, and also compares favourably with the other methods on freshly processed material and fixed tissue, stored for shorter periods. We also noted as a consistent trend, irrespective of the staining technique employed, the detection of fewer plaques and tangles in material stored in formalin, as opposed to that stored as blocks embeded in paraffin wax.

Aged↗