Abstract
BIN1 is the most important risk locus for Late Onset Alzheimer’s Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing Tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation.
Highlights
Alzheimer’s disease (AD) is the most common form of aging-related dementia currently affecting an estimated 5.7 million Americans
We focused on the relationship between Bridging INtegrator 1 (BIN1) and neuronal loss in the context of Tau pathology[1,2,3], based on the correlation between AD-associated BIN1 Single Nucleotide Polymorphisms (SNPs) and expression levels with Tau deposition[20,28], as well as with various brain morphometric measurements [21], [24][25]
Our analysis showing decreased detection of neuronal Bin1 in the brains of human Tau P301S expressing mice replicates what has been observed in post-mortem brain samples of AD-affected individuals[20],[21], and validate PS19 as a suitable in vivo model to understand the contribution of BIN1 to AD-like neuropathology
Summary
Alzheimer’s disease (AD) is the most common form of aging-related dementia currently affecting an estimated 5.7 million Americans (www.alz.org). AD is characterized by cognitive decline associated with accumulation of Amyloid β (Aβ plaques), hyper-phosphorylated misfolded Tau, and neuronal loss [1,2,3]. Susceptibility loci that contribute to Late Onset of AD (LOAD) have been identified by Genome Wide Association Studies (GWAS). Among them, noncoding Single Nucleotide Polymorphisms (SNPs) associated with the gene expressing. R.M.R. is an employee of Third Rock Venture Capital, C.R. is an employee of the Genomic Institute of The Novartis Research Foundation. A.C. is an employee of Astellas Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials
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