Ismael Bracho-Valdés

Currently, approximately 40% of patients with dementia develop some form of sleep disorder. Benzodiazepines are widely prescribed but pose the risk of tolerance and cognitive decline; however, Z-drugs may offer safer alternatives. Therefore, this systematic review aimed to analyze the effect of benzodiazepines and Z-drugs on sleep disorders in patients with dementia. Two authors conducted a systematic search in PubMed, Scopus, Web of Science, Espistemonikos, and ACCESSSS for studies published between 2019 and 2024 using the MeSH terms “dementia”, “sleep disorders”, and “pharmacotherapy”. Randomized clinical trials comparing benzodiazepines, Z-drugs, or innovative medications with placebo or other drugs were included. Sleep and cognitive outcomes were assessed using validated instruments; the ROB-2 tool evaluated the risk of bias. The protocol was registered in “PROSPERO”. Three randomized clinical trials involving a total of 192 patients were included in the review. Zopiclone increased the main duration of nighttime sleep by 81 min, Zolpidem reduced nighttime awakenings by 21 min, and Eszopiclone improved sleep quality, benefited the progression of sleep architecture, and reduced mental symptoms such as fear and anxiety. Z-drugs show superior efficacy and safety over benzodiazepines, improving sleep and cognitive symptoms in dementia. Personalized treatment and further research across dementia subtypes are needed to optimize long-term outcomes.

The serine-threonine kinase Akt plays a fundamental role in cell survival, metabolism, proliferation, and migration. To keep these essential processes under control, Akt activity and stability must be tightly regulated; otherwise, life-threatening conditions might prevail. Although it is well understood that phosphorylation regulates Akt activity, much remains to be known about how its stability is maintained. Here, we characterize BAG5, a chaperone regulator, as a novel Akt-interactor and substrate that attenuates Akt stability together with Hsp70. BAG5 switches monoubiquitination to polyubiquitination of Akt and increases its degradation caused by Hsp90 inhibition and Hsp70 overexpression. Akt interacts with BAG5 at the linker region that joins the first and second BAG domains and phosphorylates the first BAG domain. The Akt-BAG5 complex is formed in serum-starved conditions and dissociates in response to HGF, coincident with BAG5 phosphorylation. BAG5 knockdown attenuated Akt degradation and facilitated its activation, whereas the opposite effect was caused by BAG5 overexpression. Altogether, our results indicate that Akt stability and signaling are dynamically regulated by BAG5, depending on growth factor availability.