Gut-brain connections in neurodegenerative disease: immunotherapeutic targeting of Bin1 in inflammatory bowel disease and Alzheimer's disease.

Longer lifespan produces risks of age-associated neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by declines in memory and cognitive function. The pathogenic causes of AD are thought to reflect a progressive aggregation in the brain of amyloid plaques composed of beta-amyloid (Aß) peptides and neurofibrillary tangles composed of phosphorylated tau protein. Recently, long-standing investigations of the Aß disease hypothesis gained support via a passive immunotherapy targeting soluble Aß protein. Tau-targeting approaches using antibodies are also being pursued as a therapeutic approach to AD. In genome-wide association studies, the disease modifier gene Bin1 has been identified as a top risk factor for late-onset AD in human populations, with recent studies suggesting that Bin1 binds tau and influences its extracellular deposition. Interestingly, before AD emerges in the brain, tau levels rise in the colon, where Bin1-a modifier of tissue barrier function and inflammation-acts to promote inflammatory bowel disease (IBD). This connection is provocative given clinical evidence of gut-brain communication in age-associated neurodegenerative disorders, including AD. In this review, we discuss a Bin1-targeting passive immunotherapy developed in our laboratory to treat IBD that may offer a strategy to indirectly reduce tau deposition and limit AD onset or progression.