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PubMed2006

Cyclin-dependent kinase 5, Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer's disease.

Besides formation of neurofibrillary tangles and neuron loss, the Alzheimer's disease brain is characterized by neuritic plaques consisting of beta-amyloid peptide deposits and impaired neurotransmission. The proteins Munc18a, Munc18-interacting protein 1 and Munc18-interacting protein 2 mediate exocytosis and decrease beta-amyloid peptide formation. Cyclin-dependent kinase 5 and its activator p35 disrupt Munc18a-syntaxin 1 binding, thereby promoting synaptic vesicle fusion during exocytosis. We investigated protein levels of the signaling pathway: p35, cyclin-dependent kinase 5, Munc18a, syntaxin 1A and 1B, Munc18-interacting protein 1 and Munc18-interacting protein 2 in Alzheimer's disease cortex and found that this pathway was up-regulated in the Alzheimer's disease parietal and occipital cortex. In the cortex of transgenic Tg2576 mice over-expressing human beta-amyloid precursor protein with the Swedish mutation known to lead to familial Alzheimer's disease, which have substantial levels of beta-amyloid peptide but lack neurofibrillary tangles and neuron loss, no alterations of protein levels were detected. These data suggest that the pathway is enhanced in dying or surviving neurons and might serve a protective role by compensating for decreased neurotransmission and decreasing beta-amyloid peptide levels early during the progression of Alzheimer's disease.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Ultrastructural characteristics of tau filaments in tauopathies: immuno-electron microscopic demonstration of tau filaments in tauopathies.

The microtubule-associated protein tau aggregates into filaments in the form of neurofibrillary tangles, neuropil threads and argyrophilic grains in neurons, in the form of variable astrocytic tangles in astrocytes and in the form of coiled bodies and argyrophilic threads in oligodendrocytes. These tau filaments may be classified into two types, straight filaments or tubules with 9-18 nm diameters and "twisted ribbons" composed of two parallel aligned components. In the same disease, the fine structure of tau filaments in glial cells roughly resembles that in neurons. In sporadic tauopathies, individual tau filaments show characteristic sizes, shapes and arrangements, and therefore contribute to neuropathologic differential diagnosis. In frontotemporal dementias caused by tau gene mutations, variable filamentous profiles were observed in association with mutation sites and insoluble tau isoforms, including straight filaments or tubules, paired helical filament-like filaments, and twisted ribbons. Pre-embedding immunoelectron microscopic studies were carried out using anti-3-repeat tau and anti-4-repeat tau specific antibodies, RD3 and RD4. Straight tubules in neuronal and astrocytic Pick bodies were immunolabeled by the anti-3-repeat tau antibody. The anti-4-repeat tau antibody recognized abnormal tubules comprising neurofibrillary tangles, coiled bodies and argyrophilic threads in progressive supranuclear palsy (PSP) and corticobasal degeneration. In the pre-embedding immunoelectron microscopic study using the phosphorylated tau AT8 antibody, tuft-shaped astrocytes of PSP were found to be composed of bundles of abnormal tubules in processes and perikarya of protoplasmic astrocytes. In this study, the 3-repeat tau or 4-repeat tau epitope was detected in situ at the ultrastructural level in abnormal tubules in representative pathological lesions in Pick's disease, PSP and corticobasal degeneration.

Astrocytes↗
PubMed1996

Distinct patterns of neuronal loss and Alzheimer's disease lesion distribution in elderly individuals older than 90 years.

To explore the characteristics of brain aging in very old individuals, we performed a quantitative analysis of neurofibrillary tangle (NFT) and senile plaque (SP) distribution and neuron densities in 13 nondemented patients, 15 patients with very mild cognitive impairment, and 22 patients with Alzheimer's disease (AD), all older than 96 years of age. Non-demented cases displayed substantial NFT formation in the CAI field and entorhinal cortex only. Very mild cognitive impairment cases were characterized by the presence of high NFT densities in layers V and VI of area 20, and AD cases had very high NFT densities in the CAI field compared to nondemented cases. Moreover, high SP densities were found in areas 9 and 20 in AD, but not in cases with very mild cognitive impairment and nondemented cases. In contrast to previous reports concerning younger demented patients, neuron densities were preserved in the CAI field, dentate hilus, and subiculum in centenarians with AD. In these cases, there was a marked neuronal loss in layers II and V of the entorhinal cortex, and in areas 9 and 20. In the present series, no correlation was found between neurofibrillary tangle and neuron densities in the areas studied, whereas there was a negative correlation between senile plaque and neuron densities in area 20. The comparison between the present data and those reported previously concerning younger cohorts suggests that there is a differential cortical vulnerability to the degenerative process near the upper age-limit of life.

Aged↗
PubMed2006

Brain site-specific gene expression analysis in Alzheimer's disease patients.

BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Abeta) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD. MATERIALS AND METHODS: We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy. RESULTS: We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro. CONCLUSION: Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.

Aged↗
PubMed1987

Loss of pedunculopontine neurons in progressive supranuclear palsy.

In the present study, the number of neurons (greater than 20 microns in diameter) within the lateral part of the pedunculopontine nucleus pars compacta (PPNc) was determined at six rostrocaudal levels in 3 subjects with progressive supranuclear palsy (PSP), in 9 subjects with Alzheimer's disease, and in 6 age-matched control subjects. At each level examined, significantly fewer neurons were present in patients with PSP than in control subjects (49 to 69% reduction). Significant differences in numbers of neurons were not demonstrated between control subjects and patients with Alzheimer's disease. The extent of pathological changes, particularly neurofibrillary tangles, was examined within the PPNc of subjects in these three groups. The average number of neurofibrillary tangles in a 12-microns-thick midlevel section of the lateral PPNc was 68.7 in subjects with PSP, 18.3 in those with Alzheimer's disease, and 3.0 in aged control subjects. These abnormalities of PPNc neurons in PSP may play important roles in some of the clinical features characteristic of this disease.

Aged↗
PubMed1989

Microtubular reorganization and dendritic growth response in Alzheimer's disease.

Cytoskeletal disruption is a key pathological feature of Alzheimer's disease (AD). We used refined immunocytochemical techniques to define the range of abnormalities affecting the microtubule system in AD hippocampus. Minimal tau and tubulin immunoreactivity was granular and accumulated in otherwise normal neuronal perikarya. As tau-reactive neurofibrillary tangles formed, granular tau and tubulin staining diminished, and ubiquitin reactivity developed. In regions of high neurofibrillary tangle density, microtubule-associated protein 2 (MAP2) histochemical features of remaining nontangled neurons included apical dendritic degeneration with proliferation of basal dendrites. In addition to perisomatic dendritic proliferation, there was massive sprouting of tau-immunoreactive distal dystrophic neurites. Sprouting proximal dendrites and dystrophic neurites often demonstrated growth-cone-like lamellipodia and filopodia. Degeneration of the perisomatic proliferating dendrites was characterized by the accumulation of fibrillar tau immunoreactivity. The colocalization of MAP2 and tau in growth structures recapitulated their codistribution in developing neurites. The data suggest that extensive plasticity and growth response occur in tandem with neuronal degeneration in AD, and that reorganization of the cytoskeletal microtubule system may underlie these proliferative changes.

Aged↗
PubMedDate not supplied

The influence of aging in one tauopathy: Alzheimer 's disease.

In this short review, the link between aging and the onset of Alzheimer 's disease is discussed. It has been widely suggested that aging is the greatest risk factor for Alzheimer 's disease,in which a failure in the insulin signal-transduction pathway could occur with age and, thereby, the assembly of senile plaques and neurofibrillary tangles (two aberrant structures present in Alzheimer 's disease)could be promoted. The main component of neurofibrillary tangles is the microtubule-associated protein tau, and the assembly of tau protein appears to occur after its modification by phosphorylation. In this phosphorylation, some protein kinases related to the insulin-transduction pathway could play a role.

Aging↗
PubMed1994

Glutamate, beta-amyloid precursor proteins, and calcium mediated neurofibrillary degeneration.

In this article we present evidence supporting the interaction between excitotoxicity, beta APP mismetabolism, metabolic compromise and intracellular calcium destabilization in the process of neurodegeneration associated with Alzheimer's disease (AD). AD is characterized by the presence of neurofibrillary tangles and amyloid-containing plaques in specific regions of the brain. There appear to be several processes which contribute to the neurodegeneration associated with AD. Although AD has been linked to genetic mutations on chromosomes 21, 19 and 14, there are sporadic forms of AD that have no known genetic mutation involved. Aging is the major risk factor for AD. During the course of normal aging several metabolic compromises may occur in the brain. Both decreased glucose transport and utilization, and increased glucocorticoid levels are known to occur with aging and may lead to decreased energy supplies, ATP depletion, failure of Ca2+ buffering systems, excess glutamate release and activation of glutamate receptors. In addition, a reduction in antioxidant enzymes and consequently an increase in free radicals has also been associated with aging. Each of the preceeding alterations would lead to an increase in neuronal [Ca2+]i. Elevated calcium could then activate calcium-dependent proteases which degrade particular cytoskeletal proteins, and lipases which generate free radicals resulting in membrane damage and possible cell death. In this article we provide evidence that amyloid beta-peptide (A beta), the substance which accumulates in AD plaques, exacerbates excitotoxic and metabolic compromises to neurons resulting in changes in the cytoskeleton which resemble those seen in the neurofibrillary tangles of AD. We also provide evidence that secreted forms of beta-amyloid precursor protein (beta APP) are neuroprotective against excitotoxic insults. Recent findings concerning the normal function of beta APP and the mechanism of A beta toxicity place beta APP at the center of changes leading to neuronal degeneration in AD.

Alzheimer Disease↗
PubMed1995

Dephosphorylation of abnormal sites of tau factor by protein phosphatases and its implication for Alzheimer's disease.

The abnormally phosphorylated forms of tau factor are major constituents of neurofibrillary tangles in Alzheimer's disease brain. In order to investigate protein phosphatases which are related to dephosphorylation of abnormal phosphorylation sites, we examined the dephosphorylation of tau factor phosphorylated by three proline-directed type protein kinases. Tau factor phosphorylated by cdc2 kinase and tau protein kinase II was dephosphorylated by the holoenzyme of protein phosphatase 2A and calcineurin, while either the catalytic subunit of protein phosphatase 2A or protein phosphatase 2C could not catalyze the dephosphorylation. From the kinetic analysis, we concluded that tau factors phosphorylated by the protein kinases serve as good substrates for protein phosphatase 2A and calcineurin. On the other hand, tau factor phosphorylated by glycogen synthase kinase 3 alpha was dephosphorylated by the catalytic subunit of protein phosphatases 2A as well as the holoenzyme of protein phosphatase 2A and calcineurin. It has been reported that serines 199, 202 and 396 according to the numbering of the longest human tau isoform are among the major abnormal phosphorylation sites of tau factor. We synthesized two phosphopeptides which contained phosphoserines 199 and 202 or phosphoserine 396 and prepared the polyclonal antibodies specific for the phosphopeptides. Using these antibodies, we confirmed that the holoenzyme of protein phosphatase 2A and calcineurin could dephosphorylate phosphoserines 199, 202 and 396 in tau factor. The catalytic subunit of protein phosphatase 2A could dephosphorylate phosphoserine 396 but not phosphoserines 199 and 202. Neurofibrillary tangles in Alzheimer's disease brain were immunostained with both antibodies but the normal neurons in the normal aged brains were not. The results suggest that protein phosphatase 2A and calcineurin can be involved in the dephosphorylation of abnormal phosphorylation sites in tau factor and that the dephosphorylation of phosphoserine 396 is differently regulated from phosphoserines 199 and 202.

Aged↗
PubMed1998

The involvement of the ubiquitin system in Alzheimer's disease (review).

Alzheimer's disease, the most common form of senile dementia, affects more than 15 million people world-wide and is characterized by a marked deterioration in memory and all cognitive functions, as a result of a progressive degeneration and loss of cortical and limbic neurons. This process is associated with the presence of both the so-called -amyloid deposits and the cellular neurofibrillary tangles composed mainly of paired helical filaments of aberrantly hyperphosphorylated tau protein. The accumulation of ubiquitin in neurofibrillary tangles and senile plaques (both characteristic of the neuronal abnormalities associated with the disease) is postulated to play a role in the repair mechanism related to neuronal regeneration.

Alzheimer Disease↗
PubMed1980

Aluminum chloride induced neurofibrillary changes in the developing rabbit a chronic animal model.

Aluminum chloride injected into the brains of developing rabbits produced profound neurofibrillary changes to neurons of spinal cord and cerebrum similar to those produced in adult rabbits, along with a variety of clinical symptoms with the exception of seizures. Approximately half of the rabbits survived for more than three weeks, and many survived for several months. Many rabbits with large numbers of neurofibrillary changes had no clinical signs and symptoms. The dynamics and topography of the neurofibrillary changes induced by aluminum chloride are described over a period of several months. Many neurofibrillary tangles were seen in neurons of spinal cord and cerebrum up to 60 days after injection of aluminum chloride. There was no obvious correlation between the degree of neurofibrillary changes and the severity of the clinical signs and symptoms. Animals examined at 85 and 100 days after injection of aluminum chloride had fewer neurofibrillary tangles of none at all, and apparently they had recovered from the neurofibrillary changes. This chronic animal model will allow better investigations of the biochemistry and pathology of neurofibrillary changes, and it will enable behavioral studies to be performed in animals with neurofibrillary changes.

Aluminum↗
PubMed1998

[Brain lesions, pathogenic and etiologic hypotheses of Alzheimer's disease].

The main lesions of Alzheimer's disease are: 1. amyloid deposits, labelled by antibodies directed against the A beta peptide (core of the senile plaques, diffuse deposits and amyloid angiopathy), 2. neurofibrillary lesions labelled by anti-tau antibodies (neurofibrillary tangles, neuropil threads, crown of the senile plaques) and 3. loss of neurons and synapses. The distribution of neurofibrillary pathology is hierarchical: they begin in the entorhinal cortex, progress along the anterograde corticocortical pathways toward the multimodal and unimodal associative cortices to reach, in the most severe cases, the primary cortices. Amyloid lesions are more diffuse, rapidly affecting all the cortical areas. The density of neurofibrillary tangles in the cerebral cortex is correlated with the severity of dementia. Neuritic plaques, synaptic and neuronal loss also contribute to the intellectual deterioration. There are various causes of Alzheimer's disease (several mutations, trisomy 21, repeated head trauma as in dementia pugilistica): it should be considered a syndrome. Its pathophysiology is complex and involves several proteins (e.g. amyloid protein precursor, tau protein, presenilins 1 and 2, and apolipoprotein E).

Alzheimer Disease↗
PubMed1988

Immunohistochemical study of Alzheimer's disease using antibodies to synthetic amyloid and fibronectin.

Etiology and source of amyloid deposition in senile plaques of Alzheimer's disease (AD) are still unknown. In order to know whether or not fibronectin (Fn), an adhesive glycoprotein, is related to the amyloid deposition in the senile plaque, we conducted immunohistochemical studies using polyclonal anti-Fn and affinity-purified anti-amyloid component (Affi 28). Affi 28 was made by immunizing a rabbit against the synthetic peptide corresponding to residues 1-28 of the amyloid core protein reported by Masters et al. (1985). According to this study, four points became clear. First, Affi 28 is able to stain the subpial regions of AD as well as cerebrovascular amyloid and amyloid plaque cores. Second, it is suggested either that the etiology and source of neurofibrillary tangles and Pick body is distinct from that of the senile plaque or that any Affi 28 determinants of neurofibrillary tangles and Pick body are obscured sterically. Third, Affi 28 is useful to distinguish the senile plaque from the amyloid plaque of Creutzfeldt-Jakob disease. Last, there is no association between the amyloid in the senile plaque and Fn, at least immunohistochemically. The absence of Fn in the senile plaque suggests that Fn may not be requested for the deposition of amyloid fibrils.

Alzheimer Disease↗
PubMed2003

GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides.

Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.

Alzheimer Disease↗
PubMed1998

The neuropathological diagnosis of Alzheimer disease.

The unequivocal diagnosis of Alzheimer disease (AD) rests on histopathological evidence at brain autopsy or biopsy. Although the histological features of AD are well known, defining criteria for the morphological diagnosis of AD is difficult due to the phenotypical heterogeneity of the disease, absence of specific markers, and overlap of AD pathology with that observed in non-demented elderly individuals. This gray zone between normal to pathological aging and full-fledged AD represents an important diagnostic problem and should be overcome by better standardized criteria that will allow to minimize interrater and interlaboratory variability in the diagnosis of AD. Current criteria for the neuropathological diagnosis of AD are based on age-related (semi)quantitative assessment of "senile" plaques (NIA criteria), neuritic plaques (CERAD), plaques and neurofibrillary tangles in neocortex and hippocampus (Tierney et al., 1988), and staging of hierarchic spreading of neuritic AD changes in particular, neurofibrillary tangles (Braak and Braak, 1991). All these algorithms have some weaknesses and do not recognize the various subtypes of AD. Multivariant analysis of an autopsy series of elderly subjects revealed significant correlations between psychostatus assessed by the Mini-Mental State and both the CERAD criteria and Braak staging. Although the role of plaques and tangles in the pathogenesis of AD and their relationship to both neuronal loss and dementia remain to be elucidated, clinicopathological studies have shown that both lesions, if present in sufficient numbers, particularly in the neocortex, are considered the best correlates for AD related dementia. Recent consensus recommendations of the NIA- and Reagan Institute Working Group for the morphological diagnosis of AD consider AD as a heterogenous clinicopathological entity. After exclusion of other causes of dementia, the likelihood that AD accounts for dementia is considered high, intermediate or low according to the frequency of neuritic AD lesions with regard to both the CERAD criteria and Braak staging. The evaluation of small autopsy series according to these criteria demonstrated their easy and rapid application in AD and non-demented subjects, with much less reliability for other dementing disorders.

Aged↗
PubMed1993

Detection of tau proteins in normal and Alzheimer's disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay.

Alzheimer's disease is a progressive degenerative dementia characterized by the abundant presence of neurofibrillary tangles in neurons. This study was designed to test whether the microtubule-associated protein tau, a major component of neurofibrillary tangles, could be detected in CSF. Additionally, we investigated whether CSF tau levels were abnormal in Alzheimer's disease as compared with a large group of control patients. We developed a sensitive sandwich enzyme-linked immunosorbent assay using AT120, a monoclonal antibody directed to human tau, as a capturing antibody. With this technique, the detection limit for tau was less than 5 pg/ml of CSF. Using AT8, which recognizes abnormally phosphorylated serines 199-202 in tau, the detection limit was below 20 pg/ml of CSF. However, with AT8, we found no immunoreactivity in CSF, suggesting that only a small fraction of CSF tau contains the abnormally phosphorylated AT8 epitope. Our results indicate that CSF tau levels are significantly increased in Alzheimer's disease. Also, CSF tau levels in a large group of patients with a diversity of neurological diseases showed overlap with CSF tau levels in Alzheimer's disease.

Adolescent↗
PubMed1981

Congophilic angiopathy in the pathogenesis of Alzheimer's degeneration.

The pathologic manifestations in 45 valid cases of Alzheimer's degeneration were evaluated with specific focus on the presence of Congophilic angiopathy. The latter lesion was found in 89% of the cases and had a definite temporal relationship to the presence of neuritic plaques and neurofibrillary tangles. Two types of plaques were defined, the neuritic and perivascular. The latter was associated spatially with vessels, but not neurofibrillary tangles, while the converse was true of the neuritic plaques. Based on the pattern of mural involvement of vessels, distinctions could be made to differentiate morphologically between cerebral and peripheral amyloid angiopathy. Alzheimer's degeneration appears to be a disease complex with a variety of etiologies. Little or no differences in morphologic characteristics between the presenium and senium process could be discerned. Congophilic angiopathy appears to be a major feature in the pathogenesis of Alzheimer's degeneration.

Aged↗
PubMed1993

[Importance of neurofibrillary degeneration in the diagnosis of Alzheimer's disease].

For the pathological diagnosis of Alzheimer's disease ADRA-NIH recommend the quantification of plaques, without distinguishing their types, and neurofibrillary tangles. However, diffuse plaques may not be specifically associated to such diagnosis, as suggested by several authors and a previous paper. The neurofibrillary degeneration, present not only in neurofibrillary tangles but also in neuropil threads, either free in the neuropil or associated in plaques, could be more closely correlated with the decrease of cognitive functions than the plaques by themselves. In the present work, the efficiency of cholinesterase histochemical techniques and thioflavin-S is compared to the immunocytochemistry for abnormal tau, in two aspects: 1) the quantification of neurofibrillary degeneration, 2) the distribution of this degeneration, when present, within the plaques. It is concluded that immunocytochemistry for tau is the technique that better fulfills both goals, showing a better agreement with the cognitive state. For that reason tau immunocytochemistry is highly recommended in order to improve the anatomopathological diagnosis of Alzheimer's disease.

Acetylcholinesterase↗