Alzheimer\'s disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study\'s team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1\'s processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.

OBJECTIVE: To investigate the effects of hippotherapy for adult patients with brain disorders.
METHODS: Eight chronic brain disorder patients (7 males, mean age 42.4±16.6 years) were recruited. The mean duration from injury was 7.9±7.7 years. The diagnoses were stroke (n=5), traumatic brain disorder (n=2), and cerebral palsy (n=1). Hippotherapy sessions were conducted twice a week for eight consecutive weeks in an indoor riding arena. Each hippotherapy session lasted 30 minutes. All participants were evaluated by the Berg balance scale, Tinetti Performance-Oriented Mobility Assessment, 10 Meter Walking Test, Functional Ambulatory Category, Korean Beck Depression Inventory, and Hamilton Depression Rating Scale. We performed baseline assessments twice just before starting hippotherapy. We also assessed the participants immediately after hippotherapy and at eight weeks after hippotherapy.
RESULTS: All participants showed no difference in balance, gait function, and emotion between the two baseline assessments before hippotherapy. During the eight-week hippotherapy program, all participants showed neither adverse effects nor any accidents; all had good compliance. After hippotherapy, there were significant improvements in balance and gait speed in comparison with the baseline assessment (p<0.05), and these effects were sustained for two months after hippotherapy. However, there was no significant difference in emotion after hippotherapy.
CONCLUSIONS: We could observe hippotherapy to be a safe and effective alternative therapy for adult patients with brain disorders in improving balance and gait function. Further future studies are warranted to delineate the benefits of hippotherapy on chronic stroke patients.