Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease

To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-beta protein (Abeta). This complex enhances tau phosphorylation by GSK3beta, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. Abeta binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple Abeta peptides in the mid to C-terminal regions of Abeta. This binding is also significantly decreased by GSK3beta phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of Abeta for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected Abeta bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and Abeta form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble Abeta to soluble nonphosphorylated tau, thus promoting tau phosphorylation and Abeta nucleation. Blocking the sites where Abeta initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.     

Fetal Anatomy of the Human Carotid Sheath and Structures In and Around It

The aim of this study was to find basic rules governing the morphological development of the typical neurovascular sheath. We carried out histological examination of 15 paraffin‐embedded mid‐term fetuses at 9–25 weeks of gestation (three fetuses each at 9, 12, 15, 20, and 25 weeks). As the result, the vagus nerve showed a high propensity to change its topographical relationship with the common carotid artery (CCA) during 9–20 weeks of gestation: that is, from a primitive ventral course to a final dorsal course. The adventitia of the great arteries, which was distinct from other fascial structures, became evident by 15 weeks. The carotid sheath appeared at and after 20 weeks: it was clearly separated from the prevertebral lamina of the deep cervical fasciae, but fused with the pretracheal lamina covering the strap muscles. Thus the carotid sheath, as well as the topographical relationships of structures within it, seems to become established much later than the prevertebral and pretracheal laminae of the deep cervical fasciae. However, the adventitia of the cervical great arteries consistently becomes evident much earlier than the sheath, and it seems to be regarded as one of the basic components of the fetal deep cervical fasciae. Anat Rec, 293:438–445, 2010. © 2010 Wiley‐Liss, Inc.     

Cranial nonmetric variation of Yayoi people in the Kyushu District

The Yayoi people in Kyushu and Yamaguchi area are generally classified by metrical analyses mainly into the Yayoi people in the northern Kyushu and Yamaguchi area who are regarded as migrants from the Asian Continent and their posterity and the Yayoi people in the northwestern Kyushu who are regarded as having inherited the characteristics of the Jomon people. Such classification is verified by the analysis with the 22 traits in the cranial nonmetric variation. Of the 22 traits, supraorbital foramen, transverse zygomatic suture vestige, biasterionic suture vestige, jugular foramen bridging, hypoglossal foramen bridging, pterygospinous foramen, mylohyoid bridging and tympanic dehiscence are particularly important as the traits to classify two types of Yayoi peoples. The analysis by the C. A. B. Smith's Mean Measure of Divergence (MMD) suggests that out of the migrant Yayoi peoples, the very Yayoi people who are closely related to the formation of the modern Japanese are the ones in the northern Kyushu area, not the ones in the Doigahama site. Also, it is assumed that the appearance and disappearance of cranial nonmetric variations is affected by genetic elements, because the incidencies of cranial nonmetric variations is largely different between two types of Yayoi peoples in infants like in adults. Lastly the cranial nonmetric variation in the people of the period equivalent to Jomon and Yayoi in the Okinawa district, and in the Kofun people in southern Kyushu area, was briefly introduced.     

Adenoid glioblastoma arising in a patient with neurofibromatosis type-1

An unusual case of glioblastoma with adenoid structures arising in a 30-year-old Japanese woman with neurofibromatosis type-1 (NF1) is reported. The patient was admitted to University of Miyazaki Hospital, complaining of headache, nausea and vomiting. From the neuroradiological findings the patient was diagnosed as having glioblastoma, and the tumor was surgically resected. Histologically, the tumor consisted mainly of dark basophilic cells showing prominent tubular or glandular structures surrounded by large eosinophilic cells, in addition to the typical glioblastoma features in the periphery of the tumor. Both cells showed strong stainability with glial fibrillary acidic protein (GFAP) and S-100 protein immunohistochemically, so that the tumor was classified as adenoid glioblastoma. Several cases of glioblastoma have been reported to reveal the adenoid or epithelioid differentiation. The patients with NF1 are prone to develop malignant tumors including glioblastoma, but no cases representing adenoid glioblastoma associated with NF1 have been reported. This report is considered to be the first case of adenoid glioblastoma arising in a patient with NF1. The recognition of the existence of epithelial features of glioblastoma would be important in differential diagnosis of epithelioid tumors of the brain including metastatic carcinomas.     

Microglial tau undergoes phosphorylation-independent modification after ischemia

Tau2 is a phosphorylation-independent antibody that immunolabels neurofibrillary tangles (NFTs) of Alzheimer type and microglia around ischemic foci on formalin-fixed, paraffin-embedded sections. We found that copresence of polyethyleneglycol-p-isooctylphenyl ether (Triton X-100; TX) with tau2 abolished its immunoreactivity (IR) in these microglia but not its IR on NFTs. Tau2-immunoreactive bands, exclusively retrieved in Tris-soluble fraction of brain homogenates from ischemic foci, normal human and bovine brains, were of similar electrophoretic mobility, indicating that tau2 IR in these microglia is unrelated to hyperphosphorylation of tau. These tau2-immunoreactive bands except those from bovine brain were abolished in the copresence of TX. This was not due to washing out of tau, because similar immunoreactive bands were detectable with another antitau antibody even under a higher concentration of TX and because washing after TX exposure restored similar tau2 IR both on immunohistochemistry and immunoblot. These findings are explained if tau, modified after ischemia, undergoes a reversible conformational change on TX exposure. Because conformation at Ser101 of bovine tau is crucial for its affinity to tau2, this Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by microglia around ischemic foci and NFTs. Relative resistance of tau2 epitope in NFTs to TX exposure suggests that tau woven into NFTs confers additional stability to this pathological modification on tau2 epitope. Susceptibility of tau2 epitope to TX, seen in these microglia, is shared with glial cytoplasmic inclusions and will show its conformational state to be different from that in NFTs.     

Possible new assessment of patulous Eustachian tube function: audiometry for tones presented in the nasal cavity

OBJECTIVE: To assess the acoustic transfer function of the Eustachian tube by means of audiometric measurements in order to evaluate the severity of the patulous condition. MATERIAL AND METHODS: Detection thresholds for tones presented in the nasal cavity (at the nostril) were measured in subjects with a patulous Eustachian tube (PET) and in normal subjects. RESULTS: In typical cases, these thresholds were lower in the subjects with PET and were markedly elevated to the same level as those of normal subjects by the insufflation of Lugol's solution (iodine solution). The pre- versus post-insufflation threshold differences seemed to reflect the effects of a patulous tube on the acoustic characteristics via the Eustachian tube. Based on the obtained results, sound patency via a patulous tube appeared to be dominant in lower frequency tones. CONCLUSION: The present method seems to be another easy way to assess PET.     

Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer's disease,Pick's disease,progressive supranuclear palsy and corticobasal degeneration

The microtubule-associated protein tau accumulates as cytoplasmic inclusions in Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We investigated the immunoreactivity of tau-positive structures using a panel of antibodies to epitopes spanning the entire length of the tau molecule. In ethanol-fixed brain tissues, most antibodies to the microtubule-binding domain (MBD) required formic acid (FA) treatment to stain tau inclusions in PSP and CBD. This is in contrast with the intense labeling of neurofibrillary tangles in AD without FA treatment. Pick bodies (PiB) in PiD showed an intermediate pattern with respect to the immunoreactivity of the MBD because accumulated tau in PiB mostly lacks the insertion of exon 10, and the proportion of tau phosphorylated at Ser262 is smaller than in other abnormal tau structures. Such immunohistochemical profiles appeared to correlate with the occurrence of the smeared tau on immunoblot analysis of brain homogenate. The smeared tau was more abundant in AD and PiD than in PSP and CBD. Since the smeared tau was N-terminally truncated and was characteristic of advanced forms of modified tau, these findings suggest that tau accumulated in AD and PiD was processed more markedly than that in PSP and CBD. The MBD of tau may be masked in the presence of the intact N terminus and require FA treatment for antibody recognition in tissue sections. Advanced modification may expose the MBD in brain tissues of AD and PiD. It is suggested that the processing of abnormally accumulated tau characterizes the pathophysiology of each tauopathy.     

Neuronal and glial inclusions in frontotemporal dementia with or without motor neuron disease are immunopositive for p62

We examined the immunoreactivity of p62 in five cases of frontotemporal dementia (FTD) with ubiquitin-positive, tau-negative inclusions. Only one case had clinical features suggestive of motor neuron disease (MND). In all cases, ubiquitin-positive neuronal inclusions and neurites in the hippocampal region and cerebral neocortex were immunohistochemically positive for p62. Moreover, in the temporal region of a case of FTD with MND, many oligodendrocytes and some astrocytes were positive for p62. These results suggest that the degenerative process involves p62 in FTD and that the process takes place not only in neurons but also in glial cells.     

A prospective, open-label, flexible-dose study of quetiapine in the treatment of delirium

BACKGROUND: Delirium is an organic psychiatric syndrome characterized by fluctuating consciousness and impaired cognitive functioning. High-potency typical neuroleptics have traditionally been used as first-line drugs in the treatment of delirium. However, these drugs are frequently associated with undesirable adverse events including extrapyramidal symptoms (EPS). The purpose of the present open-label, flexible-dose study was to provide preliminary data on the usefulness and safety of quetiapine for patients with delirium. METHOD: Twelve patients with DSM-IV delirium were treated with flexible doses of open-label quetiapine (mean +/- SD dosage = 44.9 +/- 31.0 mg/day). To evaluate the usefulness and safety of quetiapine, scores from the Delirium Rating Scale, Japanese version, were assessed every day (for 1 outpatient, at least twice per week), and scores from the Mini-Mental State Examination, Japanese version, and the Drug-Induced Extrapyramidal Symptom Scale were assessed at baseline and after remission of delirium. Data were gathered from April to October 2001. RESULTS: All patients achieved remission of delirium several days after starting quetiapine (mean +/- SD duration until remission = 4.8 +/- 3.5 days). Quetiapine treatment was well tolerated, and no clinically relevant change in EPS was detected. CONCLUSION: Quetiapine may be a useful alternative to conventional neuroleptics in the treatment of delirium due to its rapid onset and relative lack of adverse events. Further double-blind, placebo-controlled studies are warranted.