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RSS FeedsReduction of the expression of the late-onset Alzheimer`s disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model [Molecular Bases of Disease] (Journal of Biological Chemistry)

 
 

22 march 2019 09:00:41

 
Reduction of the expression of the late-onset Alzheimer`s disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model [Molecular Bases of Disease] (Journal of Biological Chemistry)
 




Alzheimer`s disease (AD) is pathologically characterized by the deposition of the ?-amyloid (A?) peptide in senile plaques in the brain, leading to neuronal dysfunction and eventual decline in cognitive function. Genome-wide association studies have identified the bridging integrator 1 (BIN1) gene within the second most significant susceptibility locus for late-onset AD. BIN1 is a member of the amphiphysin family of proteins and has reported roles in the generation of membrane curvature and endocytosis. Endocytic dysfunction is a pathological feature of AD, and endocytosis of the amyloid precursor protein is an important step in its subsequent cleavage by ?-secretase (BACE1). In vitro evidence implicates BIN1 in endosomal sorting of BACE1 and A? generation in neurons, but a role for BIN1 in this process in vivo is yet to be described. Here, using biochemical and immunohistochemistry analyses we report that a 50% global reduction of BIN1 protein levels resulting from a single Bin1 allele deletion in mice does not change BACE1 levels or localization in vivo, nor does this reduction alter the production of endogenous murine A? in nontransgenic mice. Furthermore, we found that reduction of BIN1 levels in the 5XFAD mouse model of amyloidosis does not alter A? deposition nor behavioral deficits associated with cerebral amyloid burden. Finally, a conditional BIN1 knockout in excitatory neurons did not alter BACE1, APP, C-terminal fragments derived from BACE1 cleavage of APP, or endogenous A? levels. These results indicate that BIN1 function does not regulate A? generation in vivo.


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14 viewsCategory: Biochemistry
 
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