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PubMed1999

Lysosomal protease inhibitors induce meganeurites and tangle-like structures in entorhinohippocampal regions vulnerable to Alzheimer's disease.

Lysosomal protease inhibitors induce signs of human brain aging in rat hippocampal slices. The present studies tested if they (1) also cause neurofibrillary tangles and (2) reproduce regional patterns of pathology found in Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or generalized (chloroquine) inhibitors of lysosomal proteases generated meganeurites of the type found in aged human cortex. Surveys and quantitative analyses established that the meganeurites developed almost exclusively in AD vulnerable regions. Antibodies against the phosphorylated tau protein in neurofibrillary tangles labeled thick filaments running through neurons in the superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general appearance of the stained structures resembled that of early stage tangles. More mature tangle-like profiles were found at a number of sites after longer incubations; these were threefold more frequent in the superficial (AD vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots indicated that essentially all phosphorylated tau labeling in the slices involved approximately 29-kDa fragments of the native isoforms. These findings establish that lysosomal dysfunction triggers the parallel formation of meganeurites and tangles with the regional distribution of both effects reflecting that for AD vulnerability.

Aged↗
PubMedDate not supplied

The neuropathological diagnosis of Alzheimer's disease: clinical-pathological studies.

The neuropathological diagnosis of Alzheimer's disease currently relies on quantitative or semiquantitative criteria of senile or neuritic plaques that are adjusted for age and for the presence or absence of a clinical history of dementia. Based on clinical-pathological correlation studies, I will argue that neuropathological assessment should stand independently of clinical history and instead should describe brain lesions in the context of the topography and natural history of the disease. Only probabilistic estimates about the presence or absence of dementia can be made from a neuropathological examination, especially in the setting of Alzheimer disease lesions plus other pathological alterations such as Lewy bodies or infarcts. Moreover, I will argue that any neurofibrillary tangles or senile plaques are inherently pathological entities, even if clinically silent and so "incidental" neuropathological findings. Because the intensity and location of neurofibrillary tangles, rather than senile plaques, appears to correlate most closely with clinical symptoms, I suggest using a staging system that highlights this information rather than using absolute numerical cut-offs for diagnostic purposes.

Aged↗
PubMed2004

Mouse models of Alzheimer's disease: insight into treatment.

Mice overexpressing mutant Alzheimer's disease (AD)-related proteins exhibit many of the neuropathological and behavioral features of the human disease. Transgenic animals have been created that express mutations in the amyloid precursor protein (APP), presenilin (PS)1, and PS2, and also animals expressing more than one of these mutations. For example, in APP mouse models, there are age-related accumulations of amyloid-beta (Abeta)-containing neuritic plaques in the hippocampus and cerebral cortex, activation of astrocytes and microglial cells in regions containing plaques, and degeneration of cholinergic nerve terminals in brain regions that eventually become plaque containing. Missing in the APP and PS mouse models are neurofibrillary tangles and robust neuronal loss in cerebral cortical and subcortical regions such as the basal forebrain cholinergic and locus coeruleus noradrenergic nuclei. Neurofibrillary tangles can be produced in mice expressing mutant tau protein, and the tangle formation is further enhanced in animals that also express mutant APP. Studies in APP mouse models indicate that, like AD, there are abnormalities in adult hippocampal neurogenesis. The animal models of AD have been used to develop and test treatments that reduce brain levels of the Abeta42 protein, neuritic plaque load and glial activation, and some have been found to restore learning and memory function. If such treatments can be shown to stop the neurodegenerative process and restore hippocampal neurogenesis, damaged brain circuits may be replaceable in patients with AD.

Alzheimer Disease↗
PubMed1993

Microtubule-associated proteins tau and amyloid P component in Alzheimer's disease.

The localization of the intracerebral microtubule-associated proteins tau (MAP-tau) has been compared to that of amyloid P component (AP), an extracerebral protein, by single- and double-antigen immunohistochemistry in neurofibrillary tangles of Alzheimer's brains. The results show that, individually, MAP-tau and AP may be observed in all stages of neurofibrillary tangle (NFT) formation. However, NFT labeled by MAP-tau and those labeled by AP largely do not overlap in their distribution. Furthermore, within the few NFT double-labeled by MAP-tau and AP, there was an inverse relationship between the immunoreactivity to MAP-tau and to AP. It is suggested that MAP-tau and AP are incorporated at different times into NFT and that this difference in the timing of NFT expression of these 2 proteins may be useful in the study of progressive NFT formation.

Aged↗
PubMed1997

Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease.

Cortical atrophy and cell loss in the cholinergic nucleus basalis is a well-established characteristic of Alzheimer's disease; however, previous studies not have analysed cholinergic cell loss and cortical atrophy in concert. In autopsy brains from eight patients with Alzheimer's disease and 12 control subjects, the numbers of nucleus basalis neurons were determined from 50-microm serial Nissl-stained sections. Volumes of the cerebrum, cortical gray matter (total, lobar and subregional), white matter and deep gray structures were computed by point counting on black and white photographs of gapless 3-mm coronal slices of formalin-fixed brains. Cell loss in the nucleus basalis was found to range between 89% and 42% in Alzheimer's disease compared with controls. White matter volume was unchanged in absolute terms in Alzheimer's disease patients compared with controls, while cortical volume was significantly reduced. Gray matter atrophy was most prominent in temporal and frontal cortices. A highly significant linear relationship was found between cortical volume and nucleus basalis cell number in controls and Alzheimer's disease patients, with values for both groups on a single regression line. Whole brain and cerebral volumes were also highly correlated to nucleus basalis cell numbers in both groups. A quantitative analysis of plaque and tangle burden in cortical target areas of the nucleus basalis was performed. In contrast to the relationship with cortical volume, nucleus basalis cell number and neurofibrillary tangle number were not significantly correlated to the density of cortical histopathology. These results suggest that the volume of cortical gray matter is coupled to the number of nucleus basalis neurons. Compromised viability of nucleus basalis neurons may precede cortical volume loss as large numbers of neurofibrillary tangles, detected with nickel peroxidase staining, were found in this nucleus in all Alzheimer's disease cases, including those with minimal cell loss.

Adult↗
PubMed2006

[Neuropathologic investigation in autopsies with special emphasis on findings in Alzheimer's disease].

Out of an average total of 1400 autopsies per year, neuropathological examinations were performed in 477 cases between 1997 and 1999 to investigate the incidence of dementias. The majority of the studied subjects were over 50 years old. Bielschowsky's and/or Gallyas's silver methods and, in some cases, protein tau (MAP) immunocytochemistry and amyloid staining were performed beside routine examination. Pathological changes were found in 212 of the 364 cases studied by the above methods but histological changes associated with dementia were only detected in 167 cases. The various forms of Alzheimer's dementia were also classified by age. The "incipient" form of Alzheimer's disease was verified in 23 cases. Old infarcts of various extensions were found in 42 percent of Alzheimer's dementias. Very mild or age-related degenerative changes were observed in 82 cases among subjects over 50 years old. Of these, eight patients died in their 90s. In some cases (n = 38) the number of neuritic plaques dominated over the number of neurofibrillary tangles but a reverse finding also occurred (n = 13). Neuronal degeneration was variable and was not always proportional to the number of neurofibrillary tangles. "Simple type of senile atrophy" was defined by the presence of minor or age-related Alzheimer changes and was considered a separate entity. The "incipient" form of Alzheimer's dementia was diagnosed in relatively young individuals where mild Alzheimer changes were found at the neuropathological examination. "Preclinical" Alzheimer's dementia could only be suspected by clinical data and could very rarely be supported by the neuropathological finding of "incipient" form. The ratio of pure Alzheimer's to vascular dementias cases proved to be 54:41 in this study. The results suggest that dementias are considerably underdiagnosed both in the clinical and pathological practice and that the recently defined "preclinical" and "incipient" forms are very hard to recognize both clinically and pathologically. The neuropathological study of the degenerative, mainly Alzheimer's type, findings in the randomly selected autopsies revealed great variations which raises many questions concerning the normal and pathologic aging of the brain as well as the "incipient" and senile forms of Alzheimer's dementia.

Age Distribution↗
PubMed1991

Neuropathological stageing of Alzheimer-related changes.

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

Aged↗
PubMed1994

Accumulation of amyloid precursor protein in brain lesions of patients with Pick disease.

The expression of amyloid precursor protein (APP) was examined immunohistochemically in Pick disease brain using several antibodies to various segments of APP. Some neurons, including ballooned neurons, were intensely stained with antibodies to all but the N-terminal APP segment. However, Pick bodies were labeled with the antibody to that segment as well as the antibody to intermediate segment of APP. The pattern was similar to that previously observed for Alzheimer neurofibrillary tangles. These data provide additional evidence that Pick bodies and neurofibrillary tangles share some immunohistochemical characteristics.

Aged↗
PubMed2003

Hereditary prion protein amyloidoses.

Prion protein (PrP) amyloid accumulation is the pathologic hallmark of some inherited prion diseases such as Gerstmann-Sträussler-Scheinker disease (GSS) and PrP cerebral amyloid angiopathy (PrP-CAA). In GSS, parenchymal amyloidosis may coexist with spongiform degeneration or neurofibrillary tangles, whereas in PrP-CAA, vascular amyloid coexists with neurofibrillary tangles. In GSS, N-truncated and C-truncated proteinase K-resistant PrP isoforms are present in the brain.

Amyloid↗
PubMed2001

Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer's disease.

The Cdc2/cyclin B kinase is a critical regulator of mitosis that is normally absent from terminally differentiated neurons of adult brain. However, unscheduled expression and activation of Cdc2/cyclin B has been seen in neurons undergoing degeneration in Alzheimer's disease. The presence of this mitotic kinase correlates with accumulation of mitotic phosphoepitopes in protein components of the hallmark neurofibrillary tangles. Of importance to the pathogenic mechanism of Alzheimer's disease is the striking appearance of Cdc2/cyclin B and mitotic phosphoepitopes prior to neurofibrillary tangle formation, which has suggested that a misappropriate mitotic cascade initiates and mediates the neurodegenerative process. To explain the atypical activation of Cdc2/cyclin B in degenerating neurons we have investigated the enzyme responsible for Cdc2/cyclin B activation in mitotic cells, i.e. the Cdc25B tyrosine phosphatase, in Alzheimer's disease brain. Although the enzyme appeared abundant in affected neurons, it was also evident in unaffected neurons of Alzheimer's disease and control brain. Thus, we have found, surprisingly, that Cdc25B is a normal constituent of adult brain neurons, with detectable basal levels of activity. In Alzheimer's disease the levels and activity of the enzyme are elevated, and the active enzyme predominates in the cytoplasmic compartment of neurons. Consistent with these M phase-type changes, Cdc25B displays increased immunoreactivity towards the MPM-2 mitotic phosphoepitope antibody. We propose that aberrant expression of Cdc2/cyclin B in Alzheimer's disease leads to potentiation of mitotic activation mediated by constitutive neuronal Cdc25B activity. As a result, various downstream indices of mitotic events are generated, eventually culminating in neurodegeneration. Our data also suggest that Cdc25B is functional in normal post-mitotic neurons lacking the mitotic Cdc2/cyclin B, but it does not appear to influence the activity of Cdk5, a Cdc2-like kinase that is particularly enriched in brain.

Aged↗
PubMed1995

Neurofibrillary degeneration in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. Immunochemical characterization of tau proteins.

Neurofibrillary tangles are observed in several neurodegenerative disorders including Alzheimer's disease, progressive supranuclear palsy, and amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. The major components of neurofibrillary tangles are hyperphosphorylated tau proteins that can be directly detected in brain homogenates, using immunoblotting with specific immunological probes. To investigate whether tau proteins differ biochemically among various neurodegenerative disorders, we analyzed a series of brain samples from Guamanian patients in comparison with Alzheimer's disease, progressive supranuclear palsy, and normal aging. In Alzheimer's disease, these hyperphosphorylated tau proteins are composed of a triplet referred to as tau 55, 64, and 69, whereas in progressive supranuclear palsy, neurofibrillary degeneration is characterized by a tau doublet (tau 64 and 69). In the present study, characterization of tau proteins was performed by immunoblotting, on different cortical and subcortical regions of postmortem brain specimens from Guamanian natives. In all of the cases, biochemical data were always consistent with neuropathological findings. In contrast to Alzheimer's disease patients where the tau triplet is found mostly in cortical regions, a similar triplet was strongly detected in both cortical and subcortical areas in Guamanian patients. The tau profile differed quantitatively from case to case demonstrating that the Alzheimer's disease-related tau triplet had a heterogeneous regional distribution. These data suggest that the tau triplet found in amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam is similar to that observed in Alzheimer's disease, and the regional distribution of tau proteins differs in these disorders.

Adult↗
PubMedDate not supplied

Alzheimer disease: protein-protein interaction and oxidative stress.

Alzheimer disease, the most prevalent dementia of the aged, is defined by the concurrence of two filamentous brain lesions: neurofibrillary tangles and senile plaques. The lesions are temporally and spatially correlated to each other and to cognitive impairment suggesting that is a interaction between neurofibrillary tangles and senile plaques that might play a role in disease pathogenesis. Here we present findings demonstrating specific interactions between the major protein components of the lesions. Such an interaction is likely important to lesion genesis and to the overall cognitive deficits seen clinically. Also important are forces that stabilize and cement abnormal interactions and protect them form removal. Oxidative post-translational modifications is probably one of the major mediators that by disrupting cellular homeostatic balance both promotes abnormal interactions and makes them resistant to proteolytic removal. Overall, these findings support the view that the lesions of Alzheimer disease are intimately involved in neuronal destructions.

Alzheimer Disease↗
PubMed1992

[The thalamic changes in progressive supranuclear palsy].

This report is to investigate neuropathological changes of the thalamus observed in progressive supranuclear palsy. Six autopsy cases were examined. They were 5 males and a female, whose age was between 57 and 72 years old. They developed dementia in various degrees and three of the cases showed periodic stuporous state and akinetic mutism in the last stage. The paraffined thin-sections were stained with hematoxylin-eosin, luxol-fast-blue, Holzer, modified Bielschowsky, Gallyas and anti-tau stainings. The histological changes were evaluated in the aspects of neuronal loss, fibrillary gliosis and neurofibrillary tangles. In conclusion, there were three types in six cases. The first was seen in two cases and that there appeared many Alzheimer's neurofibrillary tangles (NFTs) in medial nuclei, lateral and ventral nuclei as well as zona incerta and reticular nucleus. The second was observed in two cases and that the loss of nerve cells was severe, especially in medial nuclei and the dorsal part of lateral and ventral nuclei and fibrillary gliosis was observed beyond the lesions of neuronal loss. The third was that the appearance of NFTs was moderate in number and neuronal loss was minimal. Moreover, neuronal loss and NFTs of zona incerta were common in these cases. Argentophilic fibrillary inclusions were observed in the neuropil and astrocytes in all cases. It is important to investigate the correlations between neuropathological changes and clinical manifestations, especially in the peculiar type of dementia observed in PSP. The thalamic changes of PSP may play an important role in causing stuporous state and akinetic mutism as well as subcortical dementia.

Aged↗
PubMed1994

An autopsy case of Alzheimer disease with myoclonus and periodic spikes on EEG.

This is a case of Alzheimer disease with myoclonus and periodic spikes on EEG. A 56-year-old man developed progressive dementia and, 3 years later, generalized convulsions. Eight years later, he showed myoclonus and periodic spikes on EEG. Cranial CT showed cortical atrophy and ventricular dilatation. He became apallic and died of pneumonia at the age of 65.9 years after the onset of the disease. The brain weighed 1,050 g. Neuropathologically, diffuse neuronal loss, abundant neurofibrillary tangles and senile plaques, particularly diffuse plaques, were found extensively in the cerebral cortex. The white matter was preserved. In the Ammon's horn, abundant neurofibrillary tangles and senile plaques were observed. Grumose degeneration of the cerebellar dentate nucleus, Kuru plaques or prions were not found. Numerous diffuse plaques of the cerebral cortex have rarely been reported in autopsy cases of Alzheimer disease with myoclonus and periodic spikes on EEG.

Alzheimer Disease↗
PubMed1998

The role of APOE polymorphisms in late-onset dementias.

Epidemiologic and laboratory results consistently implicate the APOE gene in the pathogenesis of late-onset Alzheimer's disease (AD): the epsilon 4 allele increases risk in a dose-dependent fashion, while epsilon 2 confers protection. Individuals are susceptible for AD in varying degrees depending on which combination of APOE alleles has been inherited, APOE promoter polymorphism and other factors. Deposition of both senile plaques and neurofibrillary tangles, the pathologic hallmarks of AD, are enhanced by epsilon 4 from the earliest lesions onward--diffuse plaques consisting of A beta 1-42 and neurofibrillary tangles in the entorhinal cortex. Transgenic APOE mice carrying an APP mutation and 0, 1 or 2 copies of APOE showed dose-related increases in plaque deposition in the hippocampus and cortex, a clear indication that APOEp promotes A beta deposition. The presence of each additional APOE epsilon 4 allele leads to an earlier onset of the histopathological process of about 1 decade, on average. The association of both types of AD-related changes with the occurrence of epsilon 4 suggests that the APOE polymorphism causally contributes to the pathogenesis of AD.

Age of Onset↗
PubMed1993

Serine protease inhibitor antithrombin III and its messenger RNA in the pathogenesis of Alzheimer's disease.

The classical plasma protein antithrombin III (ATIII), an inhibitor of the blood coagulation cascade, is a member of the serpins that are gaining import in the nervous system. In this study, we examined the presence of ATIII in the pathological lesions of Alzheimer's disease (AD). Antibodies to ATIII consistently detected approximately 58-kd protein(s) on immunoblots of cerebral cortex and brain microvessels. Immunocytochemical studies showed ATIII reactivity within amyloid deposits, neurites associated with plaques, and neurofibrillary tangles in neocortex and hippocampus of virtually all the AD cases examined. In some cases, astrocytes were also stained, suggesting ATIII in these cells. ATIII immunoreactivity in neurofibrillary tangles was further defined by electron microscopy, which showed it to be associated with paired helical filaments. Using the polymerase chain reaction technique to amplify ATIII complementary DNA, we found low levels of messenger RNA expression, relative to liver, in control human brain samples, and these were increased in AD samples, particularly in the white matter. Our results suggest the increased presence of ATIII commensurate with astrogliosis and association with the neurofibrillary pathology of AD. We conclude that in concert with other amyloid-associated serine protease inhibitors, ATIII may play a role in the pathogenesis of cerebral amyloidosis.

Aged↗
PubMed2005

Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase.

Tau is a major microtubule-associated protein of axons and is also the principal component of the paired helical filaments (PHFs) that comprise the neurofibrillary tangles found in Alzheimer's disease and other tauopathies. Besides phosphorylation of tau on serine and threonine residues in both normal tau and tau from neurofibrillary tangles, Tyr-18 was reported to be a site of phosphorylation by the Src-family kinase Fyn. We examined whether tyrosine residues other than Tyr-18 are phosphorylated in tau and whether other tyrosine kinases might phosphorylate tau. Using mass spectrometry, we positively identified phosphorylated Tyr-394 in PHF-tau from an Alzheimer brain and in human fetal brain tau. When wild-type human tau was transfected into fibroblasts or neuroblastoma cells, treatment with pervanadate caused tau to become phosphorylated on tyrosine by endogenous kinases. By replacing each of the five tyrosines in tau with phenylalanine, we identified Tyr-394 as the major site of tyrosine phosphorylation in tau. Tyrosine phosphorylation of tau was inhibited by PP2 (4-amino-5-(4-chlorophenyl-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), which is known to inhibit Src-family kinases and c-Abl. Cotransfection of tau and kinases showed that Tyr-18 was the major site for Fyn phosphorylation, but Tyr-394 was the main residue for Abl. In vitro, Abl phosphorylated tau directly. Abl could be coprecipitated with tau and was present in pretangle neurons in brain sections from Alzheimer cases. These results show that phosphorylation of tau on Tyr-394 is a physiological event that is potentially part of a signal relay and suggest that Abl could have a pathogenic role in Alzheimer's disease.

Aged, 80 and over↗
PubMed1997

Mechanisms of cell death in Alzheimer's disease.

The etiology of Alzheimer's disease (AD) as well as its exact pathogenesis are unknown. Eventhough the deposition of beta A4 and the formation of neurofibrillary tangles represent impressive morphological hallmarks of the disease, several lines of evidence suggest that both lesions are not sufficient as causes of the neurodegenerative process. On the other hand, in vitro studies have shown that beta A4 is neurotoxic and is able to induce apoptotic cell death in neuronal cell cultures. Cells dying by apoptosis (programmed cell death) can be visualized in the tissue with a molecular biologic technique detecting fragmented nuclear DNA. Using this method, we have detected 50 x more neurons and 25 x more glial cells with nuclear DNA fragmentation in the brains of patients with AD than in non-demented controls. In contrast to previous studies, most of these cells did not reveal the characteristic morphological hallmarks of apoptosis. Most dying cells were not located within amyloid deposits and most dying cells did not bear a tangle. On the other hand, being in physical contact with an amyloid deposit increased the risk of a cell to dye by factor 5.7 and carrying a neurofibrillary tangle imposed a 3 times higher risk compared to unaffected nerve cells. Taken together, these data indicate that nerve cell death in AD occurs via a mechanism of programmed cell death different from classical apoptosis. Eventhough plaques and tangles increase the risk of cells to degenerate, both lesions are not the sole responsibles of the degenerative process, suggesting the existence of other factors that trigger the initiation of the cell death program in AD.

Aged↗