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PubMed1994

Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease.

Heme oxygenase-1 is an important enzyme that degrades heme, a pro-oxidant, leading to the formation of antioxidant molecules. In this study we demonstrate by immunocytochemistry close association of heme oxygenase-1 with Alzheimer neurofibrillary pathology and with the neurofibrillary tangles found in progressive supranuclear palsy and subacute sclerosing panencephalitis. In Alzheimer's disease, using two different rabbit antisera against heme oxygenase-1 protein, we localized, using immunocytochemical methods, heme oxygenase-1 to neurofibrillary tangles, senile plaque neurites, granulovacuolar degeneration, and neuropil threads. Only light background staining was seen in young controls and sporadic lesion-related immunoreactivity in age-matched controls. The increase in heme oxygenase-1 protein in association with the neurofibrillary pathology of Alzheimer's disease and other diseases characterized by neurofibrillary tangles supports the notion that the generation of free radicals and oxidative stress plays a role in the pathogenesis of neurofibrillary pathology.

Aged↗

PubMed1997

4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease.

Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine-derived pyrrole adducts formed by lipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age-matched control patients. HNE-pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid-beta deposits were unlabeled. Age-matched controls showed only background HNE-pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress-related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.

Aged↗

PubMed1988

[Alzheimer's disease with early association of a hemi-parkinsonian syndrome].

A 66 year-old woman presented with severe memory disorders followed several months later with tremor of Parkinsonian type of the right upper limb totally relieved by treatment with levodopa-benserazide. Four years later she was admitted with memory disturbances, temporospatial disorientation, constructional and ideatory apraxia, dressing apraxia and language difficulties. Eight years later she had become bed-ridden, with deviation of head and eyes towards the left, hypertonus tremor and stereotyped movements. Neuropathologic examination showed neuronal loss in substantia nigra and left locus ceruleus, dorsal nucleus of the pneumogastric nerve and Meynert's basal nuclei on both sides. Neurofibrillary tangles affected the peri-aqueductal grey matter and Lewy's bodies were observed in the substantia nigra. Neurofibrillary tangles and granulovacuolar degeneration together with senile plaques were numerous in the hippocampus, but senile plaques and neurofibrillary tangles were rare in the remainder of the cortex. Combined Alzheimer's disease and Parkinson's disease could be due to simple coincidence, one of the diseases possibly predisposing to the appearance of the other.

Aged↗

PubMedDate not supplied

Diagnostic criteria for neuropathologic assessment of Alzheimer's disease.

Prior to any evaluation of morphologic brain changes, a decision must be made whether a given alteration is associated with aging or with disease. Patients with disease-related lesions may be in a clinically silent phase of a disease or show overt symptoms. Neurofibrillary tangles and neuropil threads are the hallmarks of Alzheimer's disease. They should not be considered to be age-related changes, even when they are present only in small numbers. In general, the initial changes consist of neurofibrillary tangles and neuropil threads. Plaques (amyloid deposits and/or neuritic plaques) are consistently present in the end stage of the disease. Initial neurofibrillary tangles and neuropil threads develop at specific cortical predilection sites. The changes then spread in a predictable, nonrandom manner across other portions of the telencephalic cortex. The sequential changes in the distribution pattern of the lesions provide the basis for a staging procedure that takes the slow and gradual progression of the destructive process into consideration. The staging procedure provides accurate diagnoses in the initial stages and even reveals brain changes developing prior to the appearance of clinical symptoms. It is thus advantageous in characterizing nondemented controls. The staging procedure can be carried out easily and does not require knowledge of clinical data, quantitative assessments, or adjustments for the age of the patients. Application of advanced silver techniques (Gallyas, Campbell-Switzer) to demonstrate Alzheimer's disease-related lesions also allows recognition of the hallmarks of other disorders, such as Lewy body disease (Parkinson's disease) and dementia with argyrophilic grains, which frequently co-occur with Alzheimer's disease.

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PubMed1990

Pathological alterations in the amygdala in Alzheimer's disease.

The amygdala is severely and consistently affected by pathology in Alzheimer's disease. The distribution of Thioflavin S-stained neurofibrillary tangles and neuritic plaques was examined in the various nuclei that form the amygdala in 20 cases of clinically diagnosed Alzheimer's disease and five non-demented control cases. Large numbers of neurofibrillary tangles and neuritic plaques were observed in the accessory basal and cortical nuclei and the cortical transition area, while there was lesser involvement of the mediobasal nucleus. The medial, lateral, laterobasal and central nuclei were relatively spared. The distribution of neurofibrillary tangles and neuritic plaques was compared with neuroanatomic connections known from non-human primate experimental studies. This comparison suggests that (1) nuclei receiving and giving rise to hippocampal projections are consistently affected by neuropathological alterations in Alzheimer's disease; (2) the nuclei which receive strong cholinergic projections from the nucleus basalis of Meynert (e.g. laterobasal nucleus) have, in general, relatively few neuritic plaques; and (3) nuclei which receive olfactory projections are not uniformly affected, the cortical nucleus being heavily affected but the medial nucleus consistently spared.

Aged↗

PubMed1995

Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype.

BACKGROUND: The neuropathological changes of Alzheimer's disease occur universally in individuals with Down's syndrome as they reach middle age and worsen with increasing age. Thus, evaluation of patients of various ages with Down's syndrome allows one to construct a life history of the development of neuropathological changes associated with Alzheimer's disease at various points in the disease process. METHODS: We have used semiquantitative scales and quantitative computerized image analysis techniques to analyze the characteristics of neurofibrillary tangle formation and A beta amyloid deposition in the hippocampal formation and inferior temporal gyrus in 36 individuals with Down's syndrome ranging in age from 4 to 73 years. RESULTS: Neurofibrillary tangles occur in a hierarchical distribution in a circumscribed set of neuronal fields, affecting the entorhinal cortex, area CA1/subiculum, then other hippocampal subfields. Although amyloid deposition occurs more evenly in a more widespread distribution, it also accumulates over the years 30 to 50. Surprisingly, examination of the patients available older than 50 years showed no trend toward continued increased deposition of amyloid. Within this group, however, individuals who had inherited the apolipoprotein E (Apo E) epsilon 4 genotype contained more than twice the amyloid burden of individuals who did not inherit the Apo E epsilon 4 genotype. COMMENT: This large series of cases confirms earlier observations that had suggested early vulnerability of entorhinal cortex and CA1/subiculum for neurofibrillary tangles and a more widespread but specific topography of A beta deposition. Moreover, it demonstrates quantitatively that the lesions increase to a certain level and then apparently reach a plateau. The level of amyloid deposition in Down's syndrome is higher than in sporadic Alzheimer's disease. Inheritance of the Apo E epsilon 4 genotype appears to be an additional (independent) risk factor for developing higher levels of amyloid accumulation.

Adolescent↗

PubMed1991

[Morphological changes in the human cerebral cortex in dementia].

Many diseases of the brain leading to impairment of intellectual capacities are associated with morphological changes in the anteromedial portions of the temporal lobe. Among these are Alzheimer's disease, Parkinson's disease and the syndrome of dementia with argyrophilic grains. The hallmarks of Alzheimer's disease are intraneuronal neurofibrillary changes and extracellular amyloid deposits. The neurofibrillary changes consist of neurofibrillary tangles, neuritic plaques and neuropil threads. The distribution pattern of neurofibrillary changes differs from the distribution of amyloid deposits. The neurofibrillary changes exhibit a distinct but varying distribution pattern in different areas of the cerebral cortex. In fully developed Alzheimer's disease, both the hippocampal formation and isocortical association areas are severely involved while the brunt of the pathology is found in the entorhinal region. The entorhinal region receives information from various isocortical association areas and limbic circuits and projects to the hippocampal formation via the perforant path. This fibre tract is mainly generated by projection neurons within the superficial entorhinal cell layer. In Alzheimer's disease virtually all projection neurons within this layer are destroyed by neurofibrillary tangles. In cases of Parkinson's disease with progressive cognitive decline the neurofibrillary changes are confined to the outer cellular layer of the entorhinal region. In cases of "dementia with argyrophilic grains" the argyrophilic grains are predominantly encountered in the hippocampal formation and in the outer layers of the entorhinal region.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗

PubMedDate not supplied

A grading system of Alzheimer disease lesions in neocortical areas.

Progression of neuritic and Abeta pathology in the cerebral cortex during aging and Alzheimer disease is well known, but the chronology of the various types of lesions (Abeta deposition, amyloid formation, inflammation, ubiquitination, tangle formation) within a given area has not been fully elucidated. We examined these lesions in the primary visual cortex (Brodmann area 17), correlating them with the severity of the disease (as evaluated by the cognitive status and the number of cortical samples that contained neurofibrillary tangles). Four 'grades' were identified. At grade 1, only deposits of Abeta peptide were noticed. At grade 2, Congo red positive deposits, and processes containing ubiquitin and cathepsin D immunoreactivity around plaque cores could also be found. At grade 3, neuritic plaques and neuropil threads were present, and at grade 4, neurofibrillary tangles. The density of all the lesions dramatically increased at grade 4. The sequence of isocortical lesions from grade 1 to grade 4 is compatible with a cascade of events beginning with deposition of Abeta peptide and ending with neurofibrillary tangle.

Aged↗

PubMedDate not supplied

Functional alterations in neural circuits in Alzheimer's disease.

While a correlation exists at the regional level between the distribution of neurofibrillary tangles and the predicted sites of brain dysfunction based on clinical and functional neuroimaging studies, the relationship between neurofibrillary tangles and neuronal dysfunction is poorly understood. Using cytochrome oxidase activity as a marker of neuronal functional activity, we found reductions in metabolic activity both in a hippocampal subfield with a high density of neurofibrillary tangles (CA1) as well as in subfields relatively spared (CA3, dentate granule cells). In contrast, we found no reduction in activity in primary visual cortex. Using in situ hybridization, we found a selective reduction in a mitochondrial-encoded cytochrome oxidase mRNA transcript with sparing of a nuclear-encoded transcript. These results suggest that the reduction in cytochrome oxidase activity in Alzheimer's disease brain may be related to an alteration in mitochondrial gene expression. The absence of a direct correlation between structural pathology and cytochrome oxidase activity suggests that neurons that remain structurally intact in Alzheimer's disease may nonetheless undergo substantial changes in metabolic activity.

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PubMed1997

Pathological correlates of extrapyramidal signs in Alzheimer's disease.

Extrapyramidal signs frequently accompany Alzheimer's disease (AD), but the pathological substrate remains unknown. Clinical and postmortem information from patients with AD, Parkinson's disease, or progressive supranuclear palsy and control subjects seen at a large tertiary medical center between 1989 and 1994 was examined. AD patients who had taken neuroleptics and AD brains that also contained Lewy bodies were excluded. The presence of extrapyramidal signs was determined using the Unified Parkinson's Disease Rating Scale. Sections of basal ganglia, subthalamic nucleus, and substantia nigra were examined for neurofibrillary tangles and neuropil threads and the nigra for neuronal numbers. Patients with AD (with or without extrapyramidal signs) did not show neuronal loss in the nigra compared to control subjects, while both Parkinson's disease and progressive supranuclear palsy brains showed marked depletion. The number of neurofibrillary tangles and neuropil threads was increased in AD (with or without extrapyramidal signs) nigra compared to control tissue, and also in progressive supranuclear palsy nigra, but not Parkinson's disease nigra. The numbers of nigral neurofibrillary tangles and neuropil threads were positively related to extrapyramidal signs in AD. There were no correlations between tangles and threads in the basal ganglia or subthalamic nucleus and extrapyramidal signs in AD. Thus, extrapyramidal signs in AD correlate best with tangle pathology in the nigra and do not require the concomitant presence of Lewy bodies.

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PubMed2005

Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.

BACKGROUND: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. OBJECTIVE: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. METHODS: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. RESULTS: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. CONCLUSION: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

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PubMed2003

Cholesterol storage and tau pathology in Niemann-Pick type C disease in the brain.

Niemann-Pick type C disease is an inherited neurovisceral storage disorder with intracellular accumulation of cholesterol. In affected brains, many ballooned neurons are seen. Considerable nerve cell loss of unknown pathogenesis leads to neurological deterioration and dementia. Chemical examination of brains has failed to demonstrate increased levels of cholesterol. Using filipin fluorometry of neuronal cells in tissue slices, we found massive accumulation of cholesterol in neurons in four out of five human Niemann-Pick type C cases including adult patients. Neurofibrillary tangles composed of aggregates of the otherwise highly soluble protein tau were present in three Niemann-Pick type C cases and were also immunologically identical to those associated with Alzheimer's disease. However, only a thin slab of spinal cord or a tiny piece of isocortex was available for examination in the two cases without tangles. In a further semi-quantitative analysis of 576 neurons, we determined higher cholesterol content in tangle-bearing neurons than in adjacent tangle-free neurons. The association of cholesterol accumulation with neurofibrillary degeneration in Niemann-Pick type C disease and Alzheimer's disease awakens interest in the role of impaired cholesterol metabolism in the development of neurofibrillary tangles in both diseases.

Adolescent↗

PubMed1998

Alzheimer's Disease Pathology in Non-Demented Elderly.

The purpose of this study was to quantitate the extent of neuropathological lesions (neurofilbrillary tangles and senile plaques) characteristic of Alzheimer's disease in cognitively intact elderly control subjects. The subjects included twenty-six elderly individuals who were autopsied at a university-based Alzheimer's Disease Center. The mean age at autopsy was 78 years (range 51-99 years); there were 15 males and 11 females. All of these control subjects had a few neurons containing neurofibrillary tangles in the hippocampus, but no neurofibrillary tangles in the neocortex. Twelve of the 26 subjects (46%) had some senile plaques in the neocortex, while fourteen (54%) did not. Six subjects (23%) had substantial numbers of senile plaques in the neocortex. Neither the number of neurons containing neurofibrillary tangles nor the number of senile plaques correlated with age in these subjects. Possible conclusions are that there are many elderly individuals with incipient Alzheimer's Disease, or that one can have some degree of these lesions and still be cognitively normal. These data point out the need to have better pathological markers of the disease process and better diagnostic criteria to define Alzheimer's Disease.

Journal Article↗

PubMed2001

Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant beta-amyloid precursor protein (APP), thus modulating the APP-Abeta (beta-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Abeta deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Abeta influences the formation of neurofibrillary tangles. The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.

Alzheimer Disease↗

PubMed1990

Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer's disease: II. Primary and secondary visual cortex.

In this study we investigated the primary and secondary visual areas of normal and Alzheimer's disease brains by using the SMI32 antibody. It is known that in Alzheimer's disease primary sensory areas are usually less devastated than association cortices, although visual symptomatology has been documented early in the course of the disease. In area 17, the SMI32 antibody primarily labeled the perikarya and dentritic tree of the large Meynert cells and cells in layer IVB. Smaller neurons in layers III, V, and VI were also immunoreactive (ir). In area 18, very large SMI32-ir pyramidal neurons in layers III and V were observed. In both areas, staining intensity was correlated with cell size, the largest neurons being the most intensely stained. Only a few changes were observed in the Alzheimer's disease cases. The only statistically significant differences in SMI32-ir neuron counts between control and Alzheimer's disease brains occurred in layer IVB cells and Meynert cells in area 17, and in layer III cells in area 18. In contrast with association cortices, there were no changes in staining intensity in the visual areas. There were fewer neurofibrillary tangles and neuritic plaques in these areas than in prefrontal and inferior temporal cortex, and a correlation between neurofibrillary tangle counts and SMI32-ir neuron loss was only observed in layer III of area 18. These observations show that in the primary and secondary visual cortex, SMI32 also labeled a distinct subset of pyramidal cells that are known from data obtained in the monkey brain to furnish long corticocortical as well as subcortical projections. Interestingly, although there is much less cell and/or neurofibrillary tangle formation in these occipital regions than in prefrontal and temporal association areas, there is significant loss within key subsets of pyramidal cells. The selective loss of this particular subpopulation of pyramidal neurons will disrupt association pathways linking primary visual cortex with areas involved in higher level visual processing. The partial disconnection of such pathways may be relevant to the visual symptomatology frequently observed in Alzheimer's disease patients. These data further support the hypothesis that subtypes of pyramidal neurons with specific anatomical and molecular profiles may display a differential vulnerability in Alzheimer's disease.

Aged↗

PubMed1981

Senile plaques and tangles in dialysis dementia.

The brains of 7 patients treated with hemodialysis were studied. Four of these patients had the dialysis encephalopathy syndrome (DES). Senile plaques and or neurofibrillary tangles were found in 5 of the 7 cases, 3 with and 2 without DES. One case of each group had plaques to an extent compatible with that in Alzheimer's disease, though of a different distribution. Neurofibrillary tangles were generally sparse. Plaques and tangles, both containing paired helical filaments, are the principal changes in Alzheimer's disease. Aluminum has been implicated as a possible etiologic agent behind the paired helical filaments in Alzheimer's disease, where raised cerebral aluminum contents have been demonstrated. Aluminum is known to be increased in the central nervous system also in DES, most likely as a consequence of procedures in connection with the hemodialysis. The finding of neurofibrillary tangles and senile plaques in hemodialyzed patients, some of which have developed DES, may therefore support the theories concerning aluminum as an etiological agent for cerebral changes in Alzheimer's disease.

Brain↗

PubMed1987

Sulfated glycosaminoglycans in Alzheimer's disease.

Using the sulfated alcian blue and alcian blue-MgCl2 techniques for demonstrating sulfated glycosaminoglycans (GAGs), we have shown sulfated GAGs to be associated with the amyloidotic lesions of Alzheimer's disease, the neuritic plaques, the neurofibrillary tangle, and the congophilic angiopathy. To determine how specific these findings are to Alzheimer's disease, other neurologic disorders with neurofibrillary tangles and filamentous inclusions were examined. These included progressive supranuclear palsy, Pick's disease, subacute sclerosing panencephalitis, and postencephalitic parkinsonism. Sulfated GAGs were not demonstrated in the neurofibrillary tangles or filamentous structures in any of these disorders. The relationship of GAGs to the pathology of Alzheimer's disease is discussed as is their possible importance in determining the characteristic morphology of the amyloidotic lesion.

Alzheimer Disease↗

PubMed2004

Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice.

Neurofibrillary tangles, insoluble protein deposits composed of filamentous tau aggregates, are neuropathological hallmarks of Alzheimer's disease and familial frontotemporal dementia (FTDP-17). Transgenic mice expressing the FTDP-17 mutation P301L of tau recapitulate key features of the human pathology, that is, tau proteins aggregate and neurofibrillary tangles begin to appear in the amygdala at 6 months of age. To detect early signs of tau aggregate-associated changes, we investigated behavioral alterations and cognitive deficits in such mice using an amygdala-specific test battery for anxiety-related and cognitive behavior. P301L mice had anxiety levels not different from wild-types, but their exploratory behavior was significantly increased. Acquisition of a fear response to tone and context as well as taste aversion was comparable to wild-types. However, extinction of a conditioned taste aversion was significantly accelerated. We conclude that already aggregation of tau proteins not yet accompanied by massive formation of neurofibrillary tangles causes selective behavioral deficits.

Animals↗