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NEURAL REGENERATION RESEARCH Review Abstract Alzheimer’s disease is the primary cause of dementia and imposes a significant socioeconomic burden globally.

Physical exercise, as an effective strategy for improving general health, has been largely reported for its effectiveness in slowing neurodegeneration and increasing brain functional plasticity, particularly in aging brains.

However, the underlying mechanisms of exercise in cognitive aging remain largely unclear.

Adiponectin, a cell-secreted protein hormone, has recently been found to regulate synaptic plasticity and mediate the antidepressant effects of physical exercise.

Studies on the neuroprotective effects of adiponectin have revealed potential innovative treatments for Alzheimer’s disease.

Here, we reviewed the functions of adiponectin and its receptor in the brains of human and animal models of cognitive impairment.

We summarized the role of adiponectin in Alzheimer’s disease, focusing on its impact on energy metabolism, insulin resistance, and inflammation.

We also discuss how exercise increases adiponectin secretion and its potential benefits for learning and memory.

Finally, we highlight the latest research on chemical compounds that mimic exercise- enhanced secretion of adiponectin and its receptor in Alzheimer’s disease.

Key Words: adiponectin receptor agonists; adiponectin; Alzheimer’s disease; amyloid-β; hippocampus; learning and memory; physical exercise; Tau Introduction Alzheimer’s disease (AD) is one of the most common neurodegenerative illnesses that causes dementia in older individuals.

It is characterized by the accumulation of amyloid-β (Aβ) and tau pathology in the brain (Knopman et al., 2021; Suresh et al., 2021).

Although many pharmacological and non-pharmacological interventions have been implemented, no treatments can halt the neurodegeneration process, possibly owing to an insufficient understanding of the key neuropathology underlying AD.

Physical exercise not only is known to improve mood disorders, metabolic dysregulation, such as obesity, cardiorespiratory fitness, and general health (van der Heijden et al., 2013; Vargas- Terrones et al., 2019; O’Donoghue et al., 2021; Fernández-Rodríguez et al., 2022), but it is also recognized as an effective non-pharmaceutical therapy to treat/prevent AD-associated cognitive and executive functions (Russo-Neustadt et al., 1999; Larson et al., 2006; Yau et al., 2014; Duzel et al., 2016; De la Rosa et al., 2020).

Emerging animal studies have demonstrated that physical exercise may play a role in reversing memory and learning deficits, possibly through neuroprotective effects promoting adult neurogenesis (Yau, et al., 2014), increasing the levels of hippocampal neurotrophic factors (Russo-Neustadt et al., 1999; Belaya et al., 2020; Wang et al., 2020a), promoting synaptic plasticity and dendritic complexity (Lourenco et al., 2019; Belaya et al., 2020), and ameliorating Aβ oligomer neurotoxicity or tau pathology (Brown et al., 2019; Tan et al., 2021; Zhang et al., 2021).

However, how physical exercise elicits neuroprotective effects in the brain remains largely unclear.

The cognitive benefits of physical exercise are linked to activated adiponectin (ADPN) signaling hormone that is expressed in multiple isoforms as Judd, 2018; Abou-Samra et al., 2020).

Studies have shown that ADPN mimetics significantly prevent/ treat neurocognitive disorders (Ali et al., 2015, 2021; Badshah et al., 2016; Ng et al., 2021).

In this review, we summarize the functions of ADPN signaling in the brain, focusing on the effects of ADPN on the regulation of cognition.

We also summarize the potential molecular mechanisms of ADPN in mediating the neuroprotective effects of physical exercise, providing insights into ADPN- based applications in the treatment of AD.

Search Strategy For this review, we conducted a search on Web of Science and PubMed using keywords, including “Alzheimer’s disease,” “adiponectin,” “exercise or physical activity,” “Alzheimer’s disease and hippocampus,” “adiponectin receptor,” “tau and adiponectin,” “tau and Alzheimer’s disease,” “Aβ 1Department of Rehabilitation Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong Province, China; 2Department of Rehabilitation Medicine, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, China; 3Department of Rehabilitation, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province, China; 4The Second Institute of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China; 5Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China; 6Mental Health Research Center, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, China *Correspondence to: Hector Wing Hong Tsang, PhD, hector.tsang@polyu.edu.hk; Suk-Yu Yau, PhD, sonata.yau@polyu.edu.hk.

(Hector Wing Hong Tsang); (Suk-Yu Yau)