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PubMed1996

Histopathology of the substantia nigra in Alzheimer's disease.

Histopathologic examination of the pars compacta of the substantia nigra of 17 patients with Alzheimer's disease showed Lewy bodies in six, neurofibrillary tangles in another six and only histologic changes that did not differ from age-matched controls in five patients. Four of the six patients with nigral Lewy bodies showed severe loss of neural cell bodies, reactive astrocytosis, gliosis and neuromelanin in macrophages and in the neuropile. By contrast, the loss of neuronal cell bodies in our patients without nigral Lewy bodies regardless of whether or not they also had nigral neurofibrillary tangles was no greater than what we observed in our age-matched controls. Quantitative cell counts confirmed our histopathologic estimates of neuronal loss. Our study and the findings of others show that the substantia nigra is often abnormal in Alzheimer's disease and that the abnormalities are rarely severe without nigral Lewy bodies.

Aged↗
PubMed1996

Can the controversy of the role of aluminum in Alzheimer's disease be resolved? What are the suggested approaches to this controversy and methodological issues to be considered?

Aluminum (Al) is unquestionably neurotoxic in both experimental animals and certain human diseases. Minute quantities injected intracerebrally into rabbits will induce severe neurological symptoms and neuropathological features of neurodegeneration. Hyper-aluminemia often develops in patients with renal failure being treated with intermittent hemodialysis on a chronic basis, and in severe cases results in an encephalopathy. Uremic adults and premature infants not on dialysis treatment also can develop encephalopathy due to Al toxicity, as is the case when large amounts of alum are used as a urinary bladder irrigant. There are many other examples of Al-induced neurotoxicity; however, the question as to whether Al presents a health hazard to humans as a contributing factor to Alzheimer's disease is still the subject of debate. Several lines of evidence are presented that have formed the basis of the debate concerning the possible pathogenic role for Al in Alzheimer's disease. Important evidence for an Al-Alzheimer's causal relationship is the observation by laser microprobe mass analysis (LMMS) of the presence of Al in neurofibrillary tangles, although there are conflicting data on the extent of the Al deposition. The relatively poor sensitivity of some of the analytical instruments available for these challenging in situ microanalyses could explain the discrepant results, although LMMS and perhaps secondary ion mass spectrometry (SIMS) appear to be sufficiently sensitive. Harmonization of the techniques is an essential next step. There is new evidence that exposure to Al from drinking water might result in cognitive impairment and an increased incidence of Alzheimer's disease. However, these epidemiological studies have inherent problems that must be scrutinized to determine if an association really does exist. An understanding of a possible enhanced bioavailability of Al in this type of exposure, versus other exposures such as antacid intake or industrial exposure, needs to be considered and explored. There has been one promising clinical trial of the treatment of Alzheimer's disease patients with the Al chelator desferrioxamine (DFO). Further studies are needed, and if confirmation is forthcoming then such data could also support an Al-Alzheimer's disease link as well as suggesting that DFO offers potential as a therapeutic agent. The possibility that iron might be the offending agent needs to be considered since DFO is a very strong iron chelator. The significance of Al-induced neurofibrillary degeneration in experimental animals should be assessed especially in light of new data showing that this model exhibits abnormally phosphorylated tau protein structures in the neuronal perikarya. Thus the key questions that must be answered before it can be asserted that Al possesses causal relationship to Alzheimer's disease, are as follows and are addressed in this present discussion: (1) Are there elevations of the concentration of Al in the brains of Alzheimer's disease patients? (2) Is there a relationship between environmental exposure to Al, particularly in drinking water, and an increased risk of Alzheimer's disease? (3) Is treatment with DFO a potentially useful therapeutic approach and to what extent might beneficial effects of DFO implicate Al in the etiology of Alzheimer's disease? (4) Are there similarities between the experimental animal studies and Alzheimer's disease particularly in the development of abnormal forms of tau seen in neurofibrillary tangles? (5) Does Al promote the deposition of the A beta peptide in Alzheimer's disease? (6) Does hyperaluminemia associated with long-term hemodialysis treatment induce neurofibrillary degeneration? If the answer to each of these six questions is yes, then does this assert that Al possesses a causal relationship to Alzheimer's disease? On the other hand, must all six be met to be able to make this assertion?

Aluminum↗
PubMed1994

Effects of intrahippocampal colchicine administration on the levels and localization of microtubule-associated proteins, tau and MAP2.

Colchicine, a microtubule disrupting agent, has been used to model several aspects of Alzheimer's disease-related neuropathology. The formation of neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, involves the loss of tau (a low mol. wt. microtubule-associated protein) from axons and accumulation of abnormally phosphorylated tau in somatodendritic compartments. Other cytoskeletal proteins, such as microtubule-associated protein 2 (MAP2), disappear as tau accumulates. The present study was directed at evaluating the effects of colchicine on tau and MAP2, to determine if changes in their levels or distribution might be similar to those which precede the formation of neurofibrillary tangles in Alzheimer's disease. Six hours following intrahippocampal colchicine injection (3.5 micrograms injected into two rostro-caudal locations) tau-1 immunostaining was enhanced in CA1 s. radiatum and decreased in the outer molecular layer of the dentate gyrus. In addition, a shift in the relative abundance of tau isoforms was observed in Western blots. Both the immunocytochemical and immunoblot results are consistent with a dephosphorylation of tau. Loss of MAP2 was evident 3 days postinjection which coincided with a loss of Cresyl violet staining in granule cell, CA3, subicular and entorhinal neurons. Accumulation of tau or MAP2 in neuronal perikarya was not observed at any postinjection time points. Thus, intrahippocampal colchicine administration does not model the shift in tau localization, excessive tau phosphorylation, or other cytoskeletal alterations that are suggested to precede or accompany the formation of neurofibrillary pathology in Alzheimer's disease.

Animals↗
PubMed1992

A serine-->proline change in the Alzheimer's disease-associated epitope Tau 2 results in altered secondary structure, but phosphorylation overcomes the conformational gap.

Monoclonal antibody Tau 2 was raised against bovine tau protein, was reported to recognize a conformational epitope, and stained tau was found in neurofibrillary tangles of Alzheimer's disease, but not normal human tau. We synthesized tetradeka peptides corresponding to the original bovine sequence, its serine-->proline substituted analog, the genuine human sequence of this region, and the bovine epitope phosphorylated on the crucial serine. The secondary structure of the peptides was determined by circular dichroism. It was found that only the original bovine epitope showed a tendency to form the beta-pleated sheets characteristic of the neurofibrillary tangles. The spectra of the human peptide, its analog, and the phosphorylated bovine sequence were very similar, featuring a weak, helical beta-turn character. Eventual phosphorylation of epitopes of this otherwise heavily phosphorylated protein may overcome inter-species conformational gaps.

Amino Acid Sequence↗
PubMed1998

Etiology and pathogenesis of Alzheimer's disease.

The diagnosis, genetics, risk factors, neuropathology, and pathogenesis of Alzheimer's disease (AD) are discussed. AD is a degenerative brain disorder and is the leading cause of dementia. Clinical manifestations of AD are primarily the progressive loss of memory and language. Other signs and symptoms of the disease include psychiatric and behavioral disturbances and impairments in the performance of activities of daily living (ADL). To diagnose AD, other causes of dementia-- some of which may be reversible--must be ruled out by laboratory testing and neuroimaging. The pathogenic process that causes AD has not been fully delineated; however, it clearly leads to neuropathology characterized by neuritic plaques, neurofibrillary tangles, and loss of cholinergic neurons in the nucleus basalis of Meynert. Genetic factors, including mutations in the amyloid precursor protein and the two presenilin genes, appear important in the development of early-onset familial AD, whereas the apolipoprotein E genotype influences the timing of disease onset after age 65. Genetic factors may promote or accelerate deposition of beta-amyloid protein to form plaques, as well as abnormal phosphorylation of tau protein to form neurofibrillary tangles. Several biochemical factors, such as inflammation, oxidative stress, and hormonal deficiency (estrogen), and other unmodifiable risk factors, notably aging, also play a role in the pathogenic process. The loss of neurons and synaptic connections is selective and causes deficiencies in cholinergic and other neurotransmitter systems, leading to cognitive dysfunction, psychiatric and behavioral disturbances, and eventual loss of ability to perform ADL. The etiology and pathogenesis of AD are highly complex; more effective therapeutic approaches than those currently available will be needed to address these underlying factors more specifically.

Alzheimer Disease↗
PubMed1993

Alzheimer's disease families with amyloid precursor protein mutations.

Early onset Familial Alzheimer's Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C-terminus of the beta-amyloid domain, APP 717 val-ile, APP 717 val-phe, and APP 717 val-gly, which are associated with autopsy-proven Alzheimer's disease (AD). APP 670/671 lies at the N terminus of the beta-amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val-ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive beta-amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val-gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of beta-amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.

Alzheimer Disease↗
PubMed1982

Alzheimer's disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities.

We have examined the choline acetyltransferase [CAT] activity in autopsy samples of frontal and temporal lobe cortex from 47 patients (31 with Alzheimer's disease, 4 with dementia due to cerebrovascular disease and 12 undemented controls) and compared it with the severity of dementia during life and with the numbers of argyrophilic plaques and neurofibrillary tangles in the corresponding areas of cortex in the contralateral cerebral hemisphere. CAT activity was significantly reduced, most severely in the temporal lobe, in patients with Alzheimer's disease but not in patients with a cerebrovascular cause for their dementia, and CAT activity showed no significant reduction with age in the undemented control patients. In the patients with Alzheimer's disease the reduction in CAT activity was significantly correlated with the severity of dementia and with the numbers of neurofibrillary tangles, but not argyrophilic plaques, present in the corresponding contralateral cortex.

Aged↗
PubMed1990

Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles.

The microtubule array in neuronal cells undergoes extensive growth, dynamics and rearrangements during neurite outgrowth. While little is known about how these changes are regulated, microtubule-associated proteins (MAPs) including tau protein are likely to perform an important role. Tau is one of the MAPs in mammalian brain. When isolated it is usually a mixture of several isoforms containing between 341 and 441 residues that arise from alternative splicing. Tau can be phosphorylated by several protein kinases. Phosphorylation at certain sites results in major structural and functional changes, as seen by changes in electrophoretic mobility, interaction with microtubules, molecular length and elasticity. Here we show that the sites of phosphorylation by four kinases (PKA, PKC, CK and CaMK) all lie in the C-terminal microtubule-binding half of tau, but only the phosphorylation by CaM kinase shows the pronounced shift in electrophoretic mobility characteristic for tau from Alzheimer neurofibrillary tangles. By using a combination of limited proteolysis, protein sequencing and protein engineering we show that a single phosphorylation site is responsible for this shift, located at Ser 405 in the C-terminal tail of the protein outside the region of internal repeats. Phosphorylation at this site not only reduces the electrophoretic mobility of tau, it also makes the protein long and stiff, as shown earlier. The site is likely to be phosphorylated in tau from Alzheimer neurofibrillary tangles.

Alzheimer Disease↗
PubMed1990

[Neuropathologic study of 50 cases of senile dementia].

Fifty brains from patients prospectively studied in a geriatric hospital (Charles Richet Study) were examined pathologically. The patients were senile (mean age: 85) and demented and had been clinically diagnosed as senile dementia of Alzheimer type (SDAT), vascular or multi-infarct dementia (VD), mixed dementia (MD). The whole brain was studied after formalin fixation and coronal sections. The senile changes were quantified in 6 neocortical areas, hippocampus and amygdala and subcortical structures after staining by thioflavine--S and Bodian's method. The other vascular and degenerative lesions were semiquantitatively studied. Three groups of patients were identified after microscopic examination: 1. SDAT (n = 27), 2. VD (n = 6), 3. MD (n = 15), 2 patients had no significant pathological correlate for dementia. Comparison of thioflavine S and Bodian's method in 30 cases showed the former to be more sensitive for the identification of senile plaques. In SDAT, 13/27 brains lacked neurofibrillary tangles in the neocortex. Amyloid angiopathy was observed in 78% of the brains but lacked in 5/6 cases affected by pure VD. Significant lesions of the substantia nigra were observed in 13 cases with typical features of Parkinson's disease in 2 cases. The locus coeruleus was affected mainly in SDAT cases (20/27) and in some cases of VD or MD (6/21). The raphe nuclei showed neuronal loss in 18% of the cases, mostly SDAT. In this series of cases, neocortical neurofibrillary tangles could be lacking in SDAT. Amyloid angiopathy was almost always present in SDAT and MD. Subcortical structures involved in cholinergic, noradrenergic and serotoninergic innervation of the cortex were more severely impaired in SDAT and MD than in VD. Mixed dementia was frequent in these very old demented patients. Clinical and pathological criteria are needed to identify this group of patients.

Aged↗
PubMed1984

Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia.

The present paper examines the relationship between choline acetyltransferase (ChAT) activity and gamma aminobutyric acid (GABA) concentrations with neuronal counts, senile plaque counts and estimates of neurofibrillary tangles in a series of 25 cases of senile dementia of Alzheimer type (SDAT) with appropriate controls. ChAT activity was significantly positively correlated with neuronal counts in the frontal and temporal region for the whole group but not in the demented or control subgroups. Significant negative correlations were also found between plaque counts and ChAT activity in all areas studied in the total group of subjects and in most of the SDAT groups. Significant negative correlations between ChAT activity and estimates of neurofibrillary change occurred in the frontal area and midtemporal gyrus in the SDAT cases. All the above correlations were seen most prominently in the youngest dementia patients (less than 79 years of age) who exhibited the most severe neuropathological and neurochemical deficits. The neurochemical distinction between the young and elderly age group of SDAT cases was well illustrated by the paradoxical trends of significantly increased GABA and ChAT levels with increasing age. The few significant correlations observed between GABA and cell counts were positive and occurred in the temporal lobe in the younger age group. Plaque counts and neurofibrillary tangle estimates showed little correlation with GABA concentrations.

Alzheimer Disease↗
PubMed1992

Alzheimer disease brain extract stimulates branching of laminin-mediated neuronal processes.

Patients with Alzheimer disease (AD) suffer mental deterioration associated with neurofibrillary tangle and senile plaque formation in the brain. Here we have determined the effects of brain extracts from normal and from AD patients on neuronal process formation by a pheochromocytoma (PC-12) and a neuroblastoma x glioma hybrid cell line (NG108-15). PC12 cells show a dose-related stimulation of branching of neuronal processes by AD brain extracts with cells cultured on a laminin substrate. The neurotrophic effects of extracts of AD brains may be related to the abnormal sprouting and neurofibrillary tangle formation observed in the brain in this disorder.

Adrenal Gland Neoplasms↗
PubMed1986

Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments.

A rabbit antiserum was raised against paired helical filaments (PHF). This antiserum stains specifically neurofibrillary tangles (NFT) at the light-microscopic level and PHF at the electron-microscopic level in sections of Alzheimer neocortex and hippocampus. We studied the nature of the antigens recognized by this antiserum by immunocytochemistry, immunoblots and immunoadsorption. These approaches showed that the anti-PHF specifically labels a set of low molecular weight 65-50 kDa microtubule-associated proteins, named Tau proteins, which are promoting factors of microtubule assembly. Furthermore, antisera against Tau proteins stained NFT. It is concluded that neurofibrillary tangles are very likely composed of aggregated Tau proteins. This process might be due to an abnormal Tau protein synthesis or to an unknown lesion of certain pyramidal neurons leading to an aggregation of Tau proteins.

Adult↗
PubMedDate not supplied

[Treatment of Alzheimer's disease].

OBJECTIVE: To review the experience of the last twenty years in the treatment of Alzheimer s disease (AD). METHODS: Literature review. RESULTS: The neuropathological bases of AD are centered on two important pathophysiological mechanisms: 1) Structural damage (e.g., senile plaques, neurofibrillary tangles, neuronal loss, inflammatory processes), and 2) Loss of cholinergic neurons (and acetylcholine depletion) in the nucleus basalis of Meynert, which sends cholinergic projections to all areas of the neocortex, especially the temporal lobes and frontal and parietal association areas. The indemnity of this system is essential for normal cognitive functioning. At this moment, the only long term treatment available for AD are acetylcholinesterase inhibitors (CEIs) (e.g., tacrine, donepezil, rivastigmine, galanthamine). There are being investigated several treatments that may alter the development of neurofibrillary tangles and neuritic plaques (e.g., peripherally administered antibodies against beta amyloid proteins). Nerve growth factors may have the capability of improving neuronal survival, although their form of administration remains a problem. Amelioration of oxidative stress and CNS inflammatory processes may slow dawn the rate of neurodegeneration. CONCLUSION: All suspected mechanisms of the metabolic cascade of AD have been explored with specific and non specific treatments. Current treatments (e.g., CEIs) still have to prove that their effects can last for long periods of time. With the advent of further understanding of the neurodegenerative processes that cause AD, new treatments that may slow down the progression of the disease will be available.

Acetylcholine↗
PubMed1987

A hypothesis concerning the role of endogenous colchicine-like factors in the etiology of Alzheimer's disease.

A hypothesis concerning the etiology of Alzheimer's disease is presented. It is argued that the formation of neurofibrillary tangles, paired helical filaments and senile plaques result from an increase in the activity of endogenous colchicine-like factors. The consequences of such an increase are 1) a blockade of axonal transport, 2) an accumulation of neurofilaments in the cytoplasm of neurons and 3) a redistribution of lysosomes from the cell bodies of neurons to the dendrites. In the absence of cytoplasmic lysosomal enzymes, the accumulated neurofilaments are cross-linked and metabolically stabilized by enzymes in the cell body. Neurons laden with neurofibrillary tangles and dendritic lysosomes would be prone to lysis and could participate in the formation of senile plaques.

Alzheimer Disease↗
PubMedDate not supplied

The progression of the pathological changes of Alzheimer's disease in frontal and temporal neocortex examined both at biopsy and at autopsy.

Brains were obtained at autopsy from five patients with Alzheimer's disease, each of whom had undergone diagnostic craniotomy 3-7 years previously. It was possible, therefore, to examine the number (density) and nucleolar volume of pyramidal nerve cells, and the density of senile plaques and neurofibrillary tangles within the cerebral cortex on two occasions during the progression of their illness, and to assess how these measures might have changed during the period between biopsy and death. In all five patients, at biopsy, the density and the nucleolar volume of pyramidal nerve cells was significantly less than controls and, in general, values for both these measures fell significantly further from biopsy to death. By contrast, in none of the five patients did senile plaque density consistently change from biopsy to death; neurofibrillary tangle density either did not change, or indeed sometimes decreased from biopsy to death. These data show that both the clinical and the pathological progression of Alzheimer's disease is marked by a continuing loss of pyramidal cells from frontal and temporal cortex, although the densities of plaques and tangles within the cortex do not, per se, correlate with the stage of the illness. The usefulness of measurement of plaque and tangle densities as pathological criteria by which the clinical and neurochemical deficits of Alzheimer's disease can be compared in different patients is clearly questionable.

Alzheimer Disease↗
PubMed1988

Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease.

We compared neuropsychological findings in 28 longitudinally evaluated elderly subjects with their postmortem neuropathology, including senile plaque and neurofibrillary tangle counts from standardized sections. Nine of the subjects were not demented when evaluated just prior to their death. Numerous cortical senile plaques and other changes of Alzheimer's disease (AD) occurred in six of nine nondemented old-old subjects. Five of these six subjects had shown decline on yearly neuropsychological tests but their cognitive impairment was too mild to meet clinical criteria for dementia. Whereas cortical senile plaque count did not distinguish well between demented and nondemented subjects, every subject with numerous cortical neurofibrillary tangles was demented. The nondemented subjects with Alzheimer pathology may have had "preclinical" AD, or numerous cortical plaques may occur in some elderly subjects who would never develop clinical dementia.

Aged↗
PubMed2006

Sex hormones and neuropathology in elderly men: the HAAS.

Experimental studies suggest 17-beta estradiol (E2) and testosterone (T) may have neuroprotective properties that are associated with Alzheimer's and vascular pathology. However, there are limited studies correlating steroid hormones with autopsy findings in humans. In this community-based autopsy study of elderly men (n=232) participating in the Honolulu Asia Aging Study, we found a significant decrease of neurofibrillary tangles in the highest tertile of free serum estradiol [IRR=0.43 (0.3-0.7)] after controlling for age at blood draw, interval from blood draw until death, ApoE allele, and socio-demographic health factors. Higher Free-T levels were associated with a two-fold increased risk for micro infarcts [IRR=2.2; 95% CI (1.2-4.1)]. There was no association between sex hormones and amyloid plaques or cerebral amyloid angiopathy. This community-based autopsy study suggests that peripheral levels of sex hormones are associated with neurofibrillary tangles and micro-infarcts, but not with other neuropathologic markers of brain disease in elderly men.

Aged, 80 and over↗
PubMed1991

Cerebrospinal fluid markers of Alzheimer's disease.

OBJECTIVE: To review studies on cerebrospinal fluid (CSF) in patients with Alzheimer's disease (AD) in order to answer the question whether CSF contains a specific marker which can be used to support a clinical diagnosis of AD. DATA SOURCES: Studies identified through an English-language literature search using MEDLINE (1966 to 1990) and a review of bibliographies of relevant articles. STUDY SELECTION: All studies on CSF in AD patients were selected. Double publications on the same original data were not included. Otherwise, no particular selection was made. DATA EXTRACTION: The diagnostic utility of more than 60 substances, including CSF measures related to classical neurotransmitters, (neuro)peptides, proteins, amino acids, purines, trace elements, and constituents of senile plaques and neurofibrillary tangles, is evaluated. Clinical epidemiological criteria for deciding on the usefulness of new diagnostic methods are emphasized in this analysis. DATA SYNTHESIS: Concentrations of some CSF constituents are consistently found to be significantly changed in AD. However, overlap with data of control populations and methodological shortcomings in study design, limit the diagnostic value of all CSF measurements reviewed. CONCLUSIONS: None of the CSF constituents studied so far can be used in support of the diagnosis of AD. However, increased knowledge concerning macromolecular abnormalities in amyloid containing plaques and neurofibrillary tangles makes the outlook for a diagnostic test for AD on CSF promising.

Alzheimer Disease↗