Appl1, short for Adaptor protein containing a PH domain, PTB domain and leucine zipper motif 1, is a multifunctional endosomal signaling adaptor protein [2]. It plays a central role in adiponectin, insulin, and follicle-stimulating hormone signaling pathways [1]. Also, it is involved in many biological processes such as cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling [4]. Genetic models, like mouse models, have been crucial in understanding its functions.

In mouse model systems, recent studies have shown that Appl1 deficiency can lead to metabolic and vascular disorders, while its presence can prevent diabetes, endothelial disorders, and insulin resistance [1]. In neurons, over-expressing human Appl1 in transgenic mice (Thy1-Appl1 mice) leads to enlarged neuronal early endosomes, increased synaptic endocytosis, hippocampal long-term potentiation and depression changes, degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting its role in Alzheimer's-like pathologies [3]. In macrophages, deletion of Appl1 impairs mitophagy, leading to NLRP3 inflammasome over-activation and making mice more sensitive to endotoxin-induced sepsis, obesity-induced inflammation, and glucose dysregulation [5]. Additionally, Appl1 knockdown in 3T3-L1 preadipocytes blocks adipogenic differentiation and promotes adipocyte lipolysis, suggesting its role in adipocyte biology [6].

In conclusion, Appl1 is essential in multiple signaling pathways and biological processes. Model-based research, especially using Appl1 knockout or conditional knockout mouse models, has revealed its significance in diseases such as polycystic ovary syndrome, Alzheimer's disease, metabolic and vascular disorders, and adipocyte-related pathologies. These findings contribute to a better understanding of the underlying mechanisms and potential therapeutic strategies for these diseases.