Brainwave Discovery is dedicated to the discovery and development of new drugs to combat Alzheimer's Disease. To find out more about our technology and partnering opportunities please email us.

info@brainwave-discovery.com

Amphiphysins: budding candidate genes in Alzheimer's disease

Recent genome-wide association studies (GWAS: e.g. Seshadri et al., 2010) have consistently identified variants of the human BIN1 gene as genetic factors in late-onset (i.e. standard) Alzheimer's disease, responsible for around 4% of the genetic input to this disease. In the United States alone, 5.4 million people are living with Alzheimer's*, so in population health terms BIN1 variants exert a massive effect.

BIN1 (bridging integrator 1) protein is also known as amphiphysin 2. Amphiphysin was first discovered in Drosophila thirty years ago (Poodry and Edgar, 1979), so Drosophila is an ideal place to investigate the role of amphiphysins in APP metabolism and Alzheimer's disease pathology. The Drosophila protein has significant sequence and functional homology with mammalian amphiphysins (Razzaq, 2000).

In mammals, amphiphysins 1 and 2 form a heterodimer (Wigge et al., 1997) that is well known to be a component of the molecular machinery of membrane recycling, including that of synaptic vesicles after they fuse with the presynaptic membrane. Amphiphysin 1 is primarily brain expressed, while BIN1 has a major brain expressed isoform and other isoforms that are expressed elsewhere, notably in skeletal and cardiac muscle. A mouse gene knock-out strain for AMPH (amphiphysin 1) shows partial defects in synaptic vesicle recycling, learning defects, occasional irreversible seizures and instability of the brain isoform of amphiphysin 2 (Di Paolo et al., 2002).

The amphiphysins are proteins that can deform membranes, and various isoforms have domains that bind other proteins (such as clathrin and AP2). The membrane deformation properties of the muscle BIN1 isoform determine its crucial role in the formation of T tubules in skeletal muscle, and loss-of-function variants of human BIN1 cause some versions of the muscle disease centronuclear myopathy (Böhm et al., 2010).

Metaanalysis of four large studies shows that genetic variation in BIN1, notably the BIN1 SNP rs744373, is linked to the occurrence of late-onset Alzheimer's. The biological mechanism is poorly understood. Gene ontology analysis identified BIN1 within a set of vesicle-mediated transport genes, all of which are linked statistically to Alzheimer's: BIN1, PICALM, SORL1, APOE, LDLR and CLU (Olgiati et al., 2011).

Drosophila is the only system in which interactions between multiple variants of multiple genes can be modelled and studied in a reasonable time frame and cost.

BIN1 is just one of the human proteins which Brainwave Discovery Ltd. is expressing in Drosophila synapses. We can help you better understand the effect of BIN1 variants in an Alzheimer's disease background, and test the effects that your compounds have on neurodegeneration We also link in to a Europe-wide synaptic analysis network, SynSys (SynSys). For more information check out our website or contact info@brainwave-discovery.com

*www.alz.org Alzheimer's association website

References:

<< Previous blog entry: FynD

>> Next blog entry: Synsys