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At least 811 records · Page 45Linked to original sources
PubMed1997

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease.

Although the inheritance of certain apolipoprotein E (ApoE) alleles has been recognized as a genetic risk factor for Alzheimer's disease, the role of ApoE in the pathology underlying this disease is unclear. Several reports have emphasized the association of ApoE with either beta-amyloid plaque formation or the development of neurofibrillary pathology. Utilization of multiple label immunohistochemical methods enabled us to examine directly the localization of ApoE immunoreactivity relative to beta-amyloid plaques, dystrophic neurites and neurofibrillary tangles. In Alzheimer's disease cases, beta-amyloid plaques showing high ApoE immunoreactivity were localized to layers II, III and V of the neocortex. In layer I, beta-amyloid plaques were unlabelled for ApoE relative to beta-amyloid. Dense core plaques labelled for beta-amyloid often had only the central portions labelled for ApoE. Conversely, ApoE labelled spherical structures within some plaques were not immunoreactive for beta-amyloid or dystrophic neurite markers. Unlike beta-amyloid labelled plaques, all ApoE immunoreactive plaques were associated with dystrophic neurites. In preclinical Alzheimer's disease cases, most plaques were double labelled for beta-amyloid and ApoE. ApoE did not label dystrophic neurites or the early stages of neurofibrillary tangle formation, indicating that ApoE may not be directly involved in neurofibrillary pathology. The specific presence of ApoE in plaques associated with dystrophic neurites in demented patients suggests that ApoE may contribute toward a higher degree of beta-amyloid fibrillogenesis, enhancing the ability of certain plaques to cause damage to surrounding axons.

Aged↗
PubMed2001

New temperature modification makes the Bielschowsky silver stain reproducible.

The Bielschowsky silver impregnation can be used as a single stain for the diagnosis of Alzheimer's disease. It impregnates both the amyloid and neuritic components of the senile plaques and it reliably stains neurofibrillary tangles. However, we find that the stain is highly sensitive to changes of the ambient temperature. Since the diagnostic criteria for Alzheimer's disease rely on a semi-quantitative assessment of neuritic plaques and neurofibrillary tangles the reproducibility of the Bielschowsky stain is important. In this study we compare three different modifications of the Bielschowsky stain with the methenamine silver stain and with immunohistochemistry for the beta-amyloid and the hyperphosphorylated tau proteins. We found that the most reliable and easily reproducible modification of the Bielschowsky silver impregnation is the one that uses incubations at 5 degrees C.

Alzheimer Disease↗
PubMed2004

Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by beta-amyloid peptide (Abeta) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Abeta peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.

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PubMed1994

Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam: quantitative neuropathology, immunohistochemical analysis of neuronal vulnerability, and comparison with related neurodegenerative disorders.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (lytico-bodig) is a chronic neurodegenerative disorder with high prevalence among the native Chamorro population of Guam. Neuropathological, biochemical, and immunohistochemical analyses were performed on a relatively large series of Guamanian cases and compared to Alzheimer's disease cases. Thioflavin S and antibodies to amyloid beta A4 and tau proteins were used for analysis of pathological changes, and antibodies to the calcium-binding proteins parvalbumin and calretinin, and to a nonphosphorylated epitope on neurofilament protein to study select neuronal populations. A differential distribution of neurofibrillary tangles was observed in the neocortex of Guamanian cases compared to Alzheimer's disease cases, with much higher lesion counts in supragranular than in infragranular layers. Also, Guamanian cases with predominant parkinsonism had generally higher neurofibrillary tangle densities than cases with predominant amyotrophic lateral sclerosis. In addition, there was a certain degree of heterogeneity, qualitatively and quantitatively, in the biochemical distribution of tau proteins among Guamanian and Alzheimer's disease cases as revealed by Western blot analysis. Previous studies have suggested that the clinical symptomatology observed in patients suffering from Alzheimer's disease is related to the dramatic loss of specific corticocortically projecting neurons in the neocortex. Interestingly, a subset of neurofilament-rich pyramidal neurons known to be dramatically affected in Alzheimer's disease appears to be resistant in lytico-bodig. Finally, as in Alzheimer's disease, calcium-binding protein-containing interneurons are not affected. These data suggest that the set of projection neurons affected in Guamanian cases may not correspond to those involved in Alzheimer's disease, and that both disorders are characterized by specific patterns of neuronal vulnerability.

Adult↗
PubMed1997

Neurofibrillary lesions in experimental aluminum-induced encephalopathy and Alzheimer's disease share immunoreactivity for amyloid precursor protein, A beta, alpha 1-antichymotrypsin and ubiquitin-protein conjugates.

Neurofibrillary tangles of Alzheimer's disease contain predominantly tau protein and to a lesser degree amyloid precursor protein (APP), A beta protein, alpha 1-antichymotrypsin (ACT) and ubiquitin. Previously we have demonstrated the presence of phosphorylated tau and neurofilament proteins in neurofibrillary degeneration (NFD) induced by aluminum (Al) maltolate in rabbits [Savory et al., Brain Res. 669 (1995) 325-329; Savory et al., Brain Res. 707 (1996) 272-281]. Using the same animal system we have now detected APP, A beta, ACT and ubiquitin-like immunoreactivities in NFD-bearing neurons, often colocalizing in the NFD. Diffuse cytoplasmic staining for APP, A beta and ubiquitin was also present in neurons without NFD from Al maltolate-treated rabbits. This study provides additional support for immunochemical similarities between Al-induced NFD in rabbits and the neurofibrillary tangles in human subjects with Alzheimer's disease.

Aluminum↗
PubMed1997

Primary progressive aphasia, left anterior atrophy, and neurofibrillary hippocampal pathology: observations in an unusual case.

A 71-year-old, right-handed woman experienced onset of a slowly progressive, nonfluent language disorder. She maintained normal cognitive abilities until age 80 and developed a mild spastic right hemiparesis the following year. By age 82, she had become severely demented, mute, and akinetic. Postmortem brain examination showed moderate asymmetric atrophy (wt = 1000 g), which was most prominent in the left perisylvian and posterior frontal regions, with disproportionate enlargement of the left lateral ventricle. Microscopically, a high density of neurofibrillary tangles was present in the hippocampal pyramidal cell layer and entorhinal cortex (up to 45/400 x field, R > L). Gliosis and patchy neuronal loss were symmetrically present in the frontal and parietal lobes including speech areas, but neurofibrillary tangles and neuritic plaques were present in only small numbers (0-1/400 x field). In this case of primary progressive aphasia, pathologic changes associated with Alzheimer's disease occurred in allocortex but not in neocortex. These clinical and neuropathologic findings expand on those previously reported in primary progressive aphasia and suggest a need for further study of this syndrome.

Aged↗
PubMedDate not supplied

A familial case of Alzheimer's disease without tau pathology may be linked with chromosome 3 markers.

Alzheimer's disease is the most common form of dementia that occurs in later years. The diagnosis is confirmed by the pathological findings of betaA4-amyloid-containing neuritic plaques and neurofibrillary tangles, the former being present in sufficient quantity commensurate with age. Other forms of dementia are more difficult to diagnose clinically; their pathology is noted for the lack of plaques and tangles. A patient with a family history of dementia presented with the clinical signs of Alzheimer's disease which lasted for 13 years. At autopsy the brain tissue had betaA4-amyloid-containing neuritic plaques, but no neurofibrillary tangles (i.e., the tissue was negative for staining with the tau antibody). Genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, indicating that this was not frontotemporal dementia. However, there was linkage with chromosome 3 markers. Thus, this form of Alzheimer's disease with a pathology of plaques only is linked with markers on chromosome 3.

Aged↗
PubMedDate not supplied

Progressive supranuclear palsy with widespread cerebral lesions.

A 51-year-old woman with no history of any familial neurological diseases initially presented with numbness in her extremities, slowing of movements, comprehension deficit, memory disturbance, dyscalculia, muscle rigidity, hyperreflexia, Parkinsonian gait, increasing disorientation, left-right disturbance, finger agnosia, alexia, acalculia, apraxia, aspontaneity, euphoria, gait disturbance, aphasia, echolalia, and in the terminal stage, mutism, contracture of lower extremities and cachexia. She died of bronchopneumonia at the age of 55. The brain showed widespread cerebral lesions, consisting of nerve cell loss and neurofibrillary tangles in the frontal, parietal and occipital cortex, demyelination and gliosis in the frontal, parietal and occipital subcortical white matter in addition to the typical pathological findings of progressive supranuclear palsy (PSP): severe neuronal loss with gliosis and neurofibrillary tangles (NFTs) in the subthalamic nucleus, globus pallidus and substantia nigra. In conclusion, we present a case of PSP with unusual clinical features (extrapyramidal signs, frontal and parietal lobe syndromes without ophthalmoplegia) and neuropathologically widespread cerebral lesions in addition to the typical pathological findings of PSP. The differential diagnosis of PSP and Alzheimer's disease and other degenerative disorders is discussed.

Alzheimer Disease↗
PubMed1998

Altered glycosylation pattern of proteins in Alzheimer disease.

Post-translational modifications due to glycosylation of proteins in human brains from patients with Alzheimer disease (AD) were analyzed using lectin histochemistry. Results indicate a significant increase in the production of O-glycosylated (containing Galbeta1,3GalNAc alpha1,0 Ser/Thr or GalNAc alpha1,0 Ser/Thr) proteins in neuritic plaques and neurofibrillary tangles which are the major histopathological hallmarks of AD brains. These alterations were determined by positive labelling with lectins obtained from Amaranthus leucocarpus (ALL) and Macrobrachium rosenbergii (MRL) respectively. Immunohistochemistry indicated that the lectin-staining labelled specifically both neurofibrillary tangles and neuritic plaques. In contrast, lectins labelling was restricted to microvessels in normal control brains. These results provide evidence that modifications of the specific glycosylation patterns are closely related with the presence of the hallmark lesions of this disease, suggesting that an abnormal enzymatic processing of proteins may be an early event in the neuronal degeneration which characterises AD.

Aged↗
PubMed1996

Possible implication of hippocampal cholinergic neurostimulating peptide (HCNP)-related components in Hirano body formation.

We have previously demonstrated that hippocampal cholinergic neurostimulating peptide (HCNP)-related components accumulate in almost all Hirano bodies in Sommer's sector of the hippocampus of elderly individuals, and that the number of HCNP-positive Hirano bodies is greater in patients with Alzheimer's disease. Although Hirano bodies occur preferentially in the neuronal processes of the stratum pyramidale of the hippocampus, they can be seen occasionally as small inclusions, intermingled with neurofibrillary tangles and in association with senile plaques. Here we show that the small inclusions are also recognized by an anti-HCNP antibody, and by using immunoelectron microscopy demonstrate that these HCNP-positive inclusions, intermingled with tau protein-positive neurofibrillary tangles and beta-amyloid-positive senile plaques are indeed Hirano bodies. These findings strongly suggest that HCNP-related components may be involved in Hirano body formation.

Aged↗
PubMed1998

Immunohistochemical localization of nicotinic beta2 and alpha4 receptor subunits in normal human brain and individuals with Lewy body and Alzheimer's disease: preliminary observations.

Optimum immunohistochemical methods were established to immuno-localize nicotinic acetylcholine receptor alpha4 and beta2 subunits in temporal cortex and substantia nigra of normal aged and diseased human brain. In normal aged brain, fibers were immunoreactive for both the alpha4 and beta2 subunits of the nicotinic receptor in the temporal cortex and the substantia nigra. In the cortex of normal aged brain, rare neurofibrillary tangles occurring could be identified with either anti-alpha4 or anti-beta2 antibodies, but existing senile plaques were demonstrable with neither. In Alzheimer's disease temporal cortex, there were diminished numbers of nicotinic receptor subunit immunoreactive fibers, and there were appreciable numbers of neuropil threads, neurofibrillary tangles and senile plaques immunoreactive with both the alpha4 and beta2 antibodies.

Alzheimer Disease↗
PubMed1991

Senile dementia of the Alzheimer type: is there a correlation between entorhinal cortex and dentate gyrus lesions?

Senile plaques (SP) are one of the neuropathological hallmarks of senile dementia of the Alzheimer type (SDAT). In 14 patients affected with SDAT (over 74 years of age), thioflavine S, Tau and acetylcholinesterase (AChE) stainings demonstrated an increased density of SP in the outer two thirds of the dentate gyrus molecular layer. However, a wide range of SP density was observed among the cases. The molecular layer of the dentate gyrus is one of the termination site of the perforant pathway that originates in layers II and III of the entorhinal cortex. We have found that the number of AChE-, thioflavine S- and Tau-positive SP that accumulate in the dentate gyrus is positively correlated with the density of thioflavine S-stained neurofibrillary tangles in layers II and III of the entorhinal cortex. In contrast, a similar correlation is not found when using Tau immunolabeling of the entorhinal tangles. These observations show an association between the accumulation of AChE-positive SP in the dentate molecular layer and the lesions of the perforant pathway. Furthermore, they suggest that the density of SP in the dentate gyrus correlates with the late stages of neurofibrillary tangles formation (thioflavine S positive), but not with the early stages (Tau positive).

Acetylcholinesterase↗
PubMed2001

Suicide and Alzheimer's pathology in the elderly: a case-control study.

BACKGROUND: The single most important risk factor for Alzheimer's pathology is age. Elderly individuals are also at increased risk for suicide, but comprehensive studies of the association between Alzheimer's pathology and suicide are lacking. We designed the current study to determine if Alzheimer's disease changes are overrepresented in elderly people committing suicide. METHODS: The design is a case-control study. Cases (n = 28) were subjects older than 60 years of age who completed suicide. For each case, two age- and gender-matched individuals who died naturally were selected as control subjects (n = 56). Neuropathologic examination of hippocampal sections was performed blindly and included a modified Braak scoring system and semiquantitative assessment of neurofibrillary tangles, amyloid deposition, Lewy bodies, and Lewy-associated neurites. Data were analyzed by conditional logistic regression. RESULTS: The brains of individuals who committed suicide had higher modified Braak scores than those of matching control subjects (p =.0028). The number of neurofibrillary tangles in CA1 was not an independent predictor of suicide status in the statistical analysis (p =.16), although the distribution was more highly skewed among the cases (75th percentile of 10.5 for cases, vs. 2 for control subjects). CONCLUSIONS: Severe Alzheimer's disease pathology is overrepresented in elderly patients who complete suicide.

Aged↗
PubMed2000

Expression profile of transcripts in Alzheimer's disease tangle-bearing CA1 neurons.

The pathogenesis of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) is poorly understood, but changes in the expression of specific messenger RNAs (mRNAs) may reflect mechanisms underlying the formation of NFTs and their consequences in affected neurons. For these reasons, we compared the relative abundance of multiple mRNAs in tangle-bearing versus normal CA1 neurons aspirated from sections of AD and control brains. Amplified antisense RNA expression profiling was performed on individual isolated neurons for analysis of greater than 18,000 expressed sequence tagged complementary DNAs (cDNAs) with cDNA microarrays, and further quantitative analyses were performed by reverse Northern blot analysis on 120 selected mRNAs on custom cDNA arrays. Relative to normal CA1 neurons, those harboring NFTs in AD brains showed significant reductions in several classes of mRNAs that are known to encode proteins implicated in AD neuropathology, including phosphatases/kinases, cytoskeletal proteins, synaptic proteins, glutamate receptors, and dopamine receptors. Because cathepsin D mRNA was upregulated in NFT-bearing CA1 neurons in AD brains, we performed immunohistochemical studies that demonstrated abundant cathepsin D immunoreactivity in the same population of tangle-bearing CA1 neurons. In addition, levels of mRNAs encoding proteins not previously implicated in AD were reduced in CA1 tangle-bearing neurons, suggesting that these proteins (eg, activity-regulated cytoskeleton-associated protein, focal adhesion kinase, glutaredoxin, utrophin) may be novel mediators of NFT formation or degeneration in affected neurons. Thus, the profile of mRNAs differentially expressed by tangle-bearing CA1 neurons may represent a "molecular fingerprint" of these neurons, and we speculate that mRNA expression profiles of diseased neurons in AD may suggest new directions for AD research or identify novel targets for developing more effective AD therapies.

Aged↗
PubMed1996

Neuropathological evaluation and apolipoprotein E gene polymorphism analysis in diffuse Lewy body disease.

We performed a quantitative neuropathological investigation of senile plaques and neurofibrillary tangles in the brains of 14 Japanese patients with diffuse Lewy body disease (DLBD), and examined apolipoprotein E (APOE) gene polymorphism in these patients. Most DLBD brains had as many senile plaques as those with Alzheimer-type dementia (ATD), but fewer neurofibrillary tangles. The APOE epsilon 4 allele frequency in DLBD was 39.3%, similar to that previously reported in pathologically diagnosed ATD. DLBD and ATD are clinically and pathologically distinct, but may have common mechanisms with regard to the formation of amyloid deposition based on these findings. Future investigation of the pure form of DLBD may clarify the association between Lewy body dementia and APOE.

Aged↗
PubMed1996

Temporal bone findings in Alzheimer's disease.

Sensorineural hearing loss has been reported in Alzheimer's disease (AD) and a topographically specific pattern of degeneration in the central auditory system has been described. Although peripheral visual and olfactory systems have been extensively studied, there is no report of peripheral auditory system abnormalities in AD patients. Comparison of temporal bones from eight AD patients with those from eight non-AD controls revealed a significant difference in the percentage of remaining hair cells, peripheral processes, and spiral ganglion cells in the basal cochlear turn but no significant differences in the overall percentage between the two groups. Furthermore, special stains (thioflavin S and Bielschowsky's silver impregnation) of temporal bone nervous tissue from AD patients did not show neuritic plaques and neurofibrillary tangles. It is unclear whether the differences between the two groups in the basal portion of the cochlea are due to AD or some other process, such as presbycusis. However, lack of significant degeneration in other parts of the cochlea and absence of neurofibrillary tangles and neuritic plaques in all eight patients may suggest that the peripheral auditory system, unlike the peripheral visual and olfactory systems, is not involved in AD. A larger sample of AD patients is necessary to clarify the peripheral auditory system findings in the present study.

Aged↗
PubMedDate not supplied

Proposal to revise the morphologic criteria for the diagnosis of Alzheimer's disease.

Ten years have passed since the drafting of the original National Institute on Aging/American Association of Retired Persons or Khatchaturian criteria for the neuropathologic diagnosis of Alzheimer's disease. In that time, much progress has been made in the study of this disorder. It is clear that although the Khatchaturian criteria have been useful, advances in our understanding of the morphologic substrate of the disease needs to be incorporated in any newly proposed diagnostic criteria. We propose diagnostic criteria to be employed in establishing the diagnosis of Alzheimer's disease in a research setting. Here, we require that a level of density and distribution of senile plaques and neurofibrillary tangles be identified and that other superimposed conditions, such as major cerebral infarcts and/or Parkinson's disease changes, are absent. We also propose separate criteria for diagnosing individuals who die in the early stages of the disease. These latter cases are of extreme research interest and are characterized by a distribution of neurofibrillary tangles that remains primarily restricted to the entorhinal cortex and hippocampus.

Aged↗
PubMed1994

Ultrastructural localization of complement membrane attack complex (MAC)-like immunoreactivity in brains of patients with Alzheimer's disease.

The membrane attack complex (MAC) of complement, also known as C5b-9, was localized in Alzheimer's disease (AD) brain by immunoelectron microscopy using a monoclonal antibody to a neoantigenic epitope of soluble C5b-9 (SC5b-9). Immunopositivity was detected in association with lamellated bodies in the neuronal cytoplasm, lipofuscin granules, lysosomes and neurofibrillary tangles (NFTs). Such intracellular localization of MAC-like immunoreactive (MAC-LI) staining suggests that neurons remove membrane-inserted MAC fragments by endocytosis. These endocytosed membrane fragments then proceed by retrograde transport to the perikaryon for lysosomal degradation. Attachment to the abnormal cytoskeletal proteins found in neurofibrillary tangles also occurs. The results provide further evidence that complement-mediated injury of neurons plays a part in the pathophysiology of AD.

Aged↗