Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model

Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid β-peptide (Aβ) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis

Sex Differences in the Cerebellum and Frontal Cortex: Roles of Estrogen Receptor Alpha and Sex Chromosome Genes

Most neurobehavioral diseases are sexually dimorphic in their incidence, and sex differences in the brain may be key for understanding and treating these diseases. Calbindin (Calb) D28K is used as a biomarker for the well-studied sexually dimorphic nucleus, a hypothalamic structure that is larger in males than in females. In the current study weanling C56BL/6J mice were used to examine sex differences in the Calb protein and message focusing on regions outside of the hypothalamus. A robust sex difference was found in Calb in the frontal cortex (FC) and cerebellum (CB; specifically in Purkinje cells); mRNA and protein were higher in females than in males. Using 2 mouse lines, i.e. one with a complete deletion of estrogen receptor alpha (ERα) and the other with uncoupled gonads and sex chromosomes, we probed the mechanisms that underlie sexual dimorphisms. In the FC, deletion of ERα reduced Calb1 mRNA in females compared to males. In addition, females with XY sex chromosomes had levels of Calb1 equal to those of males. Thus, both ERα and the sex chromosome complement regulate Calb1 in the FC. In the CB, ERα knockout mice of both sexes had reduced Calb1 mRNA, yet sex differences were retained. However, the sex chromosome complement, regardless of gonadal sex, dictated Calb1 mRNA levels. Mice with XX chromosomes had significantly greater Calb1 than did XY mice. This is the first study demonstrating that sex chromosome genes are a driving force producing sex differences in the CB and FC, which are neuoranatomical regions involved in many normal functions and in neurobehavioral diseases

PTPRR protein tyrosine phosphatase isoforms and locomotion of vesicles and mice.

Contains fulltext : 81710.pdf (publisher's version ) (Closed access)Protein tyrosine phosphatases (PTPs) are central players in many different cellular processes and their aberrant activity is associated with multiple human pathologies. In this review, we present current knowledge on the PTPRR subfamily of classical PTPs that is expressed in neuronal cells and comprises receptor-type (PTPBR7, PTP-SL) as well as cytosolic (PTPPBSgamma-37, PTPPBSgamma-42) isoforms. The two receptor-type isoforms PTPBR7 and PTP-SL both localize in late endosomes and the Golgi area. PTPBR7, however, is additionally localized at the cell surface and on early endosomes. During cerebellar maturation, PTPBR7 expression in developing Purkinje cells ceases and is replaced by PTP-SL expression in the mature Purkinje cells. All PTPRR isoforms contain a kinase interacting motif that makes them mitogen-activated protein kinase phosphatases. The distinct subcellular localization of the different PTPRR isoforms may reflect differential roles in growth-factor-induced MAPK-mediated retrograde signaling cascades. Studies in PTPRR-deficient mice established that PTPRR isoforms are physiological regulators of MAPK phosphorylation levels. Surprisingly, PTPRR-deficient mice display defects in motor coordination and balancing skills, while cerebellar morphological abnormalities, which are often encountered in ataxic mouse models, are absent. This is reminiscent of the phenotype observed in a handful of mouse mutants that have alterations in cerebellar calcium ion homeostasis. Elucidation of the molecular mechanisms by which PTPRR deficiency imposes impairment of cerebellar neurons and motor coordination may provide candidate molecules for hereditary cerebellar ataxias that still await identification of the corresponding disease genes