Research Highlights

to the brain rescued performance in memory tests and restored LTP as measured in hippocampal slices. To explore the mechanisms by which FNDC5/irisin confers

Credit: Halfpoint Credit: Images/Moment/Getty neuroprotection in the setting of AD, the team applied recombinant irisin to cultured mouse hippocampal neurons that had been exposed to Aβ oligomers in vitro. Binding studies revealed no direct interaction between irisin and Aβ. However, irisin was found to stimulate a signalling pathway involved in memory formation (the cAMP–PKA–CREB pathway), which is known to be impaired in AD models. To probe the possible link between the effects of FNDC5/ irisin and exercise, the authors subjected mice to a protocol of swimming for 1 h per day, 5 days per week for 5 weeks. This activity ALZHEIMER DISEASE prevented hippocampal FNDC5/ irisin reductions and memory deficits in response to Aβ oligomers. An exercise-linked mediator In AD transgenic mice, moreover, the exercise protocol abrogated impairments in LTP, and this of memory protection protective effect was abolished by Several lines of evidence support model of AD compared with age-​ RNA knockdown of FNDC5. a dysregulation of brain energy matched controls. Exposure of rat and Importantly, in Aβ-infused​ mice, metabolism in patients with human hippocampal brain slices to peripheral administration of FNDC5 Alzheimer disease (AD). Interventions amyloid-β (Aβ) oligomers — soluble into the caudal vein prevented the to treat metabolic disease including Aβ aggregates that accumulate reduction in hippocampal FNDC5/ management and physical in the AD brain — decreased irisin and memory impairments exercise have been shown to protect FNDC5/irisin levels. Moreover, seen in mice that did not receive against AD, but the underlying intracerebroventricular infusion of FNDC5. In addition, peripheral mechanisms are not fully understood. Aβ oligomers reduced hippocampal neutralization of FNDC5 with Now, a study in Nature Medicine expression of FNDC5/irisin in antibodies in Aβ-infused mice and reports that the exercise-induced​ wild-​type mice. in AD transgenic mice abolished called irisin (and its Knockdown of FNDC5 through the protective effect of exercise precursor, FNDC5) is an important lentivirus-mediated​ delivery of short on memory. mediator of the benefit of exercise in hairpin RNA into the brains of mice The authors note that further AD, suggesting a potential new avenue led to impaired maintenance of work is needed to identify the for therapeutic development. hippocampal long-term​ potentiation receptors for irisin in the brain. are proteins secreted by (LTP; the cellular correlate of in A -infused The potential ability of peripherally β administered FNCD5/irisin to muscle tissue that act as endocrine memory formation) and of memory mice, peripheral or paracrine signalling molecules. in a novel object recognition task. reach the brain and protect against FNDC5/irisin is expressed in muscle Conversely, boosting brain levels of administration synaptic dysfunction in the context in response to exercise and was FNDC5 in mice using an adenoviral of FNDC5 into of Aβ-related​ pathology makes this known to stimulate expression of vector protected against impaired metabolic mediator an attractive the caudal vein starting point for much needed brain-derived​ neurotrophic factor performance in memory tests prevented the in the hippocampus, suggesting a following intracerebroventricular therapeutic strategies in AD. neuroprotective role in a brain region infusion of Aβ oligomers. … memory Katie Kingwell involved in learning and memory. Quantitative PCR arrays of impairments Original article Lourenco, M. V. et al. In the current study, Lourenco hippocampal expression in seen in mice Exercise-linked FNDC5/irisin rescues synaptic et al. began by measuring FNDC5/ these mice suggested FNDC5/ plasticity and memory defects in Alzheimer’s that did not models. Nat. Med. 25, 165–175 (2019) irisin levels in the context of AD. irisin might protect against aberrant Further reading Whitham, M. & Febbraio, M. A. They found reduced levels of the expression of synapse-related​ . receive FNDC5 The ever-expanding myokinome: discovery myokine in the hippocampi of late-​ In an AD transgenic mouse challenges and therapeutic implications. Nat. Rev. Drug Discov. 15, 719–729 (2016) stage AD patients and in a mouse model, adenoviral delivery of FNDC5

NAtuRe Reviews | Drug Dis­ co­ very­ volume 18 | FEBRUARY 2019 | 97