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PubMed1990

[An autopsy case of Alzheimer's disease associated with Parkinson's disease, compared to 2 autopsy cases of diffuse Lewy body disease].

A 68 year old male, diagnosed as Alzheimer's disease clinically, pathologically showed both findings of Alzheimer's disease and Parkinson's disease. The brain weight was 940 g. Macroscopically, severe cortical brain atrophy and depigmentation of the substantia nigra was noted. Microscopic examination showed marked appearance of senile plaque and a large number of neurofibrillary tangle with sever neuronal loss of the cerebral cortex. Additionally, the loss of neuron with many Lewy bodies was found in the substantia nigra. Lewy bodies were also found in the locus ceruleus and the dorsal vagal nucleus, but few in the cerebral cortical neurons. We compared this case neuropathologically with two autopsy cases of diffuse Lewy body disease (DLBD). There was no distinction concerning the lesions of the brain stem between this case and the cases of DLBD. In all three cases, the nucleus of basalis of Meynert showed marked neuronal loss. However, the brain was lighter than those of the cases of DLBD. Senile changes such as senile plaque and neurofibrillary tangles were more marked in this cases than in the cases of DLBD. Furthermore a large number of cortical Lewy bodies were found in the cases of DLBD, but few in this case. The distribution and number of Lewy bodies did not correspond with those of senile changes in the cases of DLBD. Also the cerebral cortical structure was better preserved in the cases of DLBD than in this case. In conclusion, from the clinicopathological findings, we considered that this case is Alzheimer's disease associated with Parkinson's disease. According to Kosaka's study, this case seemed to correspond with a transitional type of the Lewy body disease.

Aged↗
PubMed1999

The presence, origin, and significance of A beta peptide in the cell bodies of neurons.

Interest in the A beta amyloid in Alzheimer disease (AD) has largely focused on the A beta in the neuropil, an extracellular site. Here much attention has been given to the possibility that A beta acts as a neurotoxin. However, increasing emphasis is now being given to the relationship between neurofibrillary tangles (NFT) and the degree of cognitive decline, as opposed to the relationship between decline and senile plaques, the sites of extracellular A beta deposition. This review focuses attention on the existence and significance of A beta in the cell body of the neuron. The review brings together diverse strands of literature indicating: (1) the tau-positive, paired helical filaments that are the main component of NFT are not themselves the source of the amyloid-like staining (Congo red birefringence) of PHF, and are not, in fact, an "amyloid"; (2) there is A beta within the cytoplasm of neurons affected by AD and in other conditions characterized by tau-positive neurofibrillary tangles; (3) peptides derived from portions of the A beta precursor can bind to PHF; (4) the affected neurons are the source of extracellular A beta in their vicinity and are also unable to maintain the synaptic structures that depend upon the integrity of the neuronal cell body; and (5) debates about whether the intracellular A beta is an amyloid depend upon beliefs about its tertiary structure and assumptions concerning the relationship between the size of self-aggregating A beta molecules, their tertiary structure, and their ability to generate Congo red birefringence without necessarily being detected as ultrastructural filaments 5-10 nm wide. Based upon this literature, it is suggested that the Congo red birefringence generated by NFT is caused by A beta, intimately bound to the NFT. Moreover, whether defined as an amyloid or not, the A beta in the neuronal cell body indicates an abnormal processing of the precursor molecule on the way to its ultimate transmembrane domain. Deranged neuronal functioning, which leads to this abnormal processing and/or the intracellular A beta itself, may be the cause of subsequent functional and morphologic abnormalities in the brain.

Alzheimer Disease↗
PubMed1989

[An Alzheimer's disease case showing recurrent subcortical hemorrhage: an autopsy findings with immunohistochemical studies of cerebral amyloid deposits].

Alzheimer's disease is a degenerative brain disorder with a progressive dementia which develops in middle or late life. The pathological findings of this disease are characterized by neurofibrillary tangles, senile plaques and cerebrovascular amyloidosis. However, cerebral hemorrhage caused by amyloid angiopathy rarely occurs. A 71-year-old woman, who had been suffering from an impairment of her cognitive ability for the past several months, suddenly developed a severe headache with vomiting and gait disturbance. Brain CT disclosed a hemorrhagic lesion in the right parieto-occipital region. In the following two years she had experienced two episodes of the similar subcortical hemorrhage which occurred in the right parietal lobe and bilateral parieto-occipital regions. She died at the age of 73. Histopathological examinations of the brain revealed a decreased number of neurons with diffuse distribution of senile plaques and neurofibrillary tangles in the neocortex and hippocampus. Severe cerebrovascular amyloid deposits were also seen. Immunostaining for amyloid was carried out using a monoclonal antibody to amyloid beta protein. The senile plaque and cerebrovascular amyloid was strongly immunoreactive to anti-beta protein antibody. Cerebral amyloid angiopathy is commonly seen in the brains with Alzheimer's disease and severe cerebrovascular degeneration secondary to heavy amyloid deposits may cause recurrent subcortical hemorrhages in the patients with this disorder.

Aged↗
PubMed1996

Neurons of the human frontal cortex display apolipoprotein E immunoreactivity: implications for Alzheimer's disease.

Apolipoprotein E (apoE) is a plasma protein that regulates lipid transport and cholesterol homeostasis. In humans, apoE occurs as 3 major isoforms (apoE2, E3, and E4). Genetic evidence demonstrates an overrepresentation of the apoE epsilon 4 allele in Alzheimer's disease (AD). While apoE immunoreactivity (IR) is associated with the amyloid plaques and neurofibrillary tangles of AD, few studies have characterized the localization of apoE in normal human brains. We examined the distribution of apoE in the cerebral cortex of normal aged individuals and compared the results to clinically diagnosed and pathologically confirmed AD cases. In addition, we characterized the apoE IR in brains from high plaque non-demented (HPND) cases. We observed consistent and widespread apoE staining in cortical neurons from normal and HPND individuals. This finding was confirmed by double immunostaining which colocalized apoE with microtubule-associated protein-2, as well as low density lipoprotein receptor-related protein, an apoE receptor found on neurons. In contrast, AD brains displayed apoE IR in plaques and neurofibrillary tangles with little neuronal staining. These data clearly establish the presence of apoE in normal neurons, supporting an intracellular role for apoE. Moreover, the results suggest that this function of apoE is disrupted in AD, where apoE staining of neurons was drastically reduced.

Aged↗
PubMed1991

Immunohistological study on brains of Alzheimer's disease using antibodies to fetal antigens, C-series gangliosides and microtubule-associated protein 5.

An immunohistological study of Alzheimer's brains was performed using antibodies to C-series gangliosides and microtubule-associated protein 5 (MAP5), and their staining patterns were compared with those of antibodies to tau and beta-amyloid precursor protein. Antibodies to C-series gangliosides and MAP5, both of which are known to preferentially expressed in the fetal brains, immunostained dystrophic neurites of senile plaques, neurofibrillary tangles and neuropil threads abundant in 3rd and 5th layers in the cerebral cortex, all of which are considered to be pathological hallmarks of Alzheimer's disease. The immunostaining patterns of these structures by antibodies to C-series gangliosides and MAP5 were similar to those by the antibody to tau. These three antibodies also immunostained some neurons in Alzheimer's brain, although their staining patterns were slightly different from one another; i.e., both diffuse and granular patterns were seen by the antibody to tau, but only granular pattern by the antibodies to C-series gangliosides and MAP5. These neurons immunostained by these three types of antibodies appeared to be the precursors of the classical neurofibrillary tangles, as positively stained neurons were not seen in the brains of non-demented cases. The presence of fetal antigens such as the C-series gangliosides and MAP5 in Alzheimer's brain may suggest that regeneration or sprouting of neurons is ongoing in association with the re-induction of gene expression characteristic for the brain in the early stage of development.

Aged↗
PubMed1991

Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease.

On tissue sections of Alzheimer brain, 4 antibodies to tau immunolabel not only neurofibrillary tangles, neuritic plaques and neuropil threads but also the tangle-free cytoplasm of a subset of hippocampal and cortical neurons we believe to be at a stage of alteration preceding the formation of paired helical filaments (PHF). Pretreatment of tissue sections with alkaline phosphatase leads to an increase in staining intensity and in number of immunoreactive lesions with antibodies directed to an amino terminal and to a mid-region of the tau molecule. The diffuse neuronal staining could not be observed with any of 7 monoclonal antibodies recognizing ubiquitin. We conclude (1) that abnormal phosphorylation of tau occurs prior to its incorporation into PHF and leads to its accumulation in the nerve cell body and (2) that ubiquitin is seen associated only when a neurofibrillary tangle is already formed.

Aged↗
PubMed2002

p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases.

Exposure of cells to stress, particularly oxidative stress, leads to misfolding of proteins and, if they are not refolded or degraded, to cytoplasmic protein aggregates. Protein aggregates are characteristic features of a variety of chronic toxic and degenerative diseases, such as Mallory bodies (MBs) in hepatocytes in alcoholic and non-alcoholic steatohepatitis, neurofibrillary tangles in neurons in Alzheimer's, and Lewy bodies in Parkinson's disease. Using 2D gel electrophoresis and mass spectrometry, we identified p62 as a novel MB component. p62 and cytokeratins (CKs) are major MB constituents; HSP 70, HSP 25, and ubiquitinated CKs are also present. These proteins characterize MBs as a prototype of disease-associated cytoplasmic inclusions generated by stress-induced protein misfolding. As revealed by transfection of tissue culture cells overexpressed p62 did not induce aggregation of regular CK filaments but selectively bound to misfolded and ubiquitinated CKs. The general role of p62 in the cellular response to misfolded proteins was substantiated by detection of p62 in other cytoplasmic inclusions, such as neurofibrillary tangles, Lewy bodies, Rosenthal fibers, intracytoplasmic hyaline bodies in hepatocellular carcinoma, and alpha1-antitrypsin aggregates. The presence of p62 along with other stress proteins and ubiquitin in cytoplasmic inclusions indicates deposition as aggregates as a third line of defense against misfolded proteins in addition to refolding and degradation.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lewy body pathology in Alzheimer's disease.

Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.

Alzheimer Disease↗
PubMed1999

Elevated transglutaminase-induced bonds in PHF tau in Alzheimer's disease.

Transglutaminase-induced epsilon-(gamma-glutamyl)lysine bonds covalently cross-link and polymerize peptides into insoluble high molecular weight protein aggregates resistant to degradation and proteolytic digestion. We investigated the hypothesis that excessive deposition of epsilon-(gamma-glutamyl)lysine bonds is a neuropathological mechanism which induces the polymerization of tau protein into stable aggregates leading to the formation of paired helical filaments (PHFs) which deposit into neurofibrillary tangles in Alzheimer's disease (AD) brain. We demonstrate a significant (45%) elevation in epsilon-(gamma-glutamyl)lysine cross-links in AD cortex as compared to control cortex. In vivo, PHF tau, and high and medium molecular weight neurofilament proteins have significantly greater cross-linking by epsilon-(gamma-glutamyl)lysine bonds in AD brains as compared to controls. The cross-linking of PHF tau occurs both intra-molecularly and inter-molecularly. The inter-molecular cross-linking of tau could account for the formation of high molecular weight tau polymers. These results suggest that transglutaminase-induced cross-linking of tau protein could play a role in the formation and stabilization of neurofibrillary tangles. Inhibition of transglutaminase-induced cross-linking may therefore, provide a novel strategy for the treatment of AD.

Aged↗
PubMed1988

Correlation of phosphorus-31 magnetic resonance spectroscopy and morphologic findings in Alzheimer's disease.

Senile plaques (SPs), especially, and neurofibrillary tangles are important pathologic markers for the diagnosis of Alzheimer's disease (AD), but neither is pathognomonic for AD. We hypothesize that elevations in levels of phosphomonoesters, precursors of membrane phospholipids, occur early in the pathogenesis of AD and precede the appearance of SPs. In contrast, elevations in levels of phosphodiesters, breakdown products of phospholipids, reflect degeneration of neural membranes and will correlate with the appearance of SPs. Correlative phosphorus-31 magnetic resonance spectroscopy and morphologic studies conducted to test this hypothesis disclosed that elevations in levels of phosphomonoesters had a negative correlation with the numbers of SPs, and elevations in levels of phosphodiesters had a positive correlation with the numbers of SPs. No correlations were observed for either membrane parameter and neurofibrillary tangles. These findings support our hypothesis and suggest that aberrations in the synthesis of membrane phospholipids are early metabolic events in the pathogenesis of AD.

Aged↗
PubMedDate not supplied

Serum amyloid P component level in Alzheimer's disease.

Serum amyloid P component (AP) is a normal plasma constituent that is observed in senile plaques and neurofibrillary tangles in brains of Alzheimer's disease (AD) patients. In this study we have evaluated the AP levels in sera of 16 patients with AD and in 16 control subjects by enzyme-linked immunosorbent assay. The AP level was 22.4 +/- (SD) 7.0 micrograms/ml in the AD group and 34.4 +/- (SD) 6.6 micrograms/ml in the control group. The AP level in the AD group was significantly lower than that of the control group (p < 0.01). In the control group, there was no correlation between AP levels and age. Our results suggest that the production of AP by the liver (hepatocytes), thought to be the only source, may be suppressed in AD patients and that the deposition of AP in senile plaques and neurofibrillary tangles is not due to its overproduction.

Adult↗
PubMed1989

An antigenic profile of Lewy bodies: immunocytochemical indication for protein phosphorylation and ubiquitination.

An antigenic profile of subcortical and cortical Lewy bodies was determined in the presence or absence of neurofibrillary tangles in the same brain using antisera and monoclonal antibodies to various cytoskeletal elements as well as to determinants not present in the normal cytoskeleton. The cores of many Lewy bodies were strongly reactive with a monoclonal antibody to paired helical filaments which has been shown to recognize ubiquitin. This antibody also stained Marinesco bodies in the same tissue sections. Two monoclonal antibodies to phosphorylated epitopes of neurofilament proteins (SM I 31, SM I 34) stained the peripheries of about 40% of all discernable Lewy bodies on untreated paraffin sections. Reactivity with a monoclonal antibody to neurofilaments (SM I 33) appeared only after pretreatment of the sections with phosphatase. Lewy bodies did not bind antibodies to tau protein. Our results show that, as previously shown for neurofibrillary tangles, Lewy bodies also contain ubiquitin. The uncovering of neurofilament epitopes by treatment with phosphatase indicates that abnormal phosphorylation of cytoskeletal elements may play a role in the pathogenesis of the Lewy body.

Aged↗
PubMed2004

Phosphorylation of tau by fyn: implications for Alzheimer's disease.

The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of Alzheimer's disease (AD). The discovery that tau could be phosphorylated on tyrosine and evidence that Abeta signal transduction involved tyrosine phosphorylation led us to question whether tyrosine phosphorylation of tau occurred during the neurodegenerative process. In this study we determined that human tau tyr18 was phosphorylated by the src family tyrosine kinase fyn. By developing both polyclonal and monoclonal probes specific for phospho-tyr18, we found that the phosphorylation of tau at tyr18 occurred at early developmental stages in mouse but was absent in the adult. Our phosphospecific probes also revealed that paired helical filament preparations exhibited phospho-tyr18 reactivity that was sensitive to phosphotyrosine-specific protein phosphatase treatment. Moreover, immunocytochemical studies indicated that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. However, the staining pattern excluded neuropil threads and dystrophic neurites indicating that tyrosine phosphorylated tau was distributed in AD brain in a manner dissimilar from other abnormally phosphorylated tau. We also found evidence suggesting that differentially phosphorylated tau existed within degenerating neurons. Our data add new support for a role for fyn in the neurodegenerative process.

Age Factors↗
PubMed1988

Cellular localization of messenger RNA encoding amyloid-beta-protein in normal tissue and in Alzheimer disease.

Amyloid precursor protein (APP) gene encodes the short peptide fragment amyloid-beta-protein present in senile plaque cores, cerebrovascular amyloid, and intracellular neurofibrillary tangles in Alzheimer disease (AD). Using in situ hybridization with biotin-labeled RNA probes, we found distinctive patterns of APP gene expression in different regions of postmortem human brain. Strong hybridization signal for APP messenger RNA (mRNA) was detected in specific classes of neurons, fascicular oligodendroglia, satellite glia, and presumptive microglia. Weaker signal was seen in other neuronal classes, fascicular astrocytes, and vascular endothelial cells, but no signal was seen in protoplasmic astrocytes. Human thymus also shows a restricted pattern of hybridization with high signal in reticular epithelial cells, and much lower signal in lymphocytes. In AD patients, neuronal hybridization for APP mRNA was specifically increased in hippocampus, but not cerebellar and visual cortex when compared to hybridization for neuron-specific enolase mRNA. Most neurons with neurofibrillary tangles had strong APP mRNA signal. These results suggest that APP gene expression is highly regulated in normal tissue, that many different cell classes in brain express the APP gene, and that neuronal expression may increase specifically in brain regions where widespread injury occurs in AD. Amyloid deposits in brains of AD patients might be explained by local production of precursor protein in endothelial cells, neurons or glia.

Aged↗
PubMedDate not supplied

[Diagnosis of Alzheimer's disease].

Alzheimer's disease is a neurodegenerative disorder leading to cognitive impairment (amnesia, aphasia, apraxia and agnosia). The prevalence of this age related disabling illness is increasing. During the course of the disease, the clinical diagnosis will be that of "possible Alzheimer's disease", then "probable Alzheimer's disease". But the diagnosis of "definite Alzheimer's disease" requires a post-mortem brain examination and the demonstration of numerous senile plaques and neurofibrillary tangles in hippocampal and association cortical areas. The neuropathological examination confirms probable Alzheimer's disease clinical diagnosis in 85% of the cases examined in medical schools. However, with much more than 15% errors, the early diagnosis of Alzheimer's disease must be improved since it is a key factor for the therapeutic approach, and more especially for the efficiency of drug trials. At the present time, there are new leads for a biological diagnosis in the blood or the CSF. However, the natural (and molecular) history of Alzheimer's disease points out that all biochemical dysfunctions remain in the CNS, and more particularly in association brain areas. This is demonstrated using reliable biochemical markers such as A beta and pathological Tau proteins, which are the basic components of amyloid deposits and neurofibrillary tangles, respectively. Also, a genetic diagnosis can be performed in half of familial autosomic dominant Alzheimer's disease, which represents less than 1% of all Alzheimer's disease cases. Together, this shows that there is a lack of reliable Alzheimer's disease markers. The search for new specific markers (clinical, epidemiological, genetic, biochemical, biological) must go on.

Alzheimer Disease↗
PubMed1987

Axonal disruption and aberrant localization of tau protein characterize the neuropil pathology of Alzheimer's disease.

The microtubule-associated protein tau, a major antigenic component of paired helical filaments, has been demonstrated in neurofibrillary tangles and in neurites of senile plaques. With optimal fixation and histochemical methods, we show the normal axonal location of tau protein in human cerebral cortex and the striking alterations of tau distribution that affect the cortical neuropil in Alzheimer's disease. Normally, cortical tau-immunoreactive fiber bundles form a pattern resembling that seen with myelin stains. The prominence of white matter staining suggests that tau may be especially enriched in projection systems. Alzheimer's disease causes massive axonal disruption and the dislocation of tau protein from its usual axonal domain into neuronal cell bodies, dendrites, and presynaptic regions. The normal pattern of axonal staining in cortex is disrupted and white matter staining is reduced. Prominent abnormal tau-immunoreactive neuropil fibers are densely present even in cortical regions without classical neurofibrillary tangle and senile plaque formation. The striking neuropil abnormalities, revealed by the aberrant localization of tau protein, are likely to contribute to neuronal dysfunction in Alzheimer's disease.

Aged↗
PubMed1999

Accumulation of intracellular amyloid-beta peptide (A beta 1-40) in mucopolysaccharidosis brains.

To evaluate whether in vivo accumulations of heparan sulfate caused by inborn errors in the metabolism of glycosaminoglycans lead to the formation of neurofibrillary tangles and/or senile plaques, as seen in Alzheimer disease (AD), we studied postmortem brains from 9 patients, ages 1 to 42 years, with mucopolysaccharidosis (MPS). The brains of patients with Hurler's syndrome (MPS I: n = 5) and Sanfilippo's syndrome (MPS III; n = 4) as well as from caprine MPS IIID and murine MPS VII models were evaluated by thioflavine-S staining and by immunohistochemistry using antibodies directed against heparan sulfate proteoglycans, hyperphosphorylated tau, amyloid-beta peptide precursor proteins (APP), and amyloid-beta peptides (A beta [1-40], and A beta [1-42]). A two-site sandwich enzyme-linked immunosorbent assay (ELISA) was also utilized to compare levels of total soluble and insoluble A beta (1-40) and A beta (1-42) obtained from temporal cortex of MPS patients. Although no neurofibrillary tangles, senile plaques, or tau-positive lesions were detected in any of the MPS brains studied here, antibodies directed against A beta (1-40) intensely and diffusely stained the cytoplasm of cells throughout the brains of the MPS patients and the caprine MPS model. The ELISA assay also demonstrated a significant 3-fold increase in the level of soluble A beta (1-40) in the MPS brains compared with normal control brains. Thus, at least some of the metabolic defects that lead to accumulations of glycosaminoglycans in MPS also are associated with an increase in immunoreactive A beta (1-40) within the cytoplasmic compartment where they could contribute to the dysfunction and death of affected cells in these disorders, but not induce the formation of plaques and tangles. Models of MPS may enable mechanistic studies of the role A beta and glycosaminoglycans play in the amyloidosis that is a neuropathological feature of AD.

Adolescent↗
PubMed1990

Study of spindle microtubule reassembly in cells from Alzheimer and Down syndrome patients following exposure to colcemid.

Numerous intraneuronal neurofibrillary tangles and senile (neuritic) plaques are the two characteristic lesions in Alzheimer disease (AD) and adult Down syndrome (DS). Evidence indicates that microtubule assembly is impaired in AD. We studied spindle microtubule repolymerization rates in EBV-transformed lymphoblasts from AD, DS, and control individuals after colcemid exposure. The distinctive arrangement of microtubules in spindle and its size make this structure an obvious choice for study. Recovery trends in the three patient groups differed significantly; in particular, the controls showed an earlier appearance of intact spindle microtubules than AD. Other researchers found similar results using AD fibroblasts. The results from the DS cells were inconsistent and difficult to interpret. It is unclear how the AD microtubules differ from controls, or whether a relationship exists between the altered microtubule repolymerization kinetics observed in this study and the presence of neurofibrillary tangles in AD patients. A difference in repolymerization rates can be the basis for a diagnostic test for AD if it can be verified.

Alzheimer Disease↗