UI  - 18587238
TI  - Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population. 
      The Role of PSEN1 and MAPT R406W Mutations.
AB  - Background: Three major causative genes have been implicated as the cause of
      early-onset familial Alzheimer's disease (AD): the amyloid precursor protein gene
      (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with
      mutations in the microtubule-associated protein tau gene (MAPT) has been
      identified in patients showing clinical presentations similar to those of AD.
      Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10
      Japanese families with early-onset dementia clinically diagnosed as probable
      Alzheimer's disease. Results: In 4 index patients, we identified 4 missense PSEN1
      mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the
      patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W
      mutation in MAPT. The mean age at onset of the patients carrying the R406W
      mutation was 52 years, and they presented with the peculiar AD-like phenotype
      without apparent behavioral or language problems. Conclusion: These observations 
      suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W
      mutation is an important cause of early-onset familial dementia clinically
      diagnosed as AD. Differentiation of patients with the MAPT mutation from AD
      patients by genetic testing would be meaningful, considering that a different
      therapeutic approach should be applied.

UI  - 18586599
TI  - Increased cortical remodeling after osteotomy causes posttraumatic osteopenia.
AB  - Following a fracture, substantial bone mineral loss can occur at the affected
      limb. The aim of this study was to analyze the changes in cortical bone around
      the site of a fracture. We analyzed bone mineral density by quantitative computed
      tomography and quantified changes in cortical remodeling by histomorphometry
      adjacent to an experimental osteotomy in sheep metatarsals. In the cortical bone 
      around the osteotomy, we found a statistically significant 16% reduction in
      app.BMD within 9 weeks following surgery. This reduction was explained (R=-0.71, 
      P<0.01) by a more than 6 fold increase in bone remodeling activity within
      cortical bone at the affected limb. The remodeling activity significantly
      increased between surgery and week 6, but remained unchanged between week 6 and
      week 9. We conclude from these findings that posttraumatic bone mineral loss
      adjacent to a fracture is related to an elevated number of active osteons,
      indicating a significant increase in bone remodeling activity. Load shielding by 
      the osteosynthesis material and local recruitment of bone mineral are likely
      causes for this increased remodeling. This post-traumatic bone loss is likely to 
      contribute significantly to frequently observed healing complications like
      refracture, failure of implant fixation, implant loosening, or cut out.

UI  - 18586401
TI  - SUMO-1 immunoreactivity co-localizes with phospho-Tau in APP transgenic mice but 
      not in mutant Tau transgenic mice.
AB  - Sumoylation is a post-translational modification process that is supposed to be
      implicated in the pathogenesis of several neurodegenerative diseases. Recently,
      the microtubule-associated protein Tau was identified as a target for sumoylation
      in the analysis of the transfected cells. We investigated the localization of
      SUMO-1 protein in APP transgenic mice and mutant Tau transgenic mice, and found
      that SUMO-1 immunoreactivity was co-localized with phosphorylated Tau aggregates 
      in amyloid plaques of APP transgenic mice. By contrast, no SUMO-1
      immunoreactivity was observed in phosphorylated Tau aggregates of mutant Tau
      transgenic mice. The contribution of sumoylation to the neurodegeneration in
      Alzheimer's disease will be further elucidated via the analysis of APP
      transgenics.

UI  - 18586097
TI  - Tau hyperphosphorylation correlates with reduced methylation of protein
      phosphatase 2A.
AB  - The down-regulation of protein phosphatase 2A (PP2A) activity is thought to play 
      an important role in the formation of tau hyperphosphorylation in the Alzheimer's
      disease (AD) brain. Methylation of the PP2A catalytic subunit at the L309 site
      can potently activate PP2A for some substrates via the increasing recruitment of 
      its regulatory subunits into the holoenzyme. Abeta is overproduced yet estrogen
      is deficient in the brains of the menopausal AD patients. Both Abeta and estrogen
      deficiency can interact with tau kinases such as protein kinase B and glycogen
      synthase kinase 3. In the current study, levels of demethylated (-m) PP2A (L309) 
      were significantly increased, and methylated (+m) PP2A (L309) were significantly 
      decreased, which corresponded with the increased tau phosphorylation at the Tau-1
      and PHF-1 sites in both mouse N2a cells carrying the human APP with Swedish
      mutation (APPswe) and transgenic APPswe/presenilin (PS) 1 (A246E) mice. These
      findings were replicated in wild-type N2a cells treated with Abeta25-35, and to a
      relatively larger extent, in both wild-type N2a cells and APPswe treated by
      okadaic acid, as well as in the brains of estrogen receptor (ER) alpha-/- and
      ERbeta-/- mice that mimic the status of estrogen deficiency in menopausal AD
      patients. Together, these findings suggested that the increased demethylation of 
      PP2A (L309) mediated by Abeta overproduction or estrogen deficiency (ERalpha-/-
      and ERbeta-/-) may contribute to the reduced PP2A activity observed in the AD
      brain, resulting in the compromised dephosphorylation of abnormally
      hyperphosphorylated tau.

UI  - 18585693
TI  - Age-dependent loss of dentate gyrus granule cells in APP/PS1KI mice.
AB  - Loss of neurons in the hippocampus and other brain regions is, besides the
      occurrence of plaques and tangles, a neuropathological feature of Alzheimer's
      disease (AD). In recent years a plethora of transgenic mouse models
      overexpressing mutant amyloid precursor protein (APP) has been developed, which
      represent valuable research tools. Whereas extracellular plaque pathology is a
      common feature of these models, neuronal loss is a rather rare characteristic. In
      the present study, we quantified the number of neurons in the dentate gyrus
      granule layer (GCL) in 2- and 12-month-old APP/PS1KI mice, a mouse model that has
      been previously shown to have significant loss of neurons in the CA1 layer of the
      hippocampus. Stereological analysis revealed a strongly significant decrease of
      GCLs in aged APP/PS1KI mice, compared to age-matched PS1KI control animals
      (-44%), however, the volume of the GCL was not different.

UI  - 18583183
TI  - Interaction between certain porphyrins and CdS colloids: A steady state and time 
      resolved fluorescence quenching study.
AB  - The interaction between porphyrins namely, meso-tetrakis
      (4-methoxyphenyl)porphyrin (TMeOPP), protoporphyrin IX (PPIX) and Zinc(II)
      meso-tetraphenylporphyrin (ZnTPP) with colloidal CdS has been studied by using
      steady state and time resolved fluorescence quenching measurements. The
      porphyrins adsorbed on the surface of colloidal CdS due to electrostatic
      interaction. This adsorption leads to changes in the absorption spectra related
      to the complex formation. The apparent association constant (K(app)) was in the
      order of 4.34-5.58x10(5)M(-1) from the effect of colloidal CdS on the absorption 
      spectra and 0.64-1.6x10(5)M(-1) from fluorescence quenching data. Quenching is
      attributable mainly to static mechanism through ground state complex formation as
      confirmed by lifetime measurements.

UI  - 18583063
TI  - Subfield and layer-specific depletion in calbindin-D28K, calretinin and
      parvalbumin immunoreactivity in the dentate gyrus of amyloid precursor
      protein/presenilin 1 transgenic mice.
AB  - The depletion of neuronal calcium binding proteins deprives neurons of the
      capacity to buffer high levels of intracellular Ca(2+) and this leaves them
      vulnerable to pathological processes, such as those present in Alzheimer's
      disease (AD). The aim of the present study was to investigate the expression of
      the calcium binding proteins, calbindin-D28K, calretinin and parvalbumin in the
      dentate gyrus (DG) of amyloid precursor protein (APP)/presenilin 1 (PS1)
      transgenic (Tg) mice and their non-Tg littermates, as well as the relation with
      the deposition of human amyloid beta (Abeta). We measured the expression of these
      three proteins at seven different rostro-caudal levels, and in the molecular,
      granular and polymorphic layers of the DG. We found that, except in the most
      caudal part of the DG, there is a substantial loss of calbindin-D28K
      immunoreactivity in all three layers of the DG in APP/PS1 mice compared with the 
      non-Tg mice. Significant loss of calretinin immunoreactivity is present in most
      of the polymorphic layer of the DG of APP/PS1 mice compared with the non-Tg mice,
      as well as in the rostral and intermediate part of the inner molecular layer.
      Compared with the non-Tg mice parvalbumin immunoreactivity is significantly
      reduced throughout the whole polymorphic layer as well as in the rostral and
      intermediate part of the granular layer of DG in APP/PS1 mice. The relatively
      preservation of calbindin immunoreactivity in the caudal part of molecular and
      granular layers as well as calretinin immunoreactivity in the caudal part of
      polymorphic layer of the DG is likely related to the lower Abeta expression in
      those parts of DG. The present data suggest an involvement of calcium-dependent
      pathways in the pathogenesis of AD and indicate that there exists a subfield and 
      layer-specific decrease in immunoreactivity which is related to the type of
      calcium-binding protein in APP/PS1 mice. Moreover, it seems that APP expression
      affects more the calbindin expression then parvalbumin and calretinin expression 
      in the DG of APP/PS1 Tg mice.


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