Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer’s disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology have not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AβPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-β 40 (Aβ40) and Aβ42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aβ plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AβPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

Ubiquilin‐1 (Ubqln1), a ubiquitin‐like protein, is implicated in a variety of pathophysiological processes, but its role in mediating body weight gain or metabolism has not been determined. Here, we demonstrate that global overexpression of Ubqln1 in a transgenic (Tg) mouse reduces the animal's body weight gain. The decreased body weight gain in Tg mice is associated with lower visceral fat content and higher metabolic rate. The Ubqln1 Tg mice exhibited reduced leptin and insulin levels as well as increased insulin sensitivity manifested by homeostatic model assessment of insulin resistance. Additionally, the reduced body weight in Tg mice was associated with the upregulation of two energy‐sensing proteins, sirtuin1 (SIRT1) in the hypothalamus and AMP‐activated protein kinase (AMPK) in the skeletal muscle. Consistent with the in vivo results, overexpression of Ubqln1 significantly increased SIRT1 and AMPK levels in the mouse embryonic fibroblast cell culture. Thus, our results not only establish the link between Ubqln1 and body weight regulation but also indicate that the metabolic function of Ubqln1 on body weight may be through regulating energy‐sensing proteins.