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P1‐204: DELETION OF A SINGLE BIN1 ALLELE DOES NOT ALTER AMYLOID PATHOLOGY IN A MOUSE MODEL OF ALZHEIMER'S DISEASE
Author(s) -
Andrew Robert J.,
De Rossi Pierre,
Guerbette Thomas,
Krause Sofia V.,
Rice Richard C.,
Rathbun Elle M.,
Thinakaran Gopal
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.209
Subject(s) - biology , allele , amyloid (mycology) , amyloidosis , alzheimer's disease , immunofluorescence , gene isoform , in vivo , pathology , microbiology and biotechnology , immunology , antibody , medicine , gene , genetics , disease , botany
Background:BIN1 was identified as the second most prevalent risk factor for late-onset Alzheimer’s disease (AD) in genome-wide association studies. A reduction in neuronal BIN1 isoform has been reported in patients with AD. Though little is known about BIN1 function in the brain, the loss of BIN1 expression has been proposed to influence BACE1 trafficking and Ab production in vitro. Methods:Mice with germline deletion of a single Bin1 allele were analysed for BACE1 and APP distribution by immunofluorescence microscopy. Following crossing to the 5XFAD model of amyloidosis, the amyloid burden was assessed at 4 months of age using mAb-3D6 (anti-Ab) and ThioflavinS staining. Endogenous Ab and soluble and insoluble Ab were measured using MesoScale Multi-plex assays. Results: Deletion of a single Bin1 allele in mice, resulted in 50% reduction in BIN1 protein levels in the brain. However, the partial loss of BIN1 expression did not grossly affect BACE1 distribution in mouse brain, alter endogenous Ab levels or cause significant cognitive or motor deficits in a range of behavioural paradigms. The loss of a single Bin1 allele in 5XFAD mice resulted in no significant difference in amyloid burden, as observed by immunofluorescence microscopy or ELISA, compared to littermate controls with two Bin1 alleles. The partial reduction in BIN1 expression did not alter behavioural deficits in 5XFAD mice associated with amyloid deposition in vivo. Conclusions:Despite prior reports of reduced neuronal BIN1 levels associated with AD and a role in BACE1 trafficking and Ab generation in vitro, reduction of BIN1 protein within the brain of non-transgenic and 5XFAD mice resulted in no significant change in amyloid production or deposition. Our results indicate that the mechanism(s) through which risk is conferred by polymorphisms in the BIN1 gene is not through a role in amyloid generation or deposition.