Interaction of BIN1 and Tau: physiological functions and pathological consequences in Alzheimer’s disease. – BINALZ

In order to address these relevant questions, we intend to evaluate BIN1's involvement in the AD process by:
(i) Characterizing potential modulators of the BIN1-Tau interaction, e.g. specific phosphorylation sites.
(ii) Characterizing the physiological and physiopathological implications of the Tau-BIN1 interaction with regard to Abeta peptide or glutamate exposure.
(iii) Determining BIN1 partners that are likely to modulate both the normal and harmful consequences of the Tau-BIN1 interaction (through the combined use of proteomics, high-content screening and Drosophila models).
(iv) Developing and studying transgenic mouse models that conditionally under- or over-express BIN1 in neurons and develop (or do not develop) AD lesions, e.g. tauopathy.

During this 18 months, we have set-up most of methodologies and models required for this project and we have generated some results. In particular, we have characterised a new mechanism of regulation of the BIN1-Tau interaction. We also fully characterised the Tau phosphorylation sites involved in this interaction.
In addition, the Tg(BIN1)16 mice have been well characterised and we already demonstrated that that BIN1 can potentate the Tau deficit.

By probing BIN1's involvement in AD, this multidisciplinary project will improve our understanding of the AD process and should enable us to determine whether BIN1 and its cellular pathways are potential drug targets.

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Alzheimer's disease (AD) is the leading cause of dementia. The main pathological features of AD are neurofibrillary tangles and senile plaque formation. The latter is caused by the progressive deposition of amyloid ß protein (Aß) in the brain.
There is no longer any doubt that a strong genetic predisposition to AD exists (accounting for 60% to 80% of the attributable risk). To characterize genetic components in AD, we and others have developed systematic, high-throughput genomic approaches (as part of genome-wide association studies, GWASs) and recently reported the characterization of 21 common genetic determinants of AD, including the bridging integrator 1 gene (BIN1). This gene currently ranks second after APOE in the AlzGene database of published meta-analyzed AD risk loci. However, the genetic and molecular mechanisms by which BIN1 affects the AD risk are not known.
We recently studied the molecular mechanism by which BIN1 protein might modulate the disease process in AD. Taken as a whole, our data suggest that BIN1 AD risk variants are associated with BIN1 expression and modulate AD pathogenesis through Tau rather than through an amyloid pathway. We have also identified genetic, neuropathologic and biochemical interactions between Tau and BIN1 in vitro and in vivo. Furthermore, we have performed a detailed characterization of the BIN1 and Tau protein interaction domains (unpublished data). In conclusion, we have potentially identified the first genetic risk factor for AD linked to tauopathy (Chapuis et al, Mol Psychiatry, 2013).

Our results raise important new questions about BIN1's involvement in the AD process:
(i) How are these interactions controlled?
(ii) What are the physiological and disease-state consequences of these interactions?
(iii) Which partners modulate these interactions and thus may be involved in the AD process?
(iv) How do BIN1 over-expression and its interaction with Tau modify the development of the AD process?

In order to address these relevant questions, we intend to evaluate BIN1's involvement in the AD process by:
(i) Characterizing potential modulators of the BIN1-Tau interaction, i.e. specific phosphorylation status of Tau or BIN1.
(ii) Characterizing the physiological and physiopathological implications of the Tau-BIN1 interaction with regard to A? peptide or glutamate exposure.
(iii) Determining BIN1 partners that are likely to modulate both the normal and harmful consequences of the Tau-BIN1 interaction (through the combined use of proteomics, high-content screening and Drosophila models).
(iv) Developing and studying transgenic mouse models that conditionally under- or over-express BIN1 in neurons and develop (or do not develop) AD lesions, e.g. tauopathy.

By probing BIN1's involvement in AD, this multidisciplinary project will improve our understanding of the AD process and should enable us to determine whether BIN1 and its cellular pathways are potential drug targets.