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PubMed1993

Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau.

Paired helical filaments, a constituent of neurofibrillary tangles in Alzheimer's disease, consist primarily of the microtubule-associated protein tau. However, the process by which the detergent-insoluble filaments of the neurofibrillary tangles are formed from soluble tau remains unknown. Here, we present a potential mechanism for the abnormal aggregation of tau in Alzheimer's disease: the covalent cross-linking of tau by the enzyme transglutaminase. Macromolecular complexes of tau, formed in the presence of transglutaminase, were found to be insoluble in ionic detergent, beta-mercaptoethanol, guanidine-HCl, and urea and, furthermore, demonstrated an increased immunoreactivity with the monoclonal antibody Alz-50. Electron microscopic studies revealed that tau cross-linked by transglutaminase has a defined filamentous structure. These results indicate that transglutaminase, the activity of which has been shown to increase during programmed cell death, may play a role in the formation of pathology associated with Alzheimer's disease.

Animals↗
PubMed1989

Exchangeable GTP binding site of the beta-subunit of brain tubulin in Alzheimer disease.

A major cytoskeletal and molecular change of yet unknown mechanism is the accumulation of argentophilic neurofibrillary tangles in certain selected neurons of the aged human brain, especially the Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). Increasing evidence suggests an association between neurofibrillary tangles and a defective microtubule (MT) assembly in AD/SDAT brain. Tubulin, the basic unit of MT is an alpha-beta heterodimer protein of about 55,000 molecular weight each. The beta subunit of tubulin has an exchangeable (E) binding site for guanosine triphosphate (GTP) which in the presence of microtubule-associated proteins (MAPS) promotes the MT assembly. The 8-azido GTP, a photoaffinity analog of GTP, which has been proven to mimic the natural ligand in promoting MT assembly, was used to examine the GTP binding of beta- tubulin in AD brain. Preliminary studies revealed a minimal photoinsertion into the beta-subunit of tubulin in AD/SDAT brain homogenate. Furthermore, the exchangeable GTP binding site was also unavailable in brain tubulin isolated from most of the AD/SDAT cases.

Alzheimer Disease↗
PubMed1986

Decreased somatostatin immunoreactivity but not neuropeptide Y immunoreactivity in cerebral cortex in senile dementia of Alzheimer type.

The content of two neuropeptides, somatostatin (SRIF) and neuropeptide Y (NPY) has been determined in two cerebral cortical areas of Alzheimer's disease brain and in age-matched control brains. The content of SRIF-like immunoreactivity (SRIF-LI) was found to be decreased in Alzheimer temporal cortex (Brodmann area 21) compared to control temporal cortex. The decreased content of SRIF was significantly correlated with the observed number of neuritic plaques and neurofibrillary tangles. No difference was observed in NPY-LI between Alzheimer cerebral cortex and control cortex. Furthermore, no correlations were observed between NPY content and plaque count, neurofibrillary tangle estimate or SRIF content despite widespread reports of NPY/SRIF coexistence.

Aged↗
PubMed1997

Changes in the ageing brain in health and disease.

The brains of individuals, who are cognitively normal, show age-related changes that include an overall reduction in brain volume and weight, which are associated with gyral atrophy and widening of the sulci of the cerebral cortex, and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. Microscopically, there are increasing amounts of the age-related pigment, lipofuscin, granulovacuolar degeneration in neurones, Hirano bodies, variable amounts of diffuse deposits of beta-amyloid in the parenchyma, the presence of neurofibrillary tangles mainly confined to the hippocampus and amygdala, and sparse numbers of senile plaques in these brain regions and also in other cortical areas. Of these changes, neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread. Alzheimer's disease has therefore been regarded as accelerated brain ageing; however, the realization that there is a strong genetic contribution to developing the disease at least implies that it may not be the inevitable, even if frequent, consequence of old age. Understanding the molecular basis of plaque and tangle formation is advancing greatly and is the main focus of research into the cellular and molecular changes observed in the ageing brain.

Alzheimer Disease↗
PubMed2004

Inhibitors beta-amyloid-induced toxicity by modulating the Akt signaling pathway.

The Akt signaling pathway plays a crucial role in neuronal survival, leading to inhibition of apoptosis. Many stimulants including neurotrophins are reported to activate this pathway in preclinical studies; however, there are no drugs for neurodegenerative diseases adopting such a concept on the market so far. Among neurodegenerative diseases, Alzheimer's disease is the most common and characterized by senile plaques and neurofibrillary tangles, which consist of beta-amyloid and hyperphosphorylated tau, respectively. Recent studies suggest that activation of Akt inhibits toxicity of beta-amyloid and formation of neurofibrillary tangles, leading to protection of neurons against apoptosis. This review discusses the possibility of treatment of Alzheimer's disease by activating the Akt signaling pathway.

Alzheimer Disease↗
PubMed1989

Immunoaffinity demonstration that paired helical filaments of Alzheimer disease share epitopes with neurofilaments, MAP2 and tau.

Identification of the neuronal components incorporated into the neurofibrillary tangles of Alzheimer disease has primarily been derived from immunocytochemical procedures. Previous antibody studies have been able to directly determine the shared epitopes of known neuronal proteins with neurofibrillary tangles (NFT) only when the appropriate monoclonal antibodies were available. In this study, we use an immuno-affinity purification protocol to directly determine the properties of the epitopes recognized by two antisera which recognize NFT. Characterization of the purified antibodies demonstrates that NFT share epitopes with the two heavier neurofilament subunits. NFH and NFM, as well as MAP2 and tau. Further, this method indicates that the epitopes shared with neurofilaments and tau are distinct from each other.

Alzheimer Disease↗
PubMed2006

Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer's disease.

Aberrant phosphorylated tau is the major component of the neurofibrillary tangles in Alzheimer's disease (AD) brains. Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates tau protein, and increased GSK-3beta expression has been associated with neurofibrillary tangles. Saitohin (STH) is a recently identified protein that shares tissue expression pattern with tau, and previous evidence in the Spanish population indicated that a polymorphism at codon 7 (Q7R) of the STH gene was associated with late-onset AD. Since both GSK-3beta and STH are related to tau, we examined the association between a polymorphism in the promoter region (-50) of the GSK-3beta gene and AD, either through an independent effect or through interaction with the STH (Q7R) polymorphism, in a well-defined group of 333 sporadic AD patients and 307 control subjects from Spain. The current study reveals that GSK-3beta (-50) TT genotype is associated with an increased risk (OR 1.99, p = 0.003) for late-onset (after the age of 72 years) AD. Our results indicate that both the GSK-3beta (-50) and STH (Q7R) polymorphisms increase the risk of late-onset (subjects >72 years) AD, although they appear to be independent and thus not to interact synergistically.

Age Factors↗
PubMed1989

Lewy bodies in Alzheimer disease--one or two diseases?

To clarify the significance of the Lewy body (LB) in Alzheimer disease (AD), we determined the incidence and distribution of LB in 150 cases of AD and 75 controls. We also examined the pathological changes in the substantia nigra and quantified neocortical alterations, including the density of neuritic plaques, neurofibrillary tangles, and LB. LBs were present in 25% of AD cases, but in only 5% of controls. The presence of LB was associated with significantly lower numbers of neurofibrillary tangles as compared with cases of AD without LB, whereas the mean density of neuritic plaques remained unchanged. Two possibilities are discussed to explain these findings. First, the high frequency of LB in AD may reflect a predisposition of AD patients to develop idiopathic Parkinson disease. Second, the LB may represent a nonspecific cytoskeletal change in selected vulnerable neuronal populations in some subjects with AD, rather than the presence of a second pathological process.

Aged↗
PubMed1999

Basal and stimulated hippocampal adenylate cyclase activity in the experimentally lesioned rat entorhinal cortex.

Early stage development of Alzheimer-related neurofibrillary tangles occurs primarily in neurons of entorhinal cortex layers pre-alpha and pre-beta. These excitatory neurons project into the hippocampus. At this stage ('entorhinal' case), while neurofibrillary tangles are still absent from the hippocampus, a significant reduction in hippocampal adenylate cyclase activity has been detected. To test whether this reduction is a consequence of a deafferentation (and thus not a specifically disease-related alteration), we performed unilateral electrolytic lesions and sham-operations of the rat entorhinal cortex. The animals were killed 2, 12 and 55 days post lesion (dpl) and hippocampal adenylate cyclase activity was assayed. The major results were as follows: (1) both lesioned and unlesioned sides showed higher activity than a sham-operated control; (2) the adenylate cyclase activity of the lesioned side increased to a significantly lesser degree than that of the unlesioned side at 12 dpl; (3) this 'decrease' was attributed to changes in G protein-mediated activation of adenylate cyclase; (4) at no time point post lesion did the pattern of rat adenylate cyclase activity resemble that observed in Alzheimer's disease. Our data suggests that the loss of entorhinal afferents alone cannot explain the reduction in cyclase-activity seen in 'entorhinal' cases.

Adenylyl Cyclases↗
PubMedDate not supplied

Immunoelectron microscopy of Alzheimer and Pick brain tissue labelled with the monoclonal antibody Alz-50.

Previous studies have shown that Alzheimer and Pick brains contain abnormally elevated amounts of a 68 Kd protein detected by the monoclonal antibody Alz-50. We have used immunoperoxidase and immunological techniques to localize Alz-50-reactive epitopes in sections from Alzheimer and Pick brains at the ultrastructural level. Detectable immunoreactivity was restricted to the paired helical filaments of Alzheimer neurofibrillary tangles and to the paired helical and straight filaments of Pick bodies. In Alzheimer tissue, the antibody also labelled scattered neuronal paired helical filaments that were not aggregated into neurofibrillary tangles. Amorphous components of Pick bodies and other constituents in the Alzheimer and Pick brain tissue were not immunostained.

Aged↗
PubMedDate not supplied

Pathogenesis of Alzheimer's disease: current status on apolipoprotein E4 gene research.

Alzheimer's disease (AD) affects millions of people throughout the world. The financial and emotional costs that are inflicted by this devastating disease are enormous. Genes responsible for the early-onset familial AD have been cloned and found to be membrane associated transport proteins. Evidence suggests that apolipoprotein E4 may be the risk factor for the late-onset form of the disease. Beta-amyloid and potassium channel dysfunction have also been implicated in the development of AD. Hyperphosphorylation of "tau" has been indicated for the generation of neurofibrillary tangles in the brains of Alzheimer's patients. Since apoE4 does not bind to "tau", apoE4 may contribute to the hyperphosphorylation of "tau" which may cause the formation of neurofibrillary tangles in AD patients. Molecular biology research on AD should help in the development of drugs for the prevention and treatment of the disease.

Age of Onset↗
PubMed1979

Neurofibrillary pathology: current status and research perspectives.

The neurofibrils seen in the light microscope are shown, by electron microscopy, to be heterogeneous structures, formed of neurotubules and neurofilaments. A variety of pathological conditions (especially, presenile and senile dementia (are characterized by the presence of neurofibrillary tangles, formed either of paired helical filaments or of single filaments. The morphology, distribution and biochemistry of these various fibrillary structures is reviewed. Particular attention is devoted to the assembly of neurotubules, to the mechanism of action of drugs which prevent assembly, and to possible implications for the experimental induction of neurofibrillary pathology. Of central importance in the arguments is the emphasis on the normal neurofibrillary structures being single forms of pleomorphic proteins. The healthy neuron assembles these proteins into the required form as is necessary for the needs of that neuron. Interference with this process in neuronal cell biology may lead to the deposition of neurofibrillary tangles. On the basis of the morphological and biochemical evidence, several approaches to the experimental study of neurofibrillary pathology are proposed.

Aging↗
PubMed2003

Differential distribution of calbindin D28k and parvalbumin among functionally distinctive sets of structures in the macaque brainstem.

In a study of brainstem in the cynomolgus monkey, we found that the distribution of calbindin D28K (CB) and parvalbumin (PV) is nonoverlapping among functionally distinct sets of brainstem structures. Nuclei involved in representation and regulation of the organism's internal state contain CB, whereas those involved in the representation of the external environment and the representation or execution of externally directed actions contain only PV. Moreover, our findings indicate that different nuclei known as components of the ascending reticular activating system (ARAS) contain either CB or PV or both, suggesting that this system in primates operates with both CB and PV. In line with previously reported findings, we also found that unmyelinated pathways contain only CB, whereas myelinated pathways contain PV. Distribution of CB and PV in the macaque brainstem follows a pattern comparable to, but in some instances significantly different than, the pattern previously reported in the rat. We argue that the nonoverlapping distribution of CB and PV among different structures of the brainstem might reflect underlying differences in the physiological, anatomic, and perhaps phylogenetic properties of these structures. Considering our recent findings of selective vulnerability of brainstem structures to Alzheimer's disease, the present data suggest that the majority of macaque brainstem nuclei that contain CB are vulnerable to neurofibrillary tangles in humans. By contrast, only few nuclei that contain PV exhibit pathologic changes. Some of these nuclei are affected with a high number of neuritic plaques without ever developing neurofibrillary tangles.

Animals↗
PubMed1987

Hirano bodies contain tau protein.

Hirano bodies are intraneuronal inclusions whose frequency increases with age and Alzheimer's disease. These paracrystalline inclusions have been shown previously using immunocytochemistry to share epitopes with actin, tropomyosin, alpha-actinin and vinculin. Hirano bodies have not previously been demonstrated to share components with neurofibrillary tangles, another intraneuronal inclusion characteristic of Alzheimer's disease. In this study, we show that Hirano bodies bind antibodies to the microtubule-associated protein tau, a component of Alzheimer neurofibrillary tangles.

Alzheimer Disease↗
PubMed1994

Association of the apolipoprotein E epsilon 4 allele with clinical subtypes of autopsy-confirmed Alzheimer's disease.

Consistent with previous reports, we observed a significant association of the APOE epsilon 4 allele with Alzheimer's Disease (AD) in a series of 91 autopsy-confirmed cases. The epsilon 4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 +/- 0.07), although the epsilon 4 allele frequency in the AD cases with a negative family history (0.38 +/- 0.05) remained significantly greater than that for the non-AD control group (0.13 +/- 0.03). A similar increase in epsilon 4 allele frequency (0.54 +/- 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.36 +/- 0.04). Contrary to previous reports, no effect of the dosage of the epsilon 4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of epsilon 4 and atherosclerosis, the epsilon 4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of epsilon 4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the epsilon 4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an epsilon 4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the epsilon 4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE epsilon 4 allele.

Aged↗
PubMed1989

Activation of the classical complement pathway in brain tissue of Alzheimer patients.

Positive immunohistochemical staining of Alzheimer brain tissue was obtained with antibodies to proteins associated with classical, but not the alternative, complement pathway. Clq, C3d, C4d are fractions of complement proteins that bind to tissue when the classical complement pathway is activated. Antibodies to these fractions stained senile plaques, dystrophic neurites and some neurofibrillary tangles. C5b-9 is the membrane attack complex which promotes cell lysis when assembled on the plasma membrane. An antibody to a neoantigenic site on this complex stained dystrophic neurites and many neurofibrillary tangles, but not extracellular amyloid. Properdin and fraction Bb of factor B, two proteins that bind to tissue when the alternative complement pathway is activated, were not detected immunohistochemically.

Aged↗
PubMed2000

Immunocytochemical study of the dorsal and median raphe nuclei in patients with Alzheimer's disease prospectively assessed for behavioural changes.

The dorsal and median raphe nuclei were examined with immunocytochemistry to display the 5-HT neurones in 16 cases of post-mortem-proven Alzheimer's disease (AD) and 12 age and sex-matched controls. The AD cases had been prospectively assessed during life for expression of behavioural changes as well as for cognitive decline. A significant (P < 0.001) 41% reduction in density of dorsal raphe neurones was found along with a significant (P < 0.02) 29% reduction in density of median raphe neurones in AD. There were significantly more neurofibrillary tangles in both dorsal and median raphe nuclei in AD than in controls (P < 0.001). There was no correlation between reduction in neurone density in these nuclei and behavioural change, cognitive decline, neurofibrillary tangle counts in these nuclei or plaque and tangle pathology in frontal and temporal cortex. It was concluded from these findings that the raphe nuclei are significantly affected by the pathology of AD and that plasticity in the 5-HT system is the probable reason for the lack of correlation of reduced 5-HT neurone density and clinical disease parameters.

Aged↗
PubMed1978

A morphologic study of central nervous system aging in Hiroshima, Japan.

The presence of intraparenchymal small vessel arteriosclerosis, senile plaques, neurofibrillary tangles and granulovacuolar degeneration was quantified in the brains of autopsided patients from three age groups: 1) 90--99 years old 2) 70--79 years old and 3) 50--59 years old. Neurofibrillary tangles particularly in the hippocampus were the best indicator of chronologic aging, but senile plaques and granulovacuolar degeneration were also age related. Intraparenchymal small vessel sclerosis, cerebral infarction and hemorrhage, cause of death and radiation exposure at the time of the atomic bomb explosion in Hiroshima apparently had little or no effect on the development of these aging changes. Each type of aging change appeared to be independent of the others, to progress to a different combination of physiologic processes.

Aged↗