Adiponectin as a new paradigm for approaching Alzheimer's disease.

Adiponectin is an adipocytokine released by the adipose tissue and has multiple roles in the immune system and in the metabolic syndromes such as cardiovascular disease, Type 2 diabetes, obesity and also in the neurodegenerative disorders including Alzheimer's disease. Adiponectin regulates the sensitivity of insulin, fatty acid catabolism, glucose homeostasis and anti-inflammatory system through various mechanisms. Previous studies demonstrated that adiponectin modulates memory and cognitive impairment and contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease. Here, we aim to summarize recent studies that suggest the potential correlation between adiponectin and Alzheimer's disease.

Introduction

Adiponectin is a protein hormone and an adipocytokine released by the adipose tissue. Adiponectin has an N-terminal collagen-like domain and a C-terminal complement factor C1q-like globular domain and circulates as trimers, hexamers, and a high molecular weight form. Adiponectin acts by binding to its receptors, adiponectin receptor type 1 and type 2. Adiponectin receptors are expressed in skeletal muscle, liver, hypothalamus and vascular endothelial cells of brain [1-3]. Adiponectin has important roles in the metabolic syndromes such as obesity, cardiovascular disease, type 2 diabetes and also neurodegenerative disorders [4-11]. In the central nervous system (CNS), previous studies suggest the neuroprotective effects of adiponectin [12, 13]. 2013Adiponectin was shown to be present in the cerebrospinal fluid of rodents [14, 15] and human [16-19]. In addition, adiponectin modulates the sensitivity of insulin in brain [20-22]. Also, adiponectin has a cardinal role in immune system in the CNS. Adiponectin decreases the expression of pro-inflammatory cytokines [23] and increases the expression of anti-inflammatory molecules [24]. To sum up, adiponectin has important functions as a regulator of glucose homeostasis and insulin mechanism and immune system. Therefore, adiponectin suggested as a potential target to cure CNS diseases.

The Effect of Adiponectin on Brain Insulin System

Insulin plays multiple roles for neuronal function and survival. In Alzheimer's disease brain, level of insulin and insulin like growth factor-1 (IGF-1) decreases definitely compared to normal brain [25, 26]. Both the expression and function of insulin and IGF-1 deteriorate with progression of Alzheimer's disease [27]. Adiponectin-mediated activation of AMP-activated protein kinase, the p38 mitogen-activated protein kinase and Rab5 leads to increased glucose transporter 4 membrane translocation [28, 29]. Adiponectin modulates the sensitivity of insulin, glucose metabolism [20-22]. In rodents, the deletion of adiponectin gene leads to insulin resistance [30, 31]. In humans, a reduced serum concentration of adiponectin incurs obesity, insulin resistance and type 2 diabetes [32-34]. Impaired proximal signaling of insulin receptor also mediates insulin resistance. Decreased insulin receptor substrate (IRS) protein levels contribute insulin resistance in rodents and humans [35]. The IRS protein levels decrease in streptozotocin induced dementia rat model which have used to study Alzheimer's disease as animal model compared with sham group (normal control group) in the hippocampus (Fig. 1A) and in the cortex (Fig. 1B). In Alzheimer's disease, insulin system dysfunction incurs severe pathology such as cognitive decline suggesting that adiponectin could be an important target for Alzheimer's disease.

Fig. 1

The phospholylation of insulin receptor substrate (IRS)-1 in streptozotocin (STZ) induced dementia rat model. To confirm the dysfunction of brain insulin system in STZ-induced dementia rat model known as common animal model to study Alzheimer's disease in vivo, we conducted immunohistochemistry using phospho IRS-1 antibody. (A) In the hippocampus, phospholylation of IRS-1 decreased in the STZ induced dementia group compared with sham (control group). (B) In the cortex, phospholylation of IRS-1 decreased in the STZ induced dementia group compared with sham (control group). Green color, phospho IRS-1; red color, propidium iodide (PI).

The Role of Adiponectin on Neuroinflammation

Adiponectin has a cardinal role in immune system in CNS. Adiponectin is the most abundant anti-inflammatory adipokine and decreases the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) [23] and increases the expression of anti-inflammatory molecules such as interleukin (IL)-10, IL-1 receptor antagonist [24] and decreases the activation of the pro-inflammatory signal pathway such as nuclear factor-κB pathway [21, 23]. In the brain endothelial cell, adiponectin reduces secretion of IL-6 as a pro-inflammatory cytokine [6]. As pro-inflammatory factors such as TNF-α, IL-6, reactive oxygen species suppress the expression of adiponectin in adipocytes, adiponectin levels are decreased in obese rodents and humans [36]. In addition, adiponectin modulates T cells activation. Adiponectin receptors are upregulated on the surface of human T cells after antigen stimulation and mediate apoptosis of antigen specific T cells resulting in the suppression of antigen specific T cells expansion [37]. Also, adiponectin modulates the inflammatory function of natural killer cells [38]. Visceral adipose tissue is positively associated with risk of insulin resistance and shows higher monocytes infiltration and IL-6 production than subcutaneous adipose tissue [39, 40]. TNF-α also induces serine phosphorylation of IRS1 to modulate the downstream effectors of the insulin receptor resulting in insulin resistance [41]. Th17 CD4+ T cells are not involved in the inflammation of obese mice [42]. Cytotoxic CD8+ T cells are significantly increased in adipose tissues of obese mice, and depletion of CD8+ T cells reverses inflammation and insulin resistance suggesting that obesity-induced infiltration of CD8+ T cells deteriorate systemic insulin sensitivity [43]. Various immune responses relate with brain insulin resistance and adiponectin involves the relationship between immune responses and insulin resistance. Collectively, adiponectin has multiple roles in immune system and affects brain insulin system. Hence, adiponectin may be a promising target for curing Alzheimer's disease which associates with inflammation and insulin resistance.

The Potential of Adiponectin to Target Alzheimer's Disease

Adiponectin modulates brain metabolism and sensitivity of insulin [1, 44] regulating memory and cognitive dysfunction [45] and it also regulates severe inflammaion observed in mild cognitive impairment and Alzheimer's disease [46-48]. In particular, adiponectin contributes to the deregulated glucose metabolism and mitochondrial dysfunction observed in Alzheimer's disease [49, 50]. Specifically, adiponectin increase in blood insulin, not glucose level in Alzheimer's disease [51]. Insulin dysregulation contribute to Alzheimer's disease pathologies by several mechanisms from reduced brain gulcose utilization to neurofibrillary tangle formation and increased amyloid β aggregation by insulin degrading enzyme inhibition [35-38, 52, 53]. Insulin affects neuronal cognition and memory through several levels by regulating ion channels, neurotransmitter receptors and synaptic transmission in Alzheimer's disease brain [39, 40]. Amyloid β accumulation induces the oxidative stress and mitochondrial dysfunction, and these dysfunctions induces Alzheimer's disease pathogenesis [54-56]. Adiponectin is protective against amyloid β neurotoxicity in Alzheimer's disease [57]. Adiponectin modulates amyloid β in Alzheimer's disease and so improves cognition [58]. Previous studies demonstrate that the insulin sensitizing action of adiponectin may be another mechanism of neuroprotection in Alzheimer's disease [59, 60]. In conclusion, adiponectin has a important role in brain insulin dysfunction and amyloid β neurotoxicity and immune system through a variety of machanisms. Thus, adiponectin is a potential target to treat Alzheimer's disease.

Future Perspective

Adiponectin associates with various disease including diabetes, obesity, cardiovascular disease and neurodegenerative diseases. Adiponectin plays multiple roles for enhancing related pathologies such as insulin resistance, hypertention, hyperlipidemia, inflammation, cognitive impairment, atherosclerosis (Table 1). Specifically, adiponectin regulates the sensitivity of insulin and modulates the immune system and enhances memory and cognitive impairment known as common pathologies of Alzheimer's disease. Thus, adiponectin may be a promising therapeutic target to alleviate Alzheimer's disease pathologies such as apoptosis and cognitive decline and dysfunctional brain insulin system.

Table 1

Adiponectin related diseases and pathologies