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PubMed1992

Accumulation of amyloid precursor protein in damaged neuronal processes and microglia following intracerebral administration of aluminum salts.

Alzheimer's disease is characterized by neurofibrillary tangles and amyloid deposits, with the latter probably occurring because of abnormal accumulation and/or processing of amyloid precursor protein (APP). Aluminum salts are known to be neurotoxic and to be capable of inducing neurofibrillary tangles. We explored the effects of intraventricular or intrastriatal injections of AlCl3 on the immunodistribution of APP in rat brain. There was a striking and long-lasting accumulation of APP in affected neurites, as well as in activated microglia/macrophages. Abnormal neurites also showed argentophilic changes, neurofilament accumulation, and Alz50 immunoreactivity. However, no extracellular amyloid fibrils were seen. The results, taken together with previous studies on colchicine, are consistent with the hypothesis that interruption of axoplasmic flow can lead to both APP accumulation and cytoskeletal changes.

Aluminum↗
PubMed1991

Neocortical neuronal subpopulations labeled by a monoclonal antibody to calbindin exhibit differential vulnerability in Alzheimer's disease.

Numerous studies have demonstrated that specific neuronal subtypes display a differential vulnerability to the pathological process in Alzheimer's disease. Large pyramidal neurons are likely to be highly vulnerable, whereas smaller neurons are more resistant to pathology. Using a monoclonal antibody to the calcium-binding protein calbindin, we observed in the human prefrontal cortex distinct populations of labeled cells. First, a subset of heavily stained interneurons was located in layers II and superficial III and in layers V-VI. Second, a subpopulation of pyramidal neurons in the mid and deep parts of layer III displayed a less intense, punctate staining pattern. The interneurons in the superficial layers were unaffected in the Alzheimer's disease cases. Interestingly, in layers V-VI, there was significant cell loss in the interneuron population, but only in the Alzheimer's disease cases with high neurofibrillary tangle densities. The calbindin-immunoreactive pyramidal neurons of layer III were dramatically affected in the disease. Moreover, there was a strong correlation between the extent of the loss of these cells and neurofibrillary tangle counts. These data suggest that calbindin is present in multiple neuronal subpopulations that exhibit a differential vulnerability in Alzheimer's disease and support the hypothesis that the degenerative process involves specific neuronal subsets with particular anatomical and molecular profiles.

Aged↗
PubMed1978

On the distribution of senile changes in the spinal cord.

Using serially sectioned spinal cords, studies were made on the number of Alzheimer's neurofibrillary tangles, and the distribution of lipofuscin in five cases of clinically and histopathologically confirmed Alzheimer's disease, 10 cases of similarly confirmed senile dementia and 10 cases of mentally normal people. Alzheimer's neurofibrillary tangles were not observed at all in Alzheimer's disease and in the conrol group. A very small number of them were found in the intermediolateral cell, posterior column cell, anterolateral cell, and anteromedian cell groups in three cases of senile dementia. The deposition of lipofuscin was high in the anterolateral and posterolateral cell groups and nucl. dorsalis in all of the cases of Alzheimer's diseases, senile dementia and the control group. It is worthy of note that the Alzheimer's group, for its age, showed a relatively greater amount of lipofuscin.

Aged↗
PubMed1991

Pathologic changes in olfactory neurons in Alzheimer's disease.

Olfactory deficits and degenerative changes in central olfactory pathways are prominent in patients with Alzheimer's disease (AD). We hypothesized that peripheral olfactory neurons that reside in the nasal epithelium would show degenerative changes similar to the characteristic pathologic features of AD brain. Immunohistochemical studies of nasal tissue taken at autopsy reveal extensive degeneration in the sensory epithelium as well as abnormal neurites that share immunoreactive epitopes with dystrophic neurites and neurofibrillary tangles of the AD brain. The neuritic masses are stained with well-characterized monoclonal antibodies that do not normally stain olfactory neurons but which are very reactive with dystrophic neuritic structures and neurofibrillary tangles in AD brain. These include antibodies to phosphorylated and nonphosphorylated neurofilament subunits, tau, and also ALZ50, which is characteristically reactive with AD but not with normal brains. Such changes are present in 81% of AD patients. Similar accumulations of ectopic neurites are found in the olfactory epithelium of about 22% of non-demented patients. Preliminary statistical analysis fails to reveal any age-linked association. It has been proposed that the aged monkey is a good model for AD inasmuch as amyloid accumulations similar to those of humans are found in monkey brain. We examined a series of 13 rhesus monkeys, including aged animals with behavioral deficits. Although the olfactory epithelium was very similar to that of humans, no abnormal olfactory structures were observed. Aged rhesus monkeys do not appear to be a good model for the neuritic abnormalities of AD.

Alzheimer Disease↗
PubMed1992

Amine accumulation: a possible precursor of Lewy body formation in Parkinson's disease.

It is now well recognized that the hypothalamus is an important site of neuropathology in Parkinson's disease (PD). Lewy bodies, a marker of nerve cell degeneration and a pathological hallmark of PD, have been observed frequently in the hypothalamus of PD patients by Lewy (1923) and other investigators and confirmed by more recent systematic studies by Langston & Forno (1978). Both Lewy and Langston & Forno found a predilection of Lewy body formation in specific hypothalamic nuclei with the tuberomammillary, lateral, and posterior areas containing by far the highest average counts per nucleus. Selective vulnerability of the tuberomammillary, lateral, and posterior hypothalamic cell groups to degeneration has been observed also in aging, postencephalitic Parkinsonism, Alzheimer's disease, and schizophrenia. The susceptibility of these particular nuclei to degenerative changes including Lewy body formation is not presently understood nor are the mechanisms by which Lewy bodies are formed in PD and other CNS disorders. Accumulation of amines, a pathological process which follows degeneration of catecholamine-containing neurons in experimental animals, also occurs most frequently in the lateral and posterior hypothalamic areas. In the present communication we propose that in PD, amine accumulation may be a precursor to Lewy body formation and that the susceptibility of certain hypothalamic areas to Lewy body formation may be related to their propensity to accumulate amines. Furthermore, the frequent co-existence of Lewy bodies and Alzheimer's neurofibrillary tangles in the lateral and posterior hypothalamic nuclei suggest that they may share a common pathogenetic etiology. If confirmed, this hypothesis may provide an experimental model by which the formation of Lewy bodies and neurofibrillary tangles may be investigated.

Animals↗
PubMed1995

Localisation and association of pathomorphological changes at the brainstem in Alzheimer's disease.

The brainstems of ten patients with Alzheimer's disease were examined with specific silver impregnations for beta-amyloid deposits, neurofibrillary tangles, neuropil threads and neuritic plaques. The results show a selective and focal involvement of brainstem nuclei, which are diffusely connected to the cortex or are neuronally connected with other damaged subcortical and cortical regions. Therefore, it is concluded that neuronal connectivity plays an important role in the pathogenesis of Alzheimer's disease lesions. This may be due to the intraneuronal transport of beta-amyloid precursor protein. There was a local association between neurofibrillary tangles and neuropil threads, but not between beta-amyloid structures on the one hand and neurofibrillary structures on the other hand. Neuritic plaques were rarely found.

Aged↗
PubMed2002

Tau is essential to beta -amyloid-induced neurotoxicity.

Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar beta-amyloid peptide (Abeta); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar Abeta-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar Abeta. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of Abeta. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of Abeta. These results provide direct evidence supporting a key role for tau in the mechanisms leading to Abeta-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Abeta-mediated neurodegeneration.

Amyloid beta-Peptides↗
PubMed2000

Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation.

Mutations in the highly homologous presenilin genes encoding presenilin-1 and presenilin-2 (PS1 and PS2) are linked to early-onset Alzheimer's disease (AD). However, apart from a role in early development, neither the normal function of the presenilins nor the mechanisms by which mutant proteins cause AD are well understood. We describe here the properties of a novel human interactor of the presenilins named ubiquilin. Yeast two-hybrid (Y2H) interaction, glutathione S-transferase pull-down experiments, and colocalization of the proteins expressed in vivo, together with coimmunoprecipitation and cell fractionation studies, provide compelling evidence that ubiquilin interacts with both PS1 and PS2. Ubiquilin is noteworthy since it contains multiple ubiquitin-related domains typically thought to be involved in targeting proteins for degradation. However, we show that ubiquilin promotes presenilin protein accumulation. Pulse-labeling experiments indicate that ubiquilin facilitates increased presenilin synthesis without substantially changing presenilin protein half-life. Immunohistochemistry of human brain tissue with ubiquilin-specific antibodies revealed prominent staining of neurons. Moreover, the anti-ubiquilin antibodies robustly stained neurofibrillary tangles and Lewy bodies in AD and Parkinson's disease affected brains, respectively. Our results indicate that ubiquilin may be an important modulator of presenilin protein accumulation and that ubiquilin protein is associated with neuropathological neurofibrillary tangles and Lewy body inclusions in diseased brain.

Adaptor Proteins, Signal Transducing↗
PubMed1981

The clinical biochemistry of aluminum.

The methods for aluminum analysis vary from the simple and often nonspecific chemical and physical procedures to the highly sophisticated types such as neutron activation and atomic absorption spectrometry. Atomic absorption procedures are the techniques of choice for most routine hospital laboratories. The wide distribution of aluminum in nature can create severe contamination problems in aluminum analysis. Procedures to avoid contamination are discussed. In recent years aluminum has been implicated as a possible etiological agent in DES and in Alzheimer's Disease. A common finding in these two conditions is an elevated brain aluminum content. The patients with Alzheimer's Disease develop characteristic neurofibrillary tangles which lead to the degeneration of the affected neurons. Similar tangles can be induced in laboratory animals injected intracerebrally with aluminum salts. Even though the laboratory animals develop tangles resembling those seen in patients with Alzheimer's Disease, no evidence has been published to show that the tangles seen in Alzheimer's Disease are induced by the elevated brain aluminum content. Although there are some similar clinical symptoms in both Alzheimer's Disease and DES, the hemodialysis patients with DES do not develop neurofibrillary tangles despite an elevated brain aluminum content. The significance of this difference is not understood. The sources of the increase in tissue aluminum levels found in hemodialysis patients are from the gastrointestinal absorption of aluminum in aluminum containing phosphate-binding gels and by transfer from the dialyzate to the blood during the hemodialysis procedure. Plasma aluminum values may be reduced by the administration of a minimum dosage of phosphate-binding gels and by the use of purified water to make up the dialysate. The incidence of DES is reduced by the use of these procedures to maintain the hemodialysis patients' plasma aluminum at a low concentration. The increased brain aluminum content of patients with Alzheimer's Disease is derived from the environment. Because of the ubiquitous occurrence of aluminum, we are exposed to it daily in our food, water, and in the air. The low levels of aluminum absorbed from the environment may explain why susceptible patients do not develop Alzheimer's Disease until after many years of exposure, if indeed aluminum is the etiological agent in Alzheimer's Disease. The many papers that have been published concerning aluminum, DES, and Alzheimer's Disease make a strong case for linking elevated tissue aluminum content with these conditions. However, conclusive evidence to support this theory has not been published. Until the effect of aluminum on cellular chemistry is more fully understood, the possibility that DES and Alzheimer's Disease may result from other causes or from aluminum and another agent acting concomitantly must be considered.

Aluminum↗
PubMedDate not supplied

Topographic relationship between neurofibrillary change and acetylcholinesterase rich neurons in the upper brain stem of patients with senile dementia of the Alzheimer's type and Down's syndrome.

In order to establish the topographical relationship between neurofibrillary change and the distribution of cholinergic neurons, the upper brain stems were studied from nine cases of senile dementia of the Alzheimer's type (SDAT). For each case, the distribution of the neurofibrillary changes was recorded and compared with the distribution in five control patients of acetylcholinesterase-rich neurons as determined by enzyme histochemistry. The numbers and distribution of neurons with neurofibrillary change were also studied in five age-matched controls and in three individuals with Down's syndrome. The results indicate that, in contrast to that in control patients, the upper brain stem is heavily involved by neurofibrillary change in SDAT. Correlation of the distribution of neurofibrillary tangles in SDAT patients with the localization of acetylcholinesterase-rich neurons suggests that most of the cholinergic nuclei in the upper brain stem are affected in SDAT, but are not exclusively or predominantly involved. Most neurofibrillary tangles were found in noncholinergic nuclei such as the raphe nuclei and the locus ceruleus. The individuals with Down's syndrome showed a heavy involvement in the older cases, thus reinforcing the significance of Down's syndrome in defining the evolution of pathologic changes in Alzheimer's disease or SDAT.

Acetylcholinesterase↗
PubMed1996

Inhibition of protein phosphatase-2B (calcineurin) activity towards Alzheimer abnormally phosphorylated tau by neuroleptics.

Abnormally hyperphosphorylated tau is the major protein component of neurofibrillary tangles, the characteristic lesion of Alzheimer's disease (AD). Protein phosphatases (PP) type 1 (PP-1), type 2A (PP-2A) and type 2B (PP-2B) appear to be involved in the regulation of tau phosphorylation. The incidence of neurofibrillary tangles is higher in brains of schizophrenic patients treated with neuroleptics than in those without this treatment. We have found that the commonly used neuroleptics chlorpromazine, trifluoperazine and clozapine inhibit PP-2B but not PP-1 or PP-2A activity towards [32P]phosphorylase kinase as a substrate. When AD abnormally hyperphosphorylated tau is used as a substrate, PP-2B activity is inhibited by trifluoperazine > chlorpromazine > clozapine. Using phosphorylation-dependent monoclonal antibodies, tau-1, AT8 and PHF-1, we have found that the dephosphorylation of the abnormal tau by PP-2B is inhibited at all the sites recognized by these antibodies. The IC50 of the inhibition of dephosphorylation at tau-1 site is approximately 20 microM for trifluoperazine and approximately 120 microM for chlorpromazine. These two neuroleptics inhibit tau dephosphorylation by PP-2B through antagonizing calmodulin as well as directly interacting with PP-2B. The inhibition of the dephosphorylation of abnormally hyperphosphorylated tau by neuroleptics raises an intriguing possibility that the chronic use of these drugs might contribute to neurofibrillary degeneration in schizophrenic and AD patients.

Alzheimer Disease↗
PubMed2001

Tau accumulation in a patient with pallidonigroluysian atrophy.

We studied the brain of a patient with pallidonigroluysian atrophy (PNLA) in whom argyrophilic and abnormally phosphorylated tau positive neurons and glia were identified in the brain on Gallyas-Braak silver staining and immunohistochemical analysis although neurofibrillary tangles were not seen by Bodian silver stain. Immunohistochemical studies using six anti-tau antibodies that recognize the different phosphorylated epitopes of tau protein revealed that these epitopes in neurons and glial cells share common characteristics with neurofibrillary tangles in Alzheimer's disease. Immunoblot analysis of phosphorylated tau protein showed major bands of 64 and 68 kDa and after dephosphorylation, tau consisted mainly of 4 repeat tau. No mutations were detected in the coding exons and their flanking intronic regions of the tau gene. This study suggests that PNLA is one of tauopathy and the biochemical characteristics of phosphorylated tau are similar to those found in progressive supranuclear palsy and corticobasal degeneration.

Aged↗
PubMed1997

Apolipoprotein E uptake and low-density lipoprotein receptor-related protein expression by the NTera2/D1 cell line: a cell culture model of relevance for late-onset Alzheimer's disease.

Apolipoprotein E has been shown to be a risk factor for late-onset Alzheimer's disease, with the apolipoprotein epsilon 4 allele conferring the risk. Apolipoprotein E is found in neurofibrillary tangles and senile plaques, the pathological characteristics of Alzheimer's disease. To date there is no direct evidence that human neurons can take up exogenous apolipoprotein E, which is necessary if apolipoprotein E is involved in the formation of neurofibrillary tangles. To examine apolipoprotein E uptake we employed the human NTera2/D1 cell line, which can be induced by retinoic acid to differentiate into postmitotic NTera2-N neurons, which have the characteristics and morphology of human central nervous system neurons. We defined the cell line as genotype apolipoprotein epsilon 3/3 and demonstrated that the cells do not synthesize apolipoprotein E but can take up and internalize exogenous recombinant apolipoprotein E3. We also confirmed the expression of the low-density lipoprotein receptor-related protein, a known receptor for apolipoprotein E. The NTera2/D1 cell line therefore provides a useful human cell model for examining the effects of other apolipoprotein E isoforms with a view to defining intraneuronal interactions of apolipoprotein E.

Alzheimer Disease↗
PubMed2005

Neuropathology of Alzheimer's disease.

In 1907, Alois Alzheimer described the presence of plaques and neurofibrillary tangles in a demented patient. Currently, Alzheimer's disease is known to be the most common cause of dementia in elderly patients. In this article, we summarize the most important neuropathologic features of Alzheimer's disease, including amyloid plaques, neurofibrillary tangles, neuronal loss, synaptic depletion, cerebral amyloid angiopathy, Hirano bodies, and granulovacuolar degeneration. We also review the history and application of Alzheimer's disease diagnostic criteria.

Alzheimer Disease↗
PubMed1994

A subset of calretinin-positive neurons are abnormal in Alzheimer's disease.

The distribution of the calcium-binding protein calretinin was investigated by immunohistochemistry in the hippocampus, the subicular areas, and the entorhinal cortex in patients with Alzheimer's disease and in control subjects. By double immunolabelling, the calretinin immunoreactivity was compared to the immunoreactivity for beta/A4 amyloid or for tau proteins. Calretinin-positive neurons were mainly observed in the molecular layer of the gyrus dentatus, the stratum radiatum of the Ammon's horn, and in layers II and III of the entorhinal cortex. The general pattern of calretinin immunoreactivity was conserved in Alzheimer's disease. Calretinin-positive neurons appeared normal in the hippocampus but had a reduced dendritic tree in the entorhinal cortex. Dystrophic calretinin immunoreactive fibres were often observed in the outer molecular layer of the gyrus dentatus and in the CA4 sector in Alzheimer's disease. Most neurons containing neurofibrillary tangles were not calretinin immunoreactive and most senile plaques were not associated with calretinin positive fibres. These results show that entorhinal calretinin-positive neurons are affected in Alzheimer's disease in spite of an absence of systematic association with neurofibrillary tangles and senile plaques.

Aged↗
PubMed2002

Neuropathological diagnosis of Alzheimer's disease in forensic autopsy of elderly persons with fatal accident.

Cognitive dysfunction in Alzheimer's disease may lead to accidental deaths in the elderly. Neuropathological diagnosis of the disease is, therefore, an important issue in forensic autopsy to determine the causal relation to accidents. To evaluate the suitability of the current histopathological diagnostic criteria for Alzheimer's disease by Khachaturian and Mirra et al. in elderly persons dying from accidents and coming for forensic autopsy, we studied the brains of nine demented and 12 non-demented persons by silver stain and immunohistochemistry. When the density of senile plaque was applied to the criteria, only four out of nine demented persons met the criteria for definite Alzheimer's disease. The demented persons had significantly higher density of diffuse plaque and higher frequencies of amyloid angiopathy, neurofibrillary tangle and neuropil thread than the non-demented persons. These results indicated that the current diagnostic criteria do not always diagnose Alzheimer's disease in forensic autopsy of elderly persons with fatal accident. The presence of abundant diffuse plaque, neurofibrillary tangle, amyloid angiopathy and neuropil thread may help to diagnose Alzheimer's disease in forensic autopsy.

Journal Article↗
PubMed1988

The association of ventral tegmental area histopathology with adult dementia.

Six cases of adult dementia with mesolimbic pathology are reported. The core clinical syndrome consists of parkinsonism, progressive dementia, and behavioral disturbances (generally depression). The histopathologic findings uniformly include a loss of pigmented neurons in the ventral tegmental area plus neurofibrillary tangles and/or cell loss in the entorhinal cortex and pyramidal cell layer of the hippocampus (perforant pathway). Neuronal depletion in the ventral tegmental area frequently is associated with similar cell loss in the adjacent substantia nigra and in the locus ceruleus. The development of neurofibrillary tangles in the perforant pathway occurs in the absence of senile plaques and is possibly related to diminished dopaminergic input.

Aged↗
PubMed1988

Cortical somatostatin, neuropeptide Y, and NADPH diaphorase neurons: normal anatomy and alterations in Alzheimer's disease.

Somatostatin and neuropeptide Y are two neuropeptides that are of particular interest in Alzheimer's disease because they are reported to be depleted in cerebral cortex. In the present study we examined somatostatin, neuropeptide Y, and nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase neurons in nine cortical regions in both normal and Alzheimer's disease brains. These three neurochemical markers show a high degree of co-localization (greater than 90%) in nonpyramidal neurons that are primarily distributed in cortical layers II-III, V-VI, and, most prominently, in infracortical white matter. The highest cell density was in temporal and parietal association cortex. The major morphological abnormality in Alzheimer's disease brains was a marked pruning and distortion of fiber plexuses with an apparent reduction in fiber density. In contrast, perikaryal density was preserved except for a reduction in parietal association cortex. Approximately 10 to 15% of senile plaques in the inferior temporal gyrus contained abnormal neurites. Additional abnormal collections of neurites without plaque cores were frequently found in layers II-III and V-VI. Neuropeptide Y and somatostatin were co-localized in abnormal neurites, suggesting an origin from local intrinsic neurons in which the two peptides are co-localized. Double immunofluorescence staining for both tau protein, a major antigenic component of paired helical filaments, and either somatostatin or neuropeptide Y showed that these neurons do not contain tau-immunoreactive neurofibrillary tangles. The morphological correlate of reduced somatostatin and neuropeptide Y content in Alzheimer's disease brain therefore appears to be a distortion and reduction in fiber plexuses. In addition, it is apparent that these neurons can develop widespread morphological abnormalities in the absence of neurofibrillary tangle formation.

Aged↗