*4.1. Adiponectin and Brain*

Adiponectin gives a beneficial effect on synaptic regulation and memory in AD (Figure 2). It also promotes synaptic plasticity in AD by improving the hippocampal's long-term potentiation [55]. Adiponectin and its homolog, osmotin, enhance neurite outgrowth and synaptic complexity and improve learning and memory defects in mouse AD models [56–59]. Furthermore, chronic adiponectin deficiency in aged mice leads to AD-like cognitive impairments and pathologies [60]. In a recent clinical study, individuals with higher-than-normal adiponectin levels performed better in cognitive tests, indicating the protective effect of adiponectin against cognitive failure. Furthermore, the study showed that adiponectin could be used to identify the risk of cognitive dysfunction [61]. The upregulation of serum adiponectin expression has been found to be associated with MCI and AD [8]. The adiponectin receptors AdipoR1 and AdipoR2 have approximately 95% homology between human and mice. They are ubiquitously expressed and structurally related in humans and mice, with variable affinity to different isoforms and predominance in some tissues [62]. The expression of AdipoR1 and AdipoR2 is mainly localized to neurons in the hypothalamus, brainstem, and cortex [22],

as well as the nucleus basalis of Meynert and the hippocampus, the two main targeted structures in AD [63]. In the hypothalamus and the brainstem, adiponectin is thought to regulate food intake and energy expenditure via AdipoR1-mediated AMPK signaling [23]. However, low levels of adiponectin in CSF may be compensated by the presence of two high-affinity receptors, AdipoR1 and AdipoR2, in the brain [64,65]. Suppression of AdipoR1 can result in metabolic diseases such as obesity and diabetes, which also potentiate spatial learning deficit, memory impairment, and AD pathologies [30]. Hence, studies have evaluated adiponectin and its receptors as therapeutic alternatives for AD.

**Figure 2.** Downregulation of adiponectin involved in the mechanism of Alzheimer's disease exacerbates AD pathology and impairment.

In AD, Aβhas to cross BBB to be transported in the brain, where it is regulated by specific receptors and transporters [66]. Therefore, it is necessary to protect BBB disruption. Adiponectin protects BBB disruption by inhibiting apoptosis of endothelial cells, protecting tight junction integrity via the AdipoR1-mediated NF-κB pathway, and maintaining the balance of Aβ transporters in endothelial cells [67].
