A locus upstream of the gene BIN1 is second only to the apolipoprotein E locus as a genetic determinant of Alzheimer disease (AD) susceptibility, but the underlying mechanism has been unclear. Now, Jean-Charles Lambert and coworkers have identified an insertion allele upstream of BIN1 that increases expression of this gene and seems to be involved in the tau pathway of AD pathology.

BIN1 is involved in numerous cellular processes, including endocytosis and regulation of cytoskeletal dynamics. “To begin to lift the veil from the role of BIN1 in AD, we adopted a multidisciplinary approach including molecular and functional genetics, cell biology, neuropathology and Drosophila biology,” says Lambert.

The researchers began by measuring BIN1 expression in human brain samples, and found increased BIN1 transcripts in AD brains compared with brains of control individuals. Genetic analysis of three independent AD case–control cohorts led to identification of a variant (rs59335482; an insertion of three C bases) ∼28 kb upstream of BIN1 that is associated with increased AD risk. In cell culture, this insertion allele was found to increase BIN1 expression.

Together, the studies in humans suggested that increased expression of BIN1 caused by the genetic variant led to increased risk of AD. To investigate the pathological underpinnings, Lambert and colleagues next turned to studies in Drosophila.

Neuronal overexpression of amyloid-β or tau, two key players in AD pathology, leads to rough-eye phenotype in these flies. Knockdown of Amph, the Drosophila homologue of BIN1, had no effect on amyloid-β-induced pathology but, importantly, ameliorated the rough-eye phenotype in tau-overexpressing flies.

To further investigate the possible interaction between Amph and tau in the brain, the team focused on the mushroom bodies—part of the Drosophila brain that, like the hippocampus in humans, is involved in learning and memory. Tau overexpression caused ablation of mushroom bodies, but knockdown of Amph enabled development of this brain area, and near-normal mushroom body morphology in some flies.

Finally, reciprocal immunoprecipitation studies in human neuroblastoma cells transfected with BIN1 and tau, and in wild-type mouse brain homogenates, suggested physical interaction between the two proteins at the physiological level.

“If confirmed, BIN1 would be the first genetic risk factor for AD linked to the tau pathway,” says Lambert.