scholarly journals Deletion of the γ-secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia

Oncotarget ◽  
2016 ◽  
Vol 7 (11) ◽  
pp. 11923-11944 ◽  
Author(s):  
Fabrizio Biundo ◽  
Keita Ishiwari ◽  
Dolores Del Prete ◽  
Luciano D’Adamio
Keyword(s):  
Familial Danish Dementia

scholarly journals Proteomic Characterization of a Mouse Model of Familial Danish Dementia

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Monica Vitale ◽  
Giovanni Renzone ◽  
Shuji Matsuda ◽  
Andrea Scaloni ◽  
Luciano D'Adamio ◽  
...  
Keyword(s):  
Ion Trap ◽  
Scaffold Protein ◽  
Synaptic Function ◽  
Differentially Expressed Proteins ◽  
Wild Type ◽  
Dominant Mutation ◽  
Immunoblotting Analysis ◽  
Familial Danish Dementia ◽  
Dual Specificity

A dominant mutation in theITM2B/BRI2gene causes familial Danish dementia (FDD) in humans. To model FDD in animal systems, a knock-in approach was recently implemented in mice expressing a wild-type and mutant allele, which bears the FDD-associated mutation. Since theseFDDKImice show behavioural alterations and impaired synaptic function, we characterized their synaptosomal proteome via two-dimensional differential in-gel electrophoresis. After identification by nanoliquid chromatography coupled to electrospray-linear ion trap tandem mass spectrometry, the differentially expressed proteins were classified according to their gene ontology descriptions and their predicted functional interactions. The Dlg4/Psd95 scaffold protein and additional signalling proteins, including protein phosphatases, were revealed by STRING analysis as potential players in the altered synaptic function ofFDDKImice. Immunoblotting analysis finally demonstrated the actual downregulation of the synaptosomal scaffold protein Dlg4/Psd95 and of the dual-specificity phosphatase Dusp3 in the synaptosomes ofFDDKImice.

O4-05-05: Modeling familial danish dementia: Implications for the amyloid hypothesis of Alzheimer's disease

2010 ◽  
Vol 6 ◽  
pp. S158-S158
Author(s):  
Janaky Coomaraswamy ◽  
Ellen Kilger ◽  
Heidrun Woelfing ◽  
Claudia Schaefer ◽  
Stephan A. Kaeser ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Hypothesis ◽  
Familial Danish Dementia

scholarly journals Familial Danish dementia young Knock-in rats expressing humanized APP and human Aβ show impaired pre and postsynaptic glutamatergic transmission

2021 ◽  
Author(s):  
Tao Yin ◽  
Wen Yao ◽  
Kelly A Norris ◽  
Luciano D'Adamio
Keyword(s):  
Glutamate Release ◽  
Amyloid Β ◽  
Integral Membrane Protein ◽  
Proteolytic Processing ◽  
Glutamatergic Synapses ◽  
Short Term ◽  
Adult Mice ◽  
Familial Danish Dementia ◽  
Collateral Pathway ◽  
Proteolytic Product

Familial British and Danish dementia (FBD and FDD) are two neurodegenerative disorders caused by mutations in the Integral membrane protein 2B (ITM2b). BRI2, the protein encoded by ITM2b, tunes excitatory synaptic transmission at both pre- and post-synaptic terminus. Too, BRI2 interacts with and modulates proteolytic processing of Amyloid-β precursor Protein (APP), whose mutations cause familial forms of Alzheimer disease (FAD). To study pathogenic mechanism triggered by the Danish mutation we generated rats carrying the Danish mutation into the rat Itm2b gene (Itm2bD rats). Given the BRI2/APP interaction and the widely accepted relevance of human Aβ, a proteolytic product of APP, to AD, Itm2bD rats were engineered to express two humanized App alleles, to produce human Aβ. Here, we studied young Itm2bD rats to investigate early pathogenic changes. We found that peri-adolescent Itm2bD rats present subtle changes in human Aβ levels along with decreased spontaneous glutamate release and AMPAR-mediated responses, but increased short-term synaptic facilitation in the hippocampal Schaeffer-collateral pathway. These changes are similar to those observed in adult mice producing rodent Aβ and carrying either the Danish or British mutations into the mouse Itm2b gene. Collectively, the data show that the pathogenic Danish mutation alters the physiological function of BRI2 at glutamatergic synapses; these functional alterations are detected across species and occur early in life. Future studies will be needed to determine whether this phenomenon represents an early pathogenic event in human dementia.

P1-076: Modeling Familial Danish dementia

2008 ◽  
Vol 4 ◽  
pp. T228-T229
Author(s):  
Janaky Coomaraswamy ◽  
Heidrun Woelfing ◽  
Claudia Schaefer ◽  
Stephan A. Kaeser ◽  
Haruhiko Akiyama ◽  
...  
Keyword(s):  
Familial Danish Dementia

scholarly journals Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

2010 ◽  
Vol 107 (17) ◽  
pp. 7969-7974 ◽  
Author(s):  
Janaky Coomaraswamy ◽  
Ellen Kilger ◽  
Heidrun Wölfing ◽  
Claudia Schäfer ◽  
Stephan A. Kaeser ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Hypothesis ◽  
Familial Danish Dementia

Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia

2003 ◽  
Vol 88 (2) ◽  
pp. 281-290 ◽  
Author(s):  
Gillian Gibson ◽  
Nicola Gunasekera ◽  
Maria Lee ◽  
Victor Lelyveld ◽  
Omar M. A. El-Agnaf ◽  
...  
Keyword(s):  
Familial Danish Dementia

scholarly journals Amyloid and Tau in Neurodegeneration

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Acacia Williams ◽  
Grace Hallinan, PhD ◽  
Maria Teresa Gomez Ponce, MS ◽  
Ruben Vidal, PhD
Keyword(s):  
Cell Culture ◽  
Western Blot ◽  
Neurodegenerative Diseases ◽  
Tau Phosphorylation ◽  
Amyloid Peptide ◽  
Amyloid Angiopathy ◽  
Cell Cytotoxicity ◽  
Serum Samples ◽  
Familial Danish Dementia ◽  
C Terminus

Background and Hypothesis:Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI2 gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles.Previous studies have shown that accumulation of Danish amyloid peptide (ADan) induces hyperphosphorylation of tau and cell cytotoxicity; however, progress in our understanding of the interaction between ADan and tau has been hindered by the lack of antibodies against ADan. In addition, whether the British amyloid peptide (ABri) has a similar effect on tau phosphorylation remains unknown. The main goals of our project are to generate monoclonal antibodies against ADan and to test whether the ABri peptide induces hyperphosphorylation of tau and cell cytotoxicity. Experimental Design or Project Methods:A peptide homologous to the C-terminus of the ADan peptide was used to immunize 5 mice. Serum samples were tested from mice with high ELISA titers and the best 2 animals were used for cell fusion. Cell culture supernatants were screened by ELISA, western blot and immunohistochemistry. ABri peptides were used as negative controls.HEK cells expressing human tau were used to assess the interaction between ABri and tau. We performed immunocytochemistry and Western blot analysis to investigate tau phosphorylation. Results:A total of 11 clones tested positive by western blot. 3 clones tested positive for ABri and were discarded. 5 clones were tested by immunohistochemistry. 3 of the positive clones will be used for subcloning to complete clonality. Work in progress on the interaction between ABri and tau will determine whether ABri induces tau hyperphosphorylation in cell culture. Conclusion and Potential Impact:Our work will provide novel tools to study the interaction between amyloid and tau in neurodegenerative diseases and may uncover possible new targets for pharmaceutical intervention in tauopathies.

Inherited Amyloidoses and Neurodegeneration: Familial British Dementia and Familial Danish Dementia

2011 ◽  
pp. 439-445
Author(s):  
Tamas Revesz ◽  
Agueda Rostagno ◽  
Gordon Plant ◽  
Tammaryn Lashley ◽  
Blas Frangione ◽  
...  
Keyword(s):  
Familial British Dementia ◽  
Familial Danish Dementia
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