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PubMed1997

Lack of association of a polymorphism in the low-density lipoprotein receptor-related protein gene with Alzheimer disease.

BACKGROUND: The apolipoprotein E epsilon 4 (ApoE epsilon 4) allele is associated with an increased risk for development of Alzheimer disease (AD). We hypothesized that polymorphisms in proteins that interact with ApoE also might have an impact on the likelihood of AD developing. We examined a polymorphism in the gene for the low-density lipoprotein receptor-related protein (LRP), because LRP is a major ApoE receptor in the brain that also mediates binding and degradation of secreted Kunitz protease inhibitor forms of amyloid precursor protein. SUBJECTS AND DESIGN: The LRP genotypes in 2 groups were studied. The first group consisted of 130 patients with probable or definite AD (mean +/- SD age, 78.2 +/- 8.9 years) and 64 nondemented, control subjects (mean +/- SD age, 81.7 +/- 12.3 years) who were primarily the spouses of the patients. The second group consisted of individuals from a population-based, epidemiologic study, including 38 cognitively impaired individuals (mean +/- SD age, 79.9 +/- 4.1 years) and 93 nondemented controls (mean +/- SD age, 78.7 +/- 4.4 years). Finally, 22 brains with a neuropathological diagnosis of AD were evaluated for neuronal loss, beta-amyloid deposition, and neurofibrillary tangle number and compared with the LRP genotype. RESULTS: No genetic disequilibrium in LRP allele frequencies between controls and patients with AD or cognitive impairment was observed. No interaction between the ApoE epsilon 4 and LRP genotypes was observed in patients with AD. Moreover, the LRP genotype did not correlate with degree of neuronal loss, beta-amyloid deposition, or neurofibrillary tangle number in individuals examined using quantitative neuropathological techniques. CONCLUSION: This LRP gene polymorphism is not linked with the pathophysiological changes of AD.

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PubMed1996

Immunolocalization and redistribution of the FAC1 protein in Alzheimer's disease.

The presence of senile plaques and neurofibrillary tangles are hallmark neuropathologic features of Alzheimer's disease (AD). Many proteins have previously been immunolocalized to amyloid-containing plaques in AD brain. Using a monoclonal antibody to a recently described developmentally regulated gene product, we demonstrate the presence of FAC1 protein in a subset of diffuse and neuritic plaques in AD brain. FAC1 is not observed in neurofibrillary tangles common in the hippocampus or entorhinal cortex, nor is it localized in diffuse plaques of nondemented elderly control subjects. FAC1 protein is also immunolocalized in swollen dendrites of hippocampal pyramidal cells observed in some cases of early stage AD. Therefore, FAC1 is a novel protein localized in early pathologic features of AD and in a subset of plaques.

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PubMed1994

Anomalous binding of radiolabeled oligonucleotide probes to plaques and tangles in Alzheimer disease hippocampus.

Several reports indicate that Alzheimer disease (AD) brain contains elevated levels of heat shock 70 proteins. To determine the cellular localization of the heat shock 70 mRNAs, specific oligonucleotide probes were in situ hybridized to AD and control brains. When oligonucleotides were in situ hybridized to brain sections with no AD neuropathology, hybridization was cell-specific and prior ribonuclease (RNase) treatment of adjacent sections resulted in no hybridization signal. However, in situ hybridization to AD hippocampus resulted in heavy grain deposition over senile plaques and neurofibrillary tangles. Despite altering a number of experimental variables, we observed a similar pattern of grain deposition with most of the oligonucleotides tested, including one oligonucleotide specific for glutamic acid decarboxylase mRNA. In situ hybridization with either an RNA probe for glutamic acid decarboxylase or an oligonucleotide probe specific for 18S rRNA did not show this pattern of grain deposition. In control studies a sense hsc70 oligonucleotide showed no grain deposition in either cerebellum or hippocampus. Sections from AD hippocampus pretreated with RNase prior to in situ hybridization demonstrated enhanced grain deposition with the majority of probes tested. Anomalous in situ hybridization to AD hippocampus was usually eliminated by removing formamide from the posthybridization washes, although post-RNase sticking often remained intense. These findings indicate that artifactual probe binding to senile plaques and neurofibrillary tangles may complicate the analysis of in situ hybridization studies using oligonucleotide probes to determine mRNA distribution in AD brain.

Adult↗
PubMed2001

Modulation of beta-amyloid production and fibrillization.

Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as beta-amyloid or A beta. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of A beta in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of A beta production and fibrillization.

Alzheimer Disease↗
PubMed1999

Interaction of aluminum with PHFtau in Alzheimer's disease neurofibrillary degeneration evidenced by desferrioxamine-assisted chelating autoclave method.

To demonstrate that aluminum III (Al) interacts with PHFtau in neurofibrillary degeneration (NFD) of Alzheimer's disease (AD) brain, we developed a "chelating autoclave method" that allows Al chelation by using trivalent-cationic chelator desferrioxamine. Its application to AD brain sections before Morin histochemistry for Al attenuated the positive fluorescence of neurofibrillary tangles, indicating Al removal from them. This method, applied for immunostaining with phosphorylation-dependent anti-tau antibodies, significantly enhanced the PHFtau immunoreactivity of the NFD. These results suggest that each of the phosphorylated epitopes in PHFtau are partially masked by Al binding. Incubation of AD sections with AlCl(3) before Morin staining revealed Al accumulation with association to neurofibrillary tangles. Such incubation before immunostaining with the phosphorylation-dependent anti-tau antibodies abolished the immunolabeling of the NFD and this abolition was reversed by the Al chelation. These findings indicate cumulative Al binding to and thereby antigenic masking of the phosphorylated epitopes of PHFtau. Al binding was further documented for electrophoretically-resolved PHFtau on immunoblots, indicating direct Al binding to PHFtau. In vitro aggregation by AlCl(3) was observed for PHFtau but was lost on dephosphorylation of PHFtau. Taken together, phosphorylation-dependent and direct PHFtau-Al interaction occurs in the NFD of the AD brain.

Aluminum↗
PubMedDate not supplied

Archival, formalin-fixed tissue: its use in the study of Alzheimer's type changes.

Preparing for a retrospective study of senile degeneration in schizophrenia, we had occasion to explore the suitability of an old collection formalin-fixed brains and paraffin blocks for study by modern staining methods. Tissue that had been in formalin for 50 years was embedded in paraffin. Sections were then stained with thioflavine S and with immunoperoxidase stains using Alz 50 and antibodies to paired helical filaments, ubiquitin, and beta-amyloid. In all 4 cases that had originally (50 years earlier) received neuropathologic diagnoses of Alzheimer's disease, large numbers of neocortical senile plaques and neurofibrillary tangles were clearly demonstrated by thioflavine S stain and by immunohistochemistry for paired helical filaments, ubiquitin, and beta-amyloid. In each of 4 other cases, in which the original neuropathologic examination had not revealed Alzheimer's disease, no plaques or tangles were observed. Immunoreactivity with Alz 50 was completely absent after 50 years in formalin. Examination of additional cases of Alzheimer's disease revealed that Alz 50 immunoreactivity was well preserved after 10 years in formalin and completely absent after 30 years in formalin. Alzheimer's disease tissue stored in paraffin for 30 years was clearly stained by all modalities. We conclude that immunohistochemical identification of senile plaques and neurofibrillary tangles is practical even after decades of storage in formalin or paraffin. The applicability of techniques that did not exist when these specimens were collected indicates that the systematic, permanent retention of formalin-fixed material may yield unanticipated future benefits.

Adult↗
PubMed1992

Down syndrome and Alzheimer disease.

The brains of individuals with Down's syndrome in their 40's and 50's begin to develop changes that are otherwise seen only in patients with Alzheimer disease. Neurons develop neurofibrillary tangles, flame-shaped alterations composed mainly of condensed cytoskeletal proteins. Another protein, beta/A4 amyloid, is deposited in large amounts in the form of senile plaques and, around blood vessels, amyloid angiopathy. With increasing age, Down syndrome individuals accumulate more and more of these changes. Different parts of the brain are affected to varying degrees by these two alterations. Surprisingly, the pattern of accumulation of neurofibrillary tangles and senile plaques is characteristic, and follows a predictable pattern. We have characterized this pattern in the hippocampal formation in a group of Down individuals, ages 13-71. Certain specific neurons such as those in layer II of entorhinal cortex and the CA1/subiculum field of the hippocampus are exquisitely vulnerable to tangle formation, and are the first neurons to be affected. Perhaps 20-30 years pass as the disease process evolves from mild to severe pathological changes. One hypothesis for why Down individuals would be predisposed to developing Alzheimer pathology is the observation that the gene that encodes the precursor of the amyloid protein is located on chromosome 21. An extra copy of this gene, such as occurs in Down syndrome, may lead to "overproduction" of amyloid, and ultimately to its accumulation as senile plaques. Experiments to test this hypothesis are now underway.

Alzheimer Disease↗
PubMed2006

A polymorphism in lipoprotein lipase affects the severity of Alzheimer's disease pathophysiology.

Emerging evidences indicate a role for lipoprotein lipase (LPL) in degenerative states. Genetic variations in the LPL gene were previously associated to lipid imbalance and coronary artery disease (CAD) risk and severity, a condition that shares pathological features with common Alzheimer's disease (AD). To evaluate whether these genetic variations associate with the risk and pathophysiology of common AD, autopsy-confirmed patients (242 controls, 153 AD) were genotyped for a PvuII single nucleotide polymorphism (SNP; rs285; referred to as the P+ allele) of LPL. Brain LPL mRNA levels, cholesterol levels, amyloid concentration, senile plaques and neurofibrillary tangles density counts were measured and contrasted with specific LPL genotypes. When adjusted for age and sex, homozygosity for the P+ allele resulted in an odds ratio of 2.3 for the risk of developing AD. More importantly, we report that the presence of the P+ allele of LPL significantly affects its mRNA expression level (n = 51; P = 0.026), brain tissue cholesterol levels (n = 55; P = 0.0013), neurofibrillary tangles (n = 52; P = 0.025) and senile plaque (n = 52; P = 0.022) densities. These results indicate that a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases.

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PubMed2004

N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease.

Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.

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PubMed1996

The nucleus raphe interpositus in the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy).

As the integrity of the omnipause neurons located in the nucleus raphe interpositus is a prerequisite of normal ocular motility, cell and neurofibrillary tangle densities were determined in 13 Steele-Richardson-Olszewski syndrome (SROS) cases [eight with supranuclear gaze palsy (SGP) and five without] and six controls. Compared with normal controls, cases with SGP were associated with approximately 50% nerve cell loss (P < 0.001), whereas data from cases without SGP were not significantly different (P = 0.18). Furthermore, cases with SGP had lower neuronal cell (P = 0.016) and higher neurofibrillary tangle densities than those without (P = 0.011). These results indicate that the involvement of the omnipause neurons, which are glycinergic, contributes to abnormal eye motility in SROS. Involvement of these glycinergic nerve cells suggests that the degeneration of brainstem structures in SROS affects neurochemically diverse systems; so far other brainstem nuclei concerned with eye motility; and known to be affected in SROS, are cholinergic. The results of this study provide evidence that clinically distinct subgroups of SROS may be differentiated histologically when adequate morphometric techniques are applied.

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PubMedDate not supplied

Staging of Alzheimer's disease-related neurofibrillary changes.

Specific immunocytochemical methods (AT8) permit evaluation of neuronal changes well before the actual formation of neurofibrillary tangles and neuropil threads. Initial changes are found in the transentorhinal region (temporal lobe). From here the destructive process encroaches upon the entorhinal region, Ammon's horn, and neocortex. Initial changes occur in comparatively young individuals and can also be observed at the same predilection sites in a few species of old aged domestic animals. In a later state of destruction, AT8 immunoreactive neurons develop typical argyrophilic neurofibrillary tangles and neuropil threads. Six stages of disease propagation can be distinguished with respect to the location of the tangle-bearing neurons and the severity of changes (transentorhinal stages I-II: clinically silent cases; limbic stages III-IV: incipient Alzheimer's disease; neocortical stages V-VI: fully developed Alzheimer's disease). Whole mount techniques reveal the lesional pattern of the particularly severely involved superficial entorhinal layer as seen from the free surface of the parahippocampal gyrus. This approach facilitates recognition of even subtle pathologic changes throughout the entire extent of cortical territories such as the transentorhinal and entorhinal regions.

Alzheimer Disease↗
PubMed1994

Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.

The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGE-recombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.

Alzheimer Disease↗
PubMed1999

Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia.

The present study correlates the severity of dementia in Alzheimer's disease with the degree of neuropathology present in the nucleus basalis of Meynert. We assessed neurofibrillary tangles, neuronal loss and morphometric changes in 21 patients with Alzheimer's disease who underwent extensive neuropsychological testing before death. We report a highly significant correlation between scores in the psychological tests and all of the neuropathological markers examined within the nucleus basalis of Meynert. The test that correlated most closely with these morphological measures was Folstein's Mini Mental State. Among the different neuropathological changes, the number of neurofibrillary tangles was strongly correlated with the degree of dementia. We also provide evidence for a differential involvement of the three subdivisions of the nucleus basalis in Alzheimer's disease neuropathology. The posterior subdivision, which provides a substantial cholinergic input to the parahippocampal gyrus, was the more profoundly affected. Taken together, these results point to an important participation of the nucleus basalis in dementia of the Alzheimer type. In addition, the strong correlation between neuropathological changes and neuropsychological scores indicates the reliability of these tests in assessing the progression of the disease.

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PubMed2003

Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation.

Tau phosphorylation has been examined by immunohistochemistry in the brain of a patient affected with familial tauopathy with progressive supranuclear palsy-like phenotype linked to the delN296 mutation in the tau gene. Phospho-specific tau antibodies Thr181, Ser202, Ser214, Ser396 and Ser422, and antibodies to glycogen synthase kinase-3alpha/beta (GSK-3alpha/beta) and to phosphorylated (P) mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), p38 kinase (p38) and GSK-3betaSer9 have been used to gain understanding of the identification of phosphorylation sites, as well as of the specific kinases that regulate tau phosphorylation at those specific sites, in a familial tauopathy. The neuropathological examination disclosed atrophy of the right precentral gyrus and the brainstem. Neurone loss and gliosis were observed in the substantia nigra, several nuclei of the brainstem and diencephalon. Hyper-phosphorylated tau accumulated in neurones with neurofibrillary tangles and in neurones with pretangles in the substantia nigra, locus ceruleus, peri-aqueductal grey matter, reticular formation, motor nuclei of the brainstem, and thalamus, amygdala and hippocampus. tau-immunoreactive astrocytes and, particularly, oligodendrocytes with coiled bodies were widespread in the brainstem, diencephalons, cerebral white matter and cerebral cortex. Increased expression of MAPK/ERK-P, SAPK/JNK-P, p-38-P and GSK-3beta-P was observed in select subpopulations of neurones with neurofibrillary tangles and in neurones with pretangles. MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3beta-P were also expressed in tau-containing astrocytes and in oligodendrocytes with coiled bodies. These findings show, for the first time, activation of precise kinases that regulate tau phosphorylation at specific sites in familial tauopathy.

Adult↗
PubMed1998

Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D.

Alois Alzheimer published two papers on the disease which was named after him by Emil Kraepelin in 1910. Each of these papers contains clinical and pathological data on a patient Alzheimer had seen at the hospital. We have previously reported on the rediscovery of tissue sections from Alzheimer's second published case of Alzheimer disease, Johann F., which probably gave the disease its name (Neurogenetics 1997; 1:73-80). Here, we describe the histopathology and APOE genotype of Alois Alzheimer's first patient, Auguste D. As in the case of Johann F., a large number of tissue sections belonging to Alzheimer's laboratory, which was later headed by Spielmeyer, were found among material kept at the Institute of Neuropathology of the University of Munich. As described by Alzheimer in his original report (Allg Zeitschr Psychiatr 1907; 64:146-148), there were numerous neurofibrillary tangles and many amyloid plaques, especially in the upper cortical layers of this patient. Yet, there was no microscopic evidence for vascular, i.e., arteriosclerotic, lesions. Interestingly, Alzheimer's histological preparations did not include the hippocampus or entorhinal region. The APOE genotype of this patient was shown to be epsilon3/epsilon3 by PCR-based restriction enzyme analysis, indicating that mutational screening of the tissue is feasible. The historical importance of the case of Auguste D. lies in the fact that it marks the beginning of research into Alzheimer disease. In addition, neurofibrillary tangles were first described in this brain.

Alzheimer Disease↗
PubMed1994

Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation.

The hypothesis that dopaminergic denervation is a factor in the development of hippocampal neurofibrillary tangles was tested in the rat with bilateral stereotaxic 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental area (VTA). This led to the postsynaptic appearance of cytoplasmic immunoreactivity to ubiquitin in neurons of the dentate gyrus. An additional postsynaptic morphologic abnormality was seen when the animals were pretreated with the D1 dopaminergic antagonist SCH 23390 and the VTA lesions were combined with septal lesions affecting cholinergic and GABAergic neurons projecting to the dentate gyrus. These changes consisted of a loss of dendritic microtubule associated protein (MAP-2) and tau immunoreactivity and a prominence of remaining dendrites in the molecular layer of the dentate gyrus. Additional investigation will be needed to determine if these transynaptic changes in dentate neurons, resulting from denervation, represent a precursor stage to neurofibrillary tangle development.

Animals↗
PubMed2003

Transglutaminase activity, protein, and mRNA expression are increased in progressive supranuclear palsy.

Transglutaminases catalyze the covalent cross-linking of substrate proteins to form insoluble protein complexes that are resistant to degradation. Our previous studies demonstrated that transglutaminase-induced cross-linking of tau proteins occurs in Alzheimer disease and progressive supranuclear palsy (PSP). The current study was designed to measure transglutaminase enzyme activity and the mRNA and protein levels of 3 transglutaminase isoforms that are expressed in human brain. Overall, transglutaminase activity was significantly increased in the globus pallidus (182% of control) and pons in PSP (171% of control) but not the occipital cortex (a region spared from pathology). Using a Spearman rank correlation test, we found that tissues with more transglutaminase-activity had more neurofibrillary tangles. Protein and mRNA levels of transglutaminase 1 were increased in globus pallidus of PSP as compared to controls. There were also significantly higher mRNA levels of the short form of transglutaminase 2 in globus pallidus of PSP (974% of control). Transglutaminase 1 mRNA and the long isoform of transglutaminase 2 mRNA (2212% of control) were significantly higher in PSP in the dentate of cerebellum. Together, these findings suggest that transglutaminase 1 and 2 enzymes may be involved in the formation and/or stabilization of neurofibrillary tangles in selectively vulnerable brain regions in PSP. These transglutaminases may be potential targets for therapeutic intervention.

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PubMed2005

Sex differences in the clinical manifestations of Alzheimer disease pathology.

CONTEXT: Sex differences in risk of clinically diagnosed Alzheimer disease (AD) have been studied extensively, but little is known about the relation of the pathologic indices of AD to the clinical manifestations of the disease in men compared with women. OBJECTIVE: To test whether the relation of AD pathology to the clinical manifestations of the disease differs in men and women. DESIGN: Longitudinal, clinicopathologic cohort study. PARTICIPANTS AND SETTING: Analyses were conducted on 141 older Catholic clergy members who underwent detailed annual clinical evaluations and brain autopsy at death. The number of neuritic plaques, diffuse plaques, and neurofibrillary tangles in a 1-mm2 area sampled from 4 cortical regions was counted, and a global measure of AD pathology (range, 0-2.98 U) and specific measures of each pathology were derived. MAIN OUTCOME MEASURES: Clinical diagnosis of probable AD and level of global cognitive function at the last evaluation before death. RESULTS: Women had more global AD pathology than did men (P = .04), due primarily to more neurofibrillary tangles (P = .02). At the last evaluation before death, 57 persons met clinical criteria for probable AD (34 [60%] of them women). In logistic regression models, sex was not related to odds of clinical AD (odds ratio [OR], 1.35; 95% confidence interval [CI], 0.56-3.25), but the relation of global AD pathology to clinical diagnosis differed for men and women. Each additional unit of AD pathology was associated with a nearly 3-fold increase in the odds of clinical AD in men (OR, 2.82; 95% CI, 1.03-7.65) compared with a more than 20-fold increase in the odds of clinical AD in women (OR, 22.67; 95% CI, 5.11-100.53). Results were unchanged after controlling for potential confounders or using level of cognition as the outcome. CONCLUSION: These data suggest that AD pathology is more likely to be clinically expressed as dementia in women than in men.

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