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PubMed1978

Deformation of isolated neurofilaments and the pathogenesis of neurofibrillary pathology.

Experimental structural alterations were studied in neurofilaments isolated from rat peripheral nerve. Structural alterations were induced in vitro by prolonged incubations of neurofilament-rich fractions in 0.1 M KCl prior to fixation and examination of neurofilaments by negative staining techniques. Neurofilaments appeared to retain their structural integrity during the first week of incubation. Subsequently, a progressive reduction in the numbers of intact neurofilaments coincided with the increasing appearance of neurofilamentous breakdown products. During the period of neurofilament breakdown, an increasing number of altered neurofilaments were observed. These abnormal neurofilaments were characterized primarily by axial enlargements with diameters frequently occurring in the 150-200 A range but measuring up to 250 A. Enlarged neurofilaments also showed a greater irregularity of their lateral margins and less ridigity in their linear course. A striking feature of enlarged neurofilaments was their tendency to display twisting deformations along their longitudinal axes. Twists occurred most frequently along neurofilaments of greatest diameter. The largest abnormal neurofilaments reveal multiple periodic twists, sometimes occurring at 800-1000 A intervals. These enlarged and twisted neurofilaments resembled the abnormal filaments described in neurofibrillary tangles and plaques. The demonstration of neurofilament plasticity as well as the resemblance of neurofilaments deformed in vitro to the abnormal filamentous structures of neurofibrillary tangles and plaques has led to the suggestion that the latter structures may be derived from alterations of normally-formed neurofilaments. Furthermore, it is proposed that the enlarged and twisted filaments of neurofibrillary pathology may arise from alterations in the turnover of neurofilaments or, more specifically, from deficiencies in the degradative processes by which these organelles are broken down.

Animals↗
PubMed1983

Paucity of morphological changes in the brains of ageing beagle dogs: further evidence that Alzheimer lesions are unique for primate central nervous system.

Twelve regions of grey matter from the brains of 25 Beagle dogs, varying from one to over 16 years in age, were serially sectioned and sequentially scanned with a semi-automated sampling stage microscope, in a morphometric search for neuritic plaques, neurofibrillary tangles, and evidence of nerve cell loss. Examination of 227,776 light microscopic fields failed to reveal any senile plaques or neurofibrillary tangles. The neuronal densities, which ranged from 473 to 37,014 nucleolated neurons/mm3, showed no significant relationship with ageing. Neuronal lesions of Alzheimer type may be more typical of the human CNS; and physiological evidence for regionally reduced glucose metabolic rate in this animal model may require other structural alterations for its explanation.

Aging↗
PubMed1985

Postmortem evaluation of Alzheimer's disease.

Postmortem evaluation of ten individuals with a diagnosis of Alzheimer's disease (AD) confirmed the clinical diagnostic accuracy at our institution and showed significant ventricular dilatation with reduced brain mass, increased neuritic plaques, neurofibrillary tangles, vascular amyloid, and Lewy bodies in these individuals. A matched control group had no or fewer cortical neuritic plaques and neurofibrillary tangles, and two of the four control patients with rare neuritic plaques had terminal dementia. Cancer and cardiovascular disease occurred more often in the control group, but pneumonia and respiratory failure were more prevalent in the patients with AD. Thorough clinical assessment can accurately indicate Alzheimer's disease, as shown in this study.

Aged↗
PubMed2006

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice.

An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.

Animals↗
PubMed2000

[A 77-year-old man with gait and gaze disturbance].

We report a 77-year-old Japanese man with progressive gait disturbance. He was well until his 71 years of the age (1992), when he noted an onset of disturbance in his speech, which was followed by difficulty in using his left hand. He did not attempt to use his left hand afterwards. He started to fall down in the spring of 1994. He was admitted to our service on October 6, 1994. Neurologic examination revealed an alert and oriented man. He showed limb-kinetic apraxia in his left hand with anosognosia for his apraxia. Vertical gaze was impaired. He walked in small steps. He had moderate axial and limb rigidity. He had no weakness, ataxia, or tremor. Deep tendon reflexes were normal. Plantar response was flexor. Sensation was intact. His gait had progressively become worse and he was admitted to another hospital in April of 1996. At that time he was disoriented to time. He was only able to walk a few steps with support. He continued to show limb-kinetic apraxia in his left hand. He developed dementia and dysphagia and he expired on October 27, 1998. He was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had corticobasal degeneration. Most of the participants agreed with this diagnosis, but a few of them thought that progressive supranuclear palsy would be more likely. Post-mortem examination revealed no gross cortical atrophy. The right hemisphere was kept frozen for future biochemical analysis. The left precentral gyrus showed spongy changes, neuronal loss and gliosis. The pallidum, putamen, and the subthalamic nucleus were unremarkable, however, neurofibrillary tangles were seen in the subthalamic nucleus. The substantia nigra showed only slight neuronal loss; neuronal pigments were well retained. A few neurofibrillary tangles were seen in the remaining neurons. The cerebellar dentate nucleus showed grumose degeneration. Gallyas-Braak staining revealed many tuft-shaped astrocytes in the precentral gyrus. Pathologic diagnosis was progressive supranuclear palsy. Some participants thought that this diagnosis was unacceptable, because the pathologic changes in the substantia nigra, globus pallidus, and the subthalamic nucleus, which were usually severely involved in PSP, did not show typical changes of PSP. In addition, the predominant clinical feature was limb-kinetic apraxia, although he showed vertical gaze paresis and parkinsonian gait, which could also be seen in corticobasal degeneration. There was a big discussion among participants with regard to the diagnosis.

Aged↗
PubMedDate not supplied

[Advances in molecular pathology of Alzheimer's disease].

INTRODUCTION: Alzheimer's disease (AD) results from the progressive accumulation of a specific protein (beta peptide) in the brain parenchyma in the form of amyloid deposits. DEVELOPMENT: Amyloid deposition in AD may be the result of multiple genetic and environmental factors which may alter the metabolism and degradation of the beta amyloid precursor protein. Amyloid deposits are toxic to the nervous tissue and lead to synaptic loss, neurofibrillary tangle formation and progressive neuronal loss. CONCLUSIONS: Synaptic loss is related to memory decline in the early stages of the disease and neurofibrillary tangle formation and neuronal loss to dementia in later stages of the disease. This series of events, known as the amyloid cascade, is supported by many genetic and experimental studies.

Alzheimer Disease↗
PubMed2001

TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam.

BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene.

Adult↗
PubMed1989

Corticobasal degeneration.

Three patients with clinical and pathological features of corticobasal degeneration are described. They presented with a progressive disease bearing some clinical resemblance to Steele-Richardson-Olszewski syndrome and displaying some pathological features of Pick's disease. Their illness began at the age of 59 to 66 yrs with focal dystonia and myoclonus of an arm, the 'alien hand' sign, or an akinetic-rigid syndrome. They developed a supranuclear gaze palsy, parkinsonian features and mild cerebellar signs. Two patients showed constructional dyspraxia when using the arms. The duration of disease to death was 4 to 6 yrs. Pathological examination showed frontoparietal atrophy with cortical cell loss, gliosis and Pick cells, but there was no significant hippocampal disease or Pick bodies in this region. There was nerve cell loss and gliosis in the thalamus, lentiform nucleus, subthalamic nucleus, red nucleus, midbrain tegmentum, substantia nigra and locus coeruleus. Neuronal inclusions in the substantia nigra, termed corticobasal inclusions, were reminiscent of the globose neurofibrillary tangle of Steele-Richardson-Olszewski syndrome, and other pale inclusions resembled the pale body of Parkinson's disease, but Lewy bodies and neurofibrillary tangles were generally absent. Some nigral inclusions were similar to those in Pick's disease. Despite some pathological similarities to Pick's disease we suggest that the distribution of nerve cell loss and the corticobasal inclusion are unique to corticobasal degeneration.

Aged↗
PubMed1996

Review. David Oppenheimer Memorial Lecture 1995: Some neuropathological aspects of Alzheimer's disease and its relevance to other disciplines.

Recent studies of diffuse A beta plaques point to the neurons as a source of A beta in diffuse plaques. The neuritic (primitive and classical) plaques appear to be the product of microglia and the myocytes are the source of amyloid deposits in the meningeal and cortical vessels. Dyshoric angiopathy is associated with deposits of amyloid by perivascular cells. Fibrillization of the neuron-derived diffuse, thioflavine-negative or benign plaques is poor or undetectable by current morphological methods including ultrastructural immunocytochemistry. It appears that fibrillization depends on the length of the A beta peptides and on the presence of amyloid-associated proteins. Four genes are now tightly linked with Alzheimer's disease (AD) and they are located on chromosomes 21, 19, 14 and 1. Therefore, AD should be considered a polyaetiological disease or syndrome. There are currently five transgenic mouse models overexpressing beta-APP. There is also a myocyte tissue culture model in which both soluble and fibrillized A beta are found. The relationship between A beta and neurofibrillary pathology is not clear and the current cascade hypothesis proposing that A beta pathology drives the formulation of neurofibrillary tangles is being questioned. There is growing evidence that it is not the A beta hypothesis, but the co-existing A beta neurofibrillary tangle pathology hypothesis which will be the basis for AD neuropathology.

Alzheimer Disease↗
PubMed2000

The cause of neuronal degeneration in Alzheimer's disease.

Alzheimer's disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration and the progressive development of dementia. Pathological hallmarks common to the disease include beta-amyloid plaques, dystrophic neurites associated with plaques and neurofibrillary tangles within nerve cell bodies. The exact relationship between these pathological features has been elusive, although it is clear that beta-amyloid plaques precede neurofibrillary tangles in neocortical areas. Examination of the brains of individuals in the preclinical stage of the disease have shown that the earliest form of neuronal pathology associated with beta-amyloid plaques resembles the cellular changes that follow structural injury to axons. Thus, the development of beta-amyloid plaques in the brain may cause physical damage to axons, and the abnormally prolonged stimulation of the neuronal response to this kind of injury ultimately results in the profound cytoskeletal alterations that underlie neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of the neuronal reaction to physical trauma may be a useful neuroprotective strategy in the earliest stages of Alzheimer's disease.

Alzheimer Disease↗
PubMed1989

Tau, paired helical filaments and amyloid in the neocortex: a morphometric study of 15 cases with graded intellectual status in aging and senile dementia of Alzheimer type.

Tau immunoreactivity was studied in temporal neocortex, area 22, in 15 cases with graded intellectual status and compared with the immunoreactivity observed with an antiserum against paired helical filaments (PHF) and with the density of amyloid revealed by thioflavin S. Samples came from women over 75 years either intellectually normal or affected by senile dementia of the Alzheimer type at various degrees of severity. Mental status had been prospectively assessed by the Blessed's test score. Anti-tau labelled a neuropil meshwork, the density of which increased with the severity of the disease. This meshwork was denser in layers II, III and V in the most affected cases. The number and the size of the tau-positive fibers within the senile plaques increased with the intellectual deficit. Senile plaques were more numerous in layers II and III and neurofibrillary tangles in layers III and V whatever the staining technique: tau or PHF immunocytochemistry, and thioflavin S. The densities of senile plaques and of neurofibrillary tangles (NFT) were correlated with the severity of the disease whatever the staining method. The three methods revealed a systematically different number of changes. This systematic difference could greatly influence the neuropathological diagnosis. It could be the consequence of various factors: different sensitivities of the staining methods or changes in the antigenic and amyloid composition of the lesion according to the stage of the disease. In line with the last hypothesis, a higher proportion of amyloid-rich plaques was noted in the less affected cases, suggesting that tau and PHF epitopes appeared secondarily.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Alzheimer disease tangles share immunological similarities with multiphosphorylation repeats in the two large neurofilament proteins.

Immunological and structural analyses of neurofilament (NF) proteins with greater than 500 anti-NF monoclonal antibodies (mAbs) enumerated epitopes shared by NF proteins and Alzheimer neurofibrillary tangles. We identified the multiphosphorylation domain of the rat heaviest NF subunit--tandem repeats of Lys-Ser-Pro-Xaa (where Xaa is a small uncharged amino acid and serine is phosphorylated)--as the determinant recognized by 15 of the 16 mAbs from this collection of greater than 500 mAbs that detected neurofibrillary tangles. Most (11) of these 16 mAbs also recognized the previously characterized multiphosphorylation repeat in the human middle sized NF subunit. However, although these mAbs shared the ability to recognize NFTs, the antigen-binding domains of these 16 mAbs represented 13 separate classes based on their differential recognition of 12 synthetic peptides derived from the rat heaviest NF subunit and the human middle-sized NF subunit multiphosphorylation sites, NF subunits of 10 diverse species, and normal human tau protein. We conclude that NFTs share highly specific immunological and structural properties with specific rat heaviest NF subunit and human middle-sized NF subunit multiphosphorylation repeats.

Alzheimer Disease↗
PubMed1989

The ultrastructural localization of sulfated proteoglycans is identical in the amyloids of Alzheimer's disease and AA, AL, senile cardiac and medullary carcinoma-associated amyloidosis.

The cationic dyes cuprolinic blue and ruthenium red were used to ultrastructurally localize proteoglycans (PGs) within the neuritic plaque and neurofibrillary tangle of Alzheimer's disease. Highly sulfated PGs were specifically localized to the amyloid fibril of the neuritic plaque and the paired filaments of the neurofibrillary tangle. This demonstrates that highly sulfated PGs either comprise part of the Alzheimer's amyloid fibril and paired filament or are intimately associated with them. Four unrelated types of amyloid--AA (inflammation-associated), AL (immunoglobulin light chain), senile cardiac (prealbumin) and medullary carcinoma-associated amyloid (procalcitonin)--showed an identical pattern of localization of highly sulfated PG to the different amyloid fibrils. This constant close spatial relationship between PGs and diverse amyloid proteins suggests that PGs may play a role in amyloidogenesis.

Alzheimer Disease↗
PubMed1988

The monoclonal antibody, Alz 50, recognizes tau proteins in Alzheimer's disease brain.

The monoclonal antibody, Alz 50, is known to label many dystrophic neurites and neurofibrillary tangles in Alzheimer's disease (AD) brain. Using immunoprecipitation and immunoblotting, we have compared Alz 50 to monoclonal antibodies directed at two known components of neurofibrillary tangles, tau and ubiquitin, in order to characterize further the antigens recognized by Alz 50 in AD brain. Alz 50 labeled purified tau proteins in a highly similar fashion to two well-characterized tau monoclonal antibodies. Alz 50 precipitated proteins at the molecular weight of 50-70 kDa from AD but not normal brain; these proteins were reactive with the tau antibodies. In addition, Alz 50 precipitated proteins migrating principally around 160-180 kDa from AD but not normal brain; the relationship of the latter proteins to tau remains unclear. None of these proteins reacted with a ubiquitin antibody. We hypothesize that the proteins recognized by Alz 50 at much higher levers in AD than normal brain include modified and aggregated forms of tau.

Alzheimer Disease↗
PubMed1999

The amyloid precursor protein of Alzheimer's disease and the Abeta peptide.

Alzheimer's disease is characterized by the accumulation of beta amyloid peptides in plaques and vessel walls and by the intraneuronal accumulation of paired helical filaments composed of hyperphosphorylated tau. In this review, we concentrate on the biology of amyloid precursor protein, and on the central role of amyloid in the pathogenesis of Alzheimer's disease. Amyloid precursor protein (APP) is part of a super-family of transmembrane and secreted proteins. It appears to have a number of roles, including regulation of haemostasis and mediation of neuroprotection. APP also has potentially important metal and heparin-binding properties, and the current challenge is to synthesize all these varied activities into a coherent view of its function. Cleavage of amyloid precursor protein by beta-and gamma-secretases results in the generation of the Abeta (betaA4) peptide, whereas alpha-secretase cleaves within the Abeta sequence and prevents formation from APP. Recent findings indicate that the site of gamma-secretase cleavage is critical to the development of amyloid deposits; Abeta1-42 is much more amyloidogenic than Abeta1-40. Abeta1-42 formation is favoured by mutations in the two presenilin genes (PS1 and PS2), and by the commonest amyloid precursor protein mutations. Transgenic mouse models of Alzheimer's disease incorporating various mutations in the presenilin gene now exist, and have shown amyloid accumulation and cognitive impairment. Neurofibrillary tangles have not been reproduced in these models, however. While aggregated Abeta is neurotoxic, perhaps via an oxidative mechanism, the relationship between such toxicity and neurofibrillary tangle formation remains a subject of ongoing research.

Alzheimer Disease↗
PubMed1993

Heterogeneity of brain gene expression in Alzheimer's disease.

We have examined the expression of several genes whose transcripts have increased levels in Alzheimer's disease and have found heterogeneity in these levels in different patients with this condition. The level of expression of these genes was compared to different clinical and pathological aspects of the disease. A case with markedly elevated alpha 1-antichymotrypsin mRNA levels demonstrated prominent neuronal accumulation of this protein. Many of the neurons which demonstrated alpha 1-antichymotrypsin staining did not have neurofibrillary tangles, and vice versa. This suggests that alpha 1-antichymotrypsin staining might identify a different facet of the pathology of Alzheimer's disease than does neurofibrillary tangle staining and may provide new information in the study of this condition.

Aged↗
PubMed1994

Calcineurin immunoreactivity in Alzheimer's disease.

Aberrant phosphorylation of tau is linked to formation of the paired helical filaments (PHF) seen in Alzheimer's disease. Protein kinases such as mitogen-activated protein kinase, and calcium-regulated protein kinases may, in part, be responsible for addition of phosphate groups to serine residues of PHFtau; however, less is known concerning the phosphatases which regulate tau. In this report, we used several well-characterized antibodies to document calcineurin immunoreactivity in brain tissue from patients with Alzheimer's disease. We now report that levels of immunoreactive calcineurin are not significantly altered in neocortex and cerebellum of Alzheimer's patients relative to similar regions of age-matched controls. Immunocytochemical studies indicated that calcineurin immunoreactivity was present in dendrites and perikarya of many different neuronal populations in both control and Alzheimer brain. When specific antibodies against PHFtau were used in double-labeling experiments with anti-calcineurin antibodies, calcineurin immunoreactivity was seen in association with neurofibrillary tangles. However, calcineurin was not seen in all tangle bearing neurons. These data suggest that calcineurin levels per se are not significantly altered in Alzheimer's disease, but that calcineurin is distributed around some neurofibrillary tangles and may play a role in regulation of tau phosphorylation.

Aged↗
PubMed2001

Mechanisms of amyloid beta protein-induced modification in ion transport systems: implications for neurodegenerative diseases.

1. Alzheimer's disease (AD) is a neurodegenerative disorder that affects the cognitive function of the brain. Pathological changes in AD are characterized by the formation of amyloid plaques and neurofibrillary tangles as well as extensive neuronal loss. Abnormal proteolytic processing of amyloid precursor protein (APP) is the central step that leads to formation of amyloid plaque, neurofibrillary tangles, and neuronal loss. 2. The plaques, which accumulate extracellularly in the brain, are composed of aggregates and cause direct neurotoxic effects and/or increase neuronal vulnerability to excitotoxic insults. The aggregates consist of soluble pathologic amyloid beta peptides AbetaP[1-42] and AbetaP[1-43] and soluble nonpathologic AbetaP[1-40]. Both APP and AbetaP interact with ion transport systems. AbetaP induces a wide range of effects as the result of activating a cascade of mechanisms. 3. The major mechanisms proposed for AbetaP-induced cytotoxicity involve the loss of Ca2+ homeostasis and the generation of reactive oxygen species (ROS). The changes in Ca2+ homeostasis could be the result of (1) changes in endogenous ion transport systems, e.g. Ca2+ and K+ channels and Na+/K+-ATPase, and membrane receptor proteins, such as ligand-driven ion channels and G-protein-driven releases of second messengers, and (2) formation of heterogeneous ion channels. 4. The consequences of changes in Ca2+-homeostasis-induced generation of ROS are (a) direct modification of intrinsic ion transport systems and their regulatory mechanisms, and (b) indirect effects on ion transport systems via peroxidation of phospholipids in the membrane, inhibition of phosphorylation, and reduction of ATP levels and cytoplasmic pH. 5. We propose that in AD, AbetaP with its different conformations alters cell regulation by modifying several ion transport systems and also by forming heterogeneous ion channels. The changes in membrane transport systems are proposed as early steps in impairing neuronal function preceding plaque formation. We conclude that these changes damage the membrane by compromising its integrity and increasing its ion permeability. This mechanism of membrane damage is not only central for AD but also may explain other malfunctioned protein-processing-related pathologies.

Amyloid beta-Peptides↗