Gonadotropin-releasing hormone (GnRH) therapy improves cognitive function in Down syndrome (DS) mouse models and male patients with DS, according to a new study. The findings reveal a previously underappreciated role of GnRH – a hormone commonly associated with fertility and reproduction – in olfaction and cognition and offer a promising pathway toward therapies that could improve the cognitive deficits in DS.
Down syndrome, also known as trisomy 21, is the most common genetic cause of intellectual disability and occurs in one in 30 pregnancies for women aged 45 or more and is caused by having 3 copies of chromosome 21 instead of the usual 2. Among the various clinical manifestations associated with the condition, many adult DS patients experience symptoms like those of early-onset Alzheimer's disease, as well as a gradual loss of olfaction.
Additionally, men with DS may also display deficits in sexual maturation. Currently, however, there are no viable treatment options for the cognitive and olfactory deficits associated with DS. Recent research has suggested that olfaction loss and male infertility is also a characteristic of GnRH deficiency, and that GnRH may play a role in higher brain functions, such as cognition. Whether GnRH plays a role in DS pathology isn't fully understood. In a mouse model of DS, Maria Manfredi-Lozano and colleagues discovered that strands of microRNA regulating the production of GnRH – which are found on chromosome 21 – were dysfunctional, resulting in abnormalities in the neurons that secrete the hormone. Manfredi-Lozano et al. show that epigenetic, cellular, chemogenic, and pharmacological interventions that restore GnRH functions reversed olfactory and cognitive defects in DS mice as well as in a mouse model of Alzheimer's disease.
Building on these findings, the authors conducted a pilot clinical trial to assess the effects of GnRH therapy on cognition in seven adult male DS patients. While the treatment did not affect olfaction, cognitive performance increased in all but one of the participants. In a related Perspective, Hanne Hoffmann discusses the study and its implications in greater detail.
Manfredi-Lozano, M., et al. (2022) GnRH replacement rescues cognition in Down Syndrome. Science. doi.org/10.1126/science.abq4515.