Presenilin-1 polymorphism and neuropathological lesions of aging brain and late-onset Alzheimer's disease

In addition to missense mutations of the presenilin-1 gene, an association between a polymorphism within the intron 3’to exon 8 and late-onset sporadic Alzheimer's disease (AD) cases has been reported. This study examined the relationship between this polymorphism and the density of lesions by studying a homogeneous group of cases with different levels (normal to severely demented) of intellectual impairment. There were no differences in age and intellectual status between the groups of different genotypes. In all areas of the brain examined (frontal, temporal, calcarine, supramarginal and subicular areas), we found no difference in the density of Aβ-deposits. Only in the subicular area, a lower density of neurofibrillary tangles (NFT) was found in the 2/2 genotype group compared with those found in the combined group of 1/1 and 1/2 genotypes. This suggests that this polymorphism influences the development of NFT preferentially detected in the subiculum, where prominent AD lesions are usually observed.     

Immunohistochemical detection of tau protein in various non-human animal brains

In order to clarify the tau phosphorylation in aged non-human animal brains, paraffin sections of human and non-human animal brains were examined immunohistochemically using two antibodies against tau. The monoclonal antibody (mAb) tau-2 is known to bind non-phosphorylated and phosphorylated forms of tau protein and to recognize neurofibrillary tangles (NFT) in the human brain, whereas rabbit antiserum against tau recognizes the protein in a wide variety of mammalian species. In this study, both antibodies recognized axons, neurites, and cytoplasm of neuronal cells together with oligodendrocytes in non-human animal brains as reported in human brains, suggesting that the distribution of normal tau is quite similar between human and non-human animal brains. Neurofibrillary tangles detected by the Gallyas method were not found in non-human animal brains. Tau-2 intensely labeled NFT in the human brain and neurons of brain stem nuclei in the canine brain. The results may suggest very early stage of abnormal tau phosphorylation leading to NFT formation in the aged canine brain. It is probable that phosphorylation develops over a long period of time (more than 25–30 years) and as a result abnormal tau becomes apparent in humans because they have a long life-span in comparison with most non-human animals.     

Toxic tau: structural origins of tau aggregation in Alzheimer's disease

Alzheimer’s disease is characterized by the extracellular accumulation of the amyloidβin the form of amyloid plaques and the intracellular deposition of the microtubule-associated protein tau in the form of neurofibrillary tangles.Most of the Alzheimer’s drugs targeting amyloidβhave been failed in clinical trials.Particularly,tau pathology connects greatly in the pathogenesis of Alzheimer’s disease.Tau protein enhances the stabilization of microtubules that leads to the appropriate function of the neuron.Changes in the quantity or the conformation of tau protein could affect its function as a microtubules stabilizer and some of the processes wherein it is involved.The molecular mechanisms leading to the accumulation of tau are principally signified by numerous posttranslational modifications that change its conformation and structural state.Therefore,aberrant phosphorylation,as well as truncation of tau protein,has come into focus as significant mechanisms that make tau protein in a pathological entity.Furthermore,the shape-shifting nature of tau advocates to comprehend the progression of Alzheimer’s disease precisely.In this review,we emphasize the recent studies about the toxic and shape-shifting nature of tau in the pathogenesis of Alzheimer’s disease.     

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

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

Neuropathological diagnostic criteria for Alzheimer's disease

Neuropathological diagnostic criteria for Alzheimer's disease (AD) are based on tau‐related pathology: NFT or neuritic plaques (NP). The Consortium to Establish a Registry for Alzheimer's disease (CERAD) criterion evaluates the highest density of neocortical NP from 0 (none) to C (abundant). Clinical documentation of dementia and NP stage A in younger cases, B in young old cases and C in older cases fulfils the criterion of AD. The CERAD criterion is most frequently used in clinical outcome studies because of its inclusion of clinical information. Braak and Braak's criterion evaluates the density and distribution of NFT and classifies them into: I/II, entorhinal; III/IV, limbic; and V/VI, neocortical stage. These three stages correspond to normal cognition, cognitive impairment and dementia, respectively. As Braak's criterion is based on morphological evaluation of the brain alone, this criterion is usually adopted in the research setting. The National Institute for Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association criterion combines these two criteria and categorizes cases into NFT V/VI and NP C, NFT III/IV and NP B, and NFT I/II and NP A, corresponding to high, middle and low probability of AD, respectively. As most AD cases in the aged population are categorized into Braak tangle stage IV and CERAD stage C, the usefulness of this criterion has not yet been determined. The combination of Braak's NFT stage equal to or above IV and Braak's senile plaque Stage C provides, arguably, the highest sensitivity and specificity. In future, the criteria should include in vivo dynamic neuropathological data, including 3D MRI, PET scan and CSF biomarkers, as well as more sensitive and specific immunohistochemical and immunochemical grading of AD.     

Relationship between microtubule-binding repeats and morphology of neurofibrillary tangle in Alzheimer's disease

OBJECTIVE: The present study was performed to compare the distributions of three-repeat (3R) and four-repeat (4R) neurofibrillary tangles (NFT) with those of pretangles (p-NFT), intracellular NFT (i-NFT), and extracellular NFT (e-NFT) in the hippocampus of Alzheimer's disease brains. METHODS: NFT labeling was performed using anti-tau antibodies: pSer262 for p-NFT, pSer422 for i-NFT, AT8 for e-NFT, RD3 for 3R, and RD4 for 4R tau, and Gallyas impregnation for the NFT population. RD4- and pSer422-positive NFT were detected predominantly in sectors from CA2 to CA4, while RD3- and pSer262-positive NFT were predominantly present in CA1, the entorhinal cortex, and the subiculum. The tau epitope recognized by pSer262 belongs to 4R tau but it showed a strong correlation with RD3- and AT8-positive NFT. CONCLUSIONS: Sectors CA2-CA4 showed predominantly 4R-NFT containing the pSer422 epitope. pSer262 may detect the process of transformation from p-NFT to i-NFT, and e-NFT consisted predominantly of 3R tau.     

Development and evaluation of [125I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6‐[¹²⁵I]iodo‐3‐(1H‐pyrrolo[2,3‐c]pyridine‐1‐yl)isoquinoline ([¹²⁵I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). Methods: Radiosynthesis of [¹²⁵I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK‐6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [³H]PIB for Aβ plaques and [¹²⁵I]IPPI for Tau in AD and CN brains and evaluate drug effects. Results: [¹²⁵I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (?7.8, ?8.1, ?8.2, ?7.5 Kcal/mol) at the four sites were comparable to MK‐6240 (?8.7, ?8.5, ?8.3, ?7.5 Kcal/mol). Ratio of average grey matter (GM) [¹²⁵I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [¹²⁵I]IPPI in CN was 1.21. Binding of [¹²⁵I]IPPI correlated with the presence of Tau, confirmed by anti‐Tau Dako A0024. Specifically bound [¹²⁵I]IPPI to Tau in AD brains was displaced by MK‐6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [¹²⁵I]IPPI binding at >1 µM concentrations. Conclusion: [¹²⁵I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.     

Monoclonal antibody PHF-9 recognizes phosphorylated serine 404 of tau protein and labels paired helical filaments

Paired helical filaments (PHFs) purified from Alzheimer's brain consist of hyperphosphorylated microtubule-associated protein tau. In PHF, phosphorylation occurs at ser/thr tau residues. Several of these ser/thr phosphorylation sites lie immediately C-terminal to the tau tubulin binding domain. The C-terminal ser³⁹⁶ to thr⁴¹³ tau region contains two or more phosphorylated residues and eight possible ser/thr phosphorylation sites. Immunologic studies and mass spectroscopy have identified ser³⁹⁶ as one of the phosphorylation sites but identification of more C-terminal phosphorylated residues has been hampered by the lack of monoclonal antibodies (Mabs) that recognize defined epitopes in this region. We have raised Mabs against PHF purified from Alzheimer's brain. One of these Mabs, PHF-9, showed phosphorylation-dependent binding to purified PHF and recognized a phosphorylated epitope in the C-terminal portion of cyanogen bromide-digested PHF. Epitope mapping studies employing synthetic tau phosphopeptides indicated that PHF-9 labeled a 13-mer tau peptide phosphorylated at ser⁴⁰⁴ but not the corresponding non-phosphorylated peptide. PHF-9 demonstrated no immunoreactivity with a synthetic peptide phosphorylated at ser³⁹⁶ indicating that the PHF-9 epitope is C-terminal to ser³⁹⁶. In conclusion, the present study describes a Mab, PHF-9, which recognizes phosphorylated ser⁴⁰⁴ of tau independently of phosphorylated ser³⁹⁶ and indicates that tau ser⁴⁰⁴ is phosphorylated in PHF. © 1996 Wiley-Liss, Inc.     

Dystrophic microglia in late-onset Alzheimer's disease

Here, we summarize current understanding of functional involvement of microglial cells in the most common neurodegenerative disease to affect humans, which is sporadic or late-onset Alzheimer's disease (LOAD). Our review narrowly focuses on insights obtained from post-mortem neuropathological examinations of human brains paying particular attention to microglia as these cells have long been implicated as pivotal players in the cellular processes that lead to AD-type neurodegeneration. Although complete understanding of the roles played by microglia in AD neurodegeneration remains elusive, our studies thus far have illuminated microglial involvement in LOAD, showing that microglial dystrophy, the morphological manifestation of senescence, can be integrated with other hallmark pathological features of AD, such as intraneuronal neurofibrillary degeneration (NFD) and extracellular deposits of amyloid-beta (Aβ) protein. We have demonstrated an in situ correlation between microglial dystrophy and presence of NFD suggesting that neurodegeneration is secondary to aging-related microglial deterioration, a concept founded on the notion that proper neuronal function is dependent on presence of healthy microglia. Diseased or weakened glia are detrimental for neuronal well-being because their ability to provide neuronal support may be impaired. Our most recent work also links microglial dystrophy with Aβ deposits by showing that there is a chronic, yet futile microglial reaction to insoluble amyloid deposits. This inability of microglia to remove aggregated amyloid (a foreign body) causes microglial exhaustion and thereby exacerbates already ongoing aging-dependent microglial deterioration. An eventual total loss of functional microglia in advanced LOAD promotes widespread NFD, dementia, and brain failure.     

A comparison of histological and immunohistochemical methods for quantifying the pathological lesions of Pick's disease

Counts of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were made in the frontal and temporal cortex from patients with Pick's disease (PD). Lesions were stained histologically with hematoxylin and eosin (HE) and the Bielschowsky silver impregnation method and labeled immunohistochemically with antibodies raised to ubiquitin and tau. The greatest numbers of PB were revealed by immunohistochemistry. Counts of PB revealed by ubiquitin and tau were highly positively correlated which suggested that the two antibodies recognized virtually identical populations of PB. The greatest numbers of PC were revealed by HE followed by the anti-ubiquitin antibody. However, the correlation between counts was poor, suggesting that HE and ubiquitin revealed different populations of PC. The greatest numbers of SP and NFT were revealed by the Bielschowsky method indicating the presence of Alzheimer-type lesions not revealed by the immunohistochemistry. In addition, more NFT were revealed by the anti-ubiquitin compared with the anti-tau antibody. The data suggested that in PD: (i) the anti-ubiquitin and anti-tau antibodies were equally effective at labeling PB; (ii) both HE and anti-ubiquitin should be used to quantitate PC; and (iii) the Bielschowsky method should be used to quantitate SP and NFT.     

The induction of glial proliferation by an astrocytoma-derived growth factor resembling glia maturation factor

Glia maturation factor (GMF)-like activity which induces DNA synthesis and morphological differentiation of density-inhibited glioblasts was detected in various glial tumor cells. A polypeptide from C6 cells (rat astrocytoma) which has a molecular weight range of 40,000–50,000 showed the highest activity. This factor also induced DNA synthesis in glioma cells (354A and LRM55) and fibroblast (Swiss 3T3). The activity was susceptible to heat treatment at 70 °C for 5 min, or to proteases such as trypsin, chymotrypsin, papain, and subtilisin, but it was devoid of esteropeptidase activity. The isoelectric point was found to be 5.3. Subcellular fractionation localized the activity in cytosomal and microsomal fractions. These properties closely resemble those of GMF from pig and bovine brain.     

Both N-terminal and C-terminal fragments of Presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer's disease

Presenilin 1 (PS1) is a causative gene for chromosome 14-linked familial Alzheimer's disease. The gene product is known to be cleaved into N-terminal fragments (PS1-N) and C-terminal fragments (PS1-C). To understand the pathophysiological role of PS1, we conducted immunohistochemical studies using antibodies specific for PS1-N and PS1-C in sporadic Alzheimer's disease (AD). Both antibodies showed punctuate staining exclusively in neurons and their processes in both control and AD brains. PS1-N immunolabeling colocalized with neurofibrillary tangles (NFTs) in 36% of NFT-bearing neurons and with dystrophic neurites in 28% of senile plaques (SPs). PS1-C immunolabeling colocalized with dystrophic neurites in 70% of NFT-bearing SPs and with intraneuronal NFTs in 32% of NFT-bearing neurons. Both antibodies did not detect PHF-tau-positive neuropil threads and Aβ amyloid fibrils. The colocalization was also found in 33–38% of NFT-bearing neurons in progressive supranuclear palsy. These results indicate that both PS1-N and PS1-C fragments are deposited in part of NFT-bearing neurons and dystrophic neurites in SPs; both are the pathologic hallmarks of AD. J. Neurosci. Res. 53:99–106, 1998. © 1998 Wiley-Liss, Inc.     

Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer's disease and Creutzfeldt-Jakob's disease

Studies in vitro have shown that phosphorylated translation initiation factor 2 alpha (TIF 2 alpha) may have several functions, including regulation of protein synthesis, control of cell death and procurement of resistance to oxidative stress in nerve cells. These properties may have implications in certain human neurodegenerative diseases, such as Alzheimer's disease (AD) and Creutzfeldt-Jakob's disease (CJD), in which oxidative stress appears to be involved in the process of neurodegeneration and neurone death. Single and double-labelling immunohistochemistry to phosphorylated TIF 2 alpha, phosphorylated SAPK/JNK, phosphorylated p38, tau, Cu/Zn superoxide dismutase 1 (SOD 1) and cleaved caspase-3 (17 kDa), and in situ end-labelling of nuclear DNA fragmentation, was carried out in postmortem samples of 10 patients with AD (stages III and VI of Braak and Braak), seven patients with CJD (five cases with methionine/methionine and two cases with methionine/valine at the codon 129 of the PrP gene) and eight age-matched controls. No phosphorylated TIF 2 alpha immunoreactivity was found in control brains, but strong phosphorylated TIF 2 alpha expression was observed in subpopulations of neurones bearing neurofibrillary tangles (NFTs) or pretangles in the hippocampus, entorhinal cortex and isocortex in AD. Phosphorylated TIF 2 alpha is restricted to neurones with abnormal tau deposition, but only approximately 80% of neurones with NFTs in the hippocampus and 60% in the isocortex colocalize phosphorylated TIF 2 alpha, thus indicating that not all neurones with NFTs over-express phosphorylated TIF 2 alpha. Moreover, phosphorylated TIF 2 alpha immunoreactivity was found in a percentage of neurones expressing phosphorylated SAPK/JNK and p38, which, in turn, are involved in tau phosphorylation in AD. However, dystrophic neurites of senile plaques that contain abnormal tau and express SOD 1 are negative to antiphosphorylated TIF 2 alpha antibodies. Smooth muscle cells in blood vessels affected by amyloid angiopathy, which are putative targets of beta A 4 amyloid-derived oxidative stress, are not associated with phosphorylated TIF 2 alpha immunoreactivity. Double-staining with the method of in situ end-labelling of nuclear DNA fragmentation demonstrated no relationship between phosphorylated TIF 2 alpha expression and increased nuclear DNA vulnerability in individual cells. Moreover, no single caspase-3-immunoreactive cell in AD expressed phosphorylated TIF 2 alpha. Oxidative stress response, manifested as positive SOD 1 expression in Bergmann glia and in a few reactive astrocytes, has been demonstrated in CJD. No phosphorylated SAPK/JNK or phosphorylated p38 kinase immunoreactivity was observed in these cases. Moreover, neurones and glial cells do not over-express phosphorylated TIF 2 alpha in CJD. The present results demonstrate selective expression of phosphorylated TIF 2 alpha in subpopulations of nerve cells with abnormal tau deposition, and suggest that factors linked with tau deposition regulate protein synthesis throughout TIF 2 alpha phosphorylation in certain neurones sensitive to oxidative stress in AD.     

The behavioral pathology in Alzheimer's disease scale (BEHAVE-AD): factor structure among community-dwelling Alzheimer's disease patients

Objective. The aims of this study were to (a) determine the factor structure of the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD), and (b) examine the associations of the observed factors to the level of cognitive impairment. Design. Cross-sectional study of geriatric patients evaluated at an outpatient memory disorders clinic. Sample. One hundred and fifty-one consecutive patients diagnosed with Alzheimer's disease (AD) according to NINCDS–ADRDA diagnostic criteria. Results. Principal factors analysis with Varimax rotation resulted in a five-factor solution that accounted for 40·0% of the common variance. The factors included agitation/anxiety (agitation, anxiety of upcoming events; other anxiety), psychosis (delusions of theft, suspiciousness/paranoia; visual hallucinations), aggression (verbal aggressiveness; physical threats/violence; fear of being left alone; other delusions), depression (tearfulness; depressed mood) and activity disturbance (wandering; delusion one's house is not one's home). Several factors were associated with level of cognitive impairment as assessed by the Mini-Mental State Examination (MMSE). Conclusion. The results of this study suggest that the BEHAVE-AD measures a wide range of behavioral pathology that can be empirically represented by five independent symptom clusters among outpatient AD patients. Copyright © 1998 John Wiley & Sons, Ltd.     

A Morphometric study of subcortical neurofibrillary tangles in Alzheimer's disease

The numbers of neurofibrillary tangles(NFT) in the subcortical nuclei detected in Gallyas-Nissl double stained sections was evaluated with computer-based image analysis techniques. This was undertaken to examine the susceptibility to NFT formation and to identify mutual correlations in NFT formation among the basal ganglia in Alzheimer's disease (AD). The numbers of NFT are insufficient to compare the regional differences of NFT in each nucleus of the AD brains because large subcortical gray nuclei tend to have more NFT, Incidences of NFT were given definitions in order to find the NFT incidences for the expected neuronal populations, The definitions used were: the ratio of total numbers of NFT observed in a given subcortical gray nucleus of AD brains to the total numbers of medium- to large-sized neurons(≥ 150μm²) in which the nucleoli were confirmed in the corresponding structure of control brains. A common order of susceptibility to NFT changes was found among the subcortical nuclei in advanced stages of AD cases, According to NFT incidences, subcortical nuclei were classified into four groups. The highest incidence of NFT (88%) was found in the nucleus basalis of Meynert. The severely affected group (NFT Incidences; 28–44%) included the raphe nucleus (superior central nucleus), anterior thalamic nucleus (anterior ventral thalamic nucleus), locus ceruleus and claustrum, The putamen, substantia nigra (zona compacta), medial thalamic nucleus (medio-dorsal thalamic nucleus) and lateral thalamic nucleus (ventro-lateral and ventro-anterior thalamic nuclei) comprised the moderately affected group (NFT incidences; 9–15%). The substantia nigra (zona reticulata), globus pallidus, subthalamic nucleus and red nucleus constituted the slightly affected group (NFT incidences;<5%). In spite of the group classifications, no significant mutual correlations in NFT incidences between any pair of subcortical nuclei were indicated. The present study suggests that the NFT formations in AD take place in the subcortical nuclei according to individual susceptibility, irrespective of the connections between the nuclei.     

Immunohistochemical evidence for macroautophagy in neurones and endothelial cells in Alzheimer's disease

J.‐F. Ma, Y. Huang, S.‐D. Chen and G. Halliday (2010) Neuropathology and Applied Neurobiology 36, 312–319
Immunohistochemical evidence for macroautophagy in neurones and endothelial cells in Alzheimer's disease Aim: To determine the pathological structures associated with macroautophagy in Alzheimer's disease (AD) and any relationship to disease progression. Methods: Immunohistochemistry using antibodies to beclin‐1, Atg5 and Atg12, early macroautophagy markers and LC3, the mammalian homologue of the later macroautophagy marker Atg8, were localized in formalin‐fixed, paraffin‐embedded medial temporal lobe sections of AD cases at variable neuritic disease stages. Double immunofluorescence labelling was used to co‐localize these macroautophagy markers with Aβ and phospho‐tau (AT8) and correlations performed using Spearman rank tests. Results: Atg12 immunoreactivity in AD was either dispersed in the soma and dendrites or concentrated in tau‐immunoreactive dystrophic neurites and some neurofibrillary tangles. Fewer Atg12‐immunopositive neurones were observed with longer disease durations. Atg12‐immunoreactive endothelial cells were found spatially associated with Aβ‐positive plaques, with more Atg12‐immunoreactive capillary endothelial cells with higher neuritic disease stage. These findings were confirmed by the other autophagy markers beclin‐1, Atg5 and LC3. Conclusion: The data confirm that macroautophagy occurs in neurones undergoing neuritic degeneration in AD, identified early macroautophagy markers in capillary endothelial cells in close proximity to Aβ plaques, and found that evidence for macroautophagy changes with disease progression.     

The absence of differentiation-promoting response of astroglioma cells to glia maturation factor

The effects of glia maturation factor (GMF) on cell proliferation and differentiation were investigated with 3 astroglioma cells (GE-12, C6, and GA-1), Schwannoma-like cells (354A), and mixed glioma cells (LRM-55). In the exponentially growing phase the growth rates of all glioma cells were enhanced by GMF regardless of the presence or absence of serum, but the factor failed to make the saturation density surpass the control level observed in the medium without GMF even in the chemically defined medium (N2 medium). GMF markedly lowered the saturation density of Schwannoma-like cells in N2 medium. Although GMF increased the intracellular content of S-100 protein 10-fold and 2′,3′-cyclic nucleotide phosphohydrolase activity 1.5-fold in Schwannoma-like cells, GMF conversely decreased the S-100 contents and glycerol phosphate dehydrogenase activity in astroglioma cells. All the astroglioma cells secreted into the culture medium large quantities of a growth-promoting factor(s) which had similar chemical properties to those of GMF and stimulated the proliferation of normal glioblasts; but Schwannoma-like cells did not, although they produced a small amount of such a factor(s). These findings imply that astroglioma cells are deprived of the differentiation-promoting response to GMF while Schwannoma-like cells still preserve the response in addition to the proliferative response to GMF.     

An autopsy case of Alzheimer's disease with a progressive supranuclear palsy overlap

A 74‐year‐old man developed abnormal forgetfulness, soon followed by unstable speech content and marked disorientation. At 77 years of age, the patient started to occasionally fall, an aspect of progressive supranuclear palsy. He then became bedridden. The patient eventually died of pneumonia at 79 years of age. Neuropathological examination revealed profiles of both progressive supranuclear palsy and Alzheimer's disease. Although the two conditions both belong to tauopathy, their pathologically proven combination was rare. Furthermore, the case had the possibility of being a subgroup of tauopathy.