Takao Senda

The osteocyte plays multiple roles in bone remodeling and mineral homeostasis

Osteocytes are the most abundant cells in bone and are the major orchestrators of bone remodeling and mineral homeostasis. They possess a specialized cellular morphology and a unique molecular feature. Osteocytes are a stellate shape with numerous long, slender dendritic processes. The osteocyte cell body resides in the bone matrix of the lacuna and the dendritic processes extend within the canaliculi to adjacent osteocytes and other cells on the bone surface. Osteocytes form extensive intercellular network to sense and respond to environmental mechanical stimulus by the lacunar–canalicular system and gap junction. Osteocytes are long-lived bone cells. They can undergo apoptosis, which may have specific regulatory effects on osteoclastic bone resorption. Osteocytes can secrete several molecules, including sclerostin, receptor activator of nuclear factor κB ligand and fibroblast growth factor 23 to regulate osteoblastic bone formation, osteoclastic bone resorption and mineral homeostasis. A deeper understanding of the complex mechanisms that mediate the control of osteoblast and osteoclast function by osteocytes may identify new osteocyte-derived molecules as potential pharmacological targets for treating osteoporosis and other skeletal diseases.

Targeted deletion of the C-terminus of the mouse adenomatous polyposis coli tumor suppressor results in neurologic phenotypes related to schizophrenia.

BackgroundLoss of adenomatous polyposis coli (APC) gene function results in constitutive activation of the canonical Wnt pathway and represents the main initiating and rate-limiting event in colorectal tumorigenesis. APC is likely to participate in a wide spectrum of biological functions via its different functional domains and is abundantly expressed in the brain as well as in peripheral tissues. However, the neuronal function of APC is poorly understood. To investigate the functional role of Apc in the central nervous system, we analyzed the neurological phenotypes of Apc1638T/1638T mice, which carry a targeted deletion of the 3′ terminal third of Apc that does not affect Wnt signaling.ResultsA series of behavioral tests revealed a working memory deficit, increased locomotor activity, reduced anxiety-related behavior, and mildly decreased social interaction in Apc1638T/1638T mice. Apc1638T/1638T mice showed abnormal morphology of the dendritic spines and impaired long-term potentiation of synaptic transmission in the hippocampal CA1 region. Moreover, Apc1638T/1638T mice showed abnormal dopamine and serotonin distribution in the brain. Some of these behavioral and neuronal phenotypes are related to symptoms and endophenotypes of schizophrenia.ConclusionsOur results demonstrate that the C-terminus of the Apc tumor suppressor plays a critical role in cognitive and neuropsychiatric functioning. This finding suggests a potential functional link between the C-terminus of APC and pathologies of the central nervous system.

Requirement of DLG1 for cardiovascular development and tissue elongation during cochlear, enteric, and skeletal development: Possible role in convergent extension

The Dlg1 gene encodes a member of the MAGUK protein family involved in the polarization of epithelial cells. Null mutant mice for the Dlg1 gene (Dlg1-/- mice) exhibit respiratory failure and cyanosis, and die soon after birth. However, the cause of this neonatal lethality has not been determined. In the present study, we further examined Dlg1-/- mice and found severe defects in the cardiovascular system, including ventricular septal defect, persistent truncus arteriosus, and double outlet right ventricle, which would cause the neonatal lethality. These cardiovascular phenotypes resemble those of mutant mice lacking planar cell polarity (PCP) genes and support a recent notion that DLG1 is involved in the PCP pathway. We assessed the degree of involvement of DLG1 in the development of other organs, as the cochlea, intestine, and skeleton, in which PCP signaling has been suggested to play a role. In the organ of Corti, tissue elongation was inhibited accompanied by disorganized arrangement of the hair cell rows, while the orientation of the stereocilia bundle was normal. In the sternum, cleft sternum, abnormal calcification pattern of cartilage, and disorganization of chondrocytes were observed. Furthermore, shortening of the intestine, sternum, and long bones of the limbs was observed. These phenotypes of Dlg1-/- mice involving cellular disorganization and insufficient tissue elongation strongly suggest a defect in the convergent extension movements in these mice. Thus, our present results provide a possibility that DLG1 is particularly required for convergent extension among PCP signaling-dependent processes.

Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer’s Disease by Removal of Blood Amyloid

As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimers disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.

BRI2 as an anti-Alzheimer gene

There are several theories regarding the etiologies of Alzheimer disease (AD). Considering that all genes responsible for familial AD are amyloid protein precursor (APP) or APP metabolizing enzymes, surely aberrant APP metabolism is crucial to pathogenesis of AD. BRI2, a type II transmembrane protein, binds APP and inhibits all α, β, and γ pathways of APP proteolysis. Crossing AD model mice with BRI2 transgenic or BRI2 knockout mice confirmed that BRI2 is an anti-Alzheimer gene. Mutations of BRI2 are known to cause rare familial dementias in human. Analysis of knock-in mice harboring the disease mutation revealed the memory defect in the mice, attributable to loss of protective function of BRI2. Further studies are needed to decipher this anti-Alzheimer mechanism of BRI2 to develop a novel therapeutic application for AD. In this review, after describing basic assumptions in AD study, we focus on BRI2 as an anti-Alzheimer gene.

Validation and application of a novel APC antibody in western blotting, immunoprecipitation, and immunohistochemistry

Adenomatous polyposis coli (APC) is a large protein with multiple binding partners, suggesting diverse functions besides its well-known role in the destruction of β-catenin. To elucidate these complex functions, it is crucial to evaluate the precise subcellular distribution of APC within a cell and tissue. However, most of the commercially available anti-APC antibodies can only be used for limited applications, resulting in the use of independently generated antibodies. This has led to various discrepancies between studies as a common antibody has not been established. In this study, we generated an antibody against the c-terminal domain of human APC, designated APC-C antibody, and evaluated its specificity and application in various immunological methods. Our data indicate that this novel APC-C antibody is a specific and versatile antibody that can be used in western blotting, immunoprecipitation, immunocytochemistry, and immunohistochemistry. Widespread use of this APC antibody will help enhance our understanding of APC’s function in both normal and cancer cell biology.

Removal of blood beta-amyloid might reduce brain beta-amyloid deposition based on the study of hemodialysis patients: Extracorporeal beta-amyloid removal system (EARS) for Alzheimer's disease therapy

P4-279 REMOVAL OF BLOOD BETA-AMYLOID MIGHT REDUCE BRAIN BETA-AMYLOID DEPOSITION BASED ON THE STUDY OF HEMODIALYSIS PATIENTS: EXTRACORPOREAL BETA-AMYLOID REMOVAL SYSTEM (EARS) FOR ALZHEIMER’S DISEASE THERAPY Nobuya Kitaguchi, Kazuyoshi Sakai, Takao Senda, Kazunori Kawaguchi, Masao Kato, Makoto Kuroda, Shigeru Nakai, Ryuji Hata, Yukio Yuzawa, Yoshiyuki Hiki, Fujita Health University, Toyoake, Japan; Gifu University Graduate School of Medicine, Gifu, Japan. Contact e-mail: nkitaguc@fujita-hu.ac.jp