Jia-Qi Zhao, Xiao-Qing Li, Yi-Ming Zhang, Mei-tong Guo, Cheng Han, Yang Shen, Qi Zhang, Shi-Feng Chu,Nai-hong Chen, Wen-Bin He,*

1Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Taiyuan, China;

2Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, China.

Abstract Alzheimer’s disease as one of the neurodegenerative diseases, its pathological mechanisms still remains unclear. There’s evidence that diabetes is associated with Alzheimer’s disease. However, the fundamental cause of diabetes is abnormal glucose metabolism. There may be an inseparable relationship between glucose metabolism regulating hormones and Alzheimer’s disease. Here, we review the studies that connect the glucose metabolism regulating hormones to Alzheimer’s disease, and that suggest the quality of Alzheimer’s patients is improved by regulating glucose metabolism.

Keywords: Alzheimer’s disease; Diabetes; Glucose metabolism; Glucose metabolism regulating hormones

Background

At present, China has the largest number of patients who are suffering from Alzheimer’s disease (AD) in the world[1]. According to the World Health Organization, by 2050,there will be more than 100 million patients suffer from AD. AD is a kind of neurodegenerative diseases, the classic pathological changes are senile plaques and neurofibrillary tangles (NFTs) arising, which are formed by beta-amyloid (Aβ) and excessive phosphorylated tau protein, and initiate the neurons’ lost and the glial cells’proliferation. Emergent evidence suggests that diabetes influence cognitive function and increases the incidence of AD [2-3]. Therefore, it suggested that AD may be a metabolic disease, even referred to as “type 3 diabetes”[4]. Moreover, numerous epidemiological studies have also demonstrated that patients with diabetes have a distinctly higher risk of developing AD [5]. The root cause of diabetes mellitus is abnormal glucose metabolism, so there may be an inseparable relationship between various glucose metabolism hormones and AD.This paper expounds the correlationship between AD and glucose metabolism regulation hormones, which includes insulin, amylin, glucagon like peptide, asprosin, and glucocorticoid. At the same time, we summarize the research perspective in nootropics of herbal medicine.

Glucose metabolism regulation hormone and AD

Insulin

AD and type 2 diabetes (T2DM) are two kinds of the most common disease of aging society. T2DM is believed to be the cause of its earliest stage from reduced sensitivity of surrounding tissues to circulating insulin,leading to impaired glucose tolerance [6]. That a similar process of intracellular insulin resistancy and insufficiency is occurring in the brain region in AD is becoming evident, including in those without systemic diabetes [7].

Insulin is a molecular weight of 6KD protein, secreted by the islet β cells that are stimulated by endogenous or exogenous substances. Insulin had been regarded as a sort of hormones which hardly can pass through the blood brain barrier and only exists in the peripheral blood. Until the end of the 1970’s, the first-hand evidence had been put forward that the insulin was present in the rat brain by RIA method, this finding demonstrated that insulin can through the blood brain barrier arrive at center, so that can be adjusted by the centers of the glucose metabolic process. In addition, neuron can synthesize insulin.

The insulin receptor (IR) is widely distributed in the central nervous system (CNS), especially in the hippocampus, cortex and other regions associated with learning and memory [8]. Since the discovery of insulin and insulin receptors existing in the CNS had been published, more studies have shown that the insulin in the central region activates signaling pathways such as PI3K/Akt. Moreover, nerve cells uptake glucose by insulin’s mediation [9] and regulate synaptic plasticity[10] by insulin signaling pathways in CNS.

The insulin signaling pathway is mainly involved: (1)Phosphoinositide3-kinase (PI3K) pathway associated with cell growth and proliferation [11]; (2)mitogenactivated protein kinase (MAPK) pathway regulated cell differentiation [12]. PI3K/Akt plays an essential role in insulin signaling pathway. Insulin resistance (IR) is insensitive to insulin in the body.Research found that there were abnormal insulin signaling pathways and insulin resistance which occur in AD patients’ brain. Insulin also affects Aβ production and clearance [13]. The main component of Aβ is amyloid precursor protein (APP) hydrolysis. The hydrolysis of the APP was induced by the PI3K/Akt signaling pathway when insulin resistance appeared, which leads to the increase of Aβ and obstruction of the transport of Aβ.Eventually, the senile plaques formed in the brain [14].Nevertheless, glycogen synthase kinase (GSK) is one of the important PI3K downstream kinase. And its activity can increase tau’s aberrant phosphorylation and finally appear NFTs [15].

Amylin

Amylin is a pancreatic β-cell hormone co-released with insulin in response to food intake. It reduces orexis,gastric acid secretion, limits the rate of gastric emptying,and diminishes pancreatic glucagon secretion [16]. It is the third important active hormone in the pancreas and regulates blood sugar balance with insulin. In the pathological state, high levels of blood amylin have inhibitory effects on insulin secreted when hyperglycemia.

There are many similarities between amylin and the composition of Aβ. For instance, they have an analogical secondary structure [17], which binds to the uniform amyloid receptor [18]. Being degraded by the same Insulin-degrading enzyme and interacted with each other in complex ways [19].

Emerging suggests emphasize that amylin impairs cerebrovascular by amyloid deposition in AD patients[20]. Meanwhile, AD patients have a high concentration of amylin expression in the blood. Therefore, there is an intimate connection between the amylin and AD, which may be the second amyloid protein in the brain of AD.Furthermore, fluorescent labeling experiment proves that the amylin was mainly distributed in mature neurons in the brain of mice, with the most distribution in the cortex,followed by the hippocampus and other parts. With the increase of the age of the AD model mice, the expression of amylin in the cortical region is gradually increasing and forming the plaques, which are the common expression with Aβ [21]. In the physiological status,amylin can fall the blood sugar, but long time high blood glucose levels can result higher levels of amylin, which can pass through the blood-brain barrier and form aggregates to impair neurocyte, eventually led to a decline in the ability of learning and memory.

Glucagon like peptides

Glucagon like peptides are two types of glucagon like peptide-1 (GLP-1) and glucagon like peptide-2 (GLP-2).The one, GLP-2 is an intestinal specific growth factor.The other one, GLP-1 is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action [22]. GLP-1 secretion is closely related to the composition of food. Significantly,GLP-1 increased after high-sugar and high-fat diet [23]. It has an important physiological function in the CNS.

GLP-1 receptors are mainly distributed in the hypothalamus, the deutocerebrum and tritocerebrum.Activating the GLP-1 receptor in these brain regions can control appetite and reduce the food intake, which can control appetite and reduce the food intake [24].

Adenylatecyclase is activated when GLP-1 binds to the GLP-1 receptor on the surface of the β cell membrane, so that can improve Cyclic Adenosine monophosphate(cAMP) levels, activate the PKA, cAMP-regulated guanine nucleotide exchange factor II (Epac2), thus promote under glucose stimulated insulin secretion.Different from the glucose-dependent insulin secretion effect, GLP-1 promotes the proliferation and differentiation of β cells independent on the concentration of glucose, which can be produced in normal blood glucose. GLP-1 receptor downstream multiple signaling pathways are involved in promoting the proliferation,differentiation and protection of β cells.

GLP-1 not only regulates the blood glucose level of peripheral blood, but also acts as a neurotransmitter in the CNS, which plays an important role in cell proliferation,apoptosis and neurogenesis [25]. Meanwhile, combined with the corresponding receptors, GLP-1 participates in PI3K and MAPK signal pathways, which can activate the downstream substrate molecule of PKA, promote the neurotransmitter release, and improve the synaptic plasticity [26]. At the same time, it not just compensates the insulin signal, more than improves insulin resistance phenomenon of AD patients. The experiment found that GLP-1 analogues had improved effect on the memory which injected Aβ [27], and decreased the formation of Aβ [28].

Asprosin

Asprosin is cut down at the end of the myofibril protein-1,which contains 140 amino acids segment. It can promot the decomposition of liver glucose by the G protein-cAMP-PKA pathway, and facilitate the absorbtion of glucose into the cells to keep blood level at optimum levels [29]. Previous studies manifested that neonatal progeroid syndrome (NPS) patients existed insulin resistance [30]. From the previous review we can catch that AD has a significant relationship with insulin resistance.

The researchers detect that diabetic mice model exerts the higher level than normal cycle of Asprosin, then it was injected a deactivation of the monoclonal antibody to combination with Asprosin, which can regulate the insulin level. If insisting on treatment, the insulin resistance returned to normal [31]. Improving insulin resistance plays a vital role in reducing the incidence of AD.

Glucocorticoids

Glucocorticoids (GC) were secreted by the adrenal cortex zonafasciculata. In human, cortisol is the main factor,whereas in rodents, it is mainly corticosterone. It has the function of regulating the metabolism of glycolipid and protein, and also inhibiting immune response,anti-inflammatory and anti-shock. The release of glucocorticoid is regulated by the hypothalamic-pituitary-adrenocortical axis (HPA) [32]. A central feature of the stress response is activating the HPA and stimulating the adrenal cortex to release glucocorticoids.

GC is a steroid hormone that passes through the blood-brain barrier to combine with receptors.Glucocorticoid has two receptors in the brain, one is mineralocorticoid receptors (MR) with high affinity, and the other is glucocorticoid receptor (GR) with low affinity.These receptors are expressed mainly in the hippocampus area, where GR was expressed in the CA1 region [33]. A temporary high levels of GC can enhance memory,whereas persistent high levels of GC makes the GR active so continuously, that can damage the body’s memory function [34].

Studies show that cortisol levels in the plasma, saliva,or cerebrospinal fluid of AD patients are higher than those in normal people. The changes of cortisol levels are positively correlated with the memory storage of AD, but the mechanism is unclear [35]. The hippocampus is the advanced center of HPA axis regulation. When the hippocampal lesions in AD patients, the function of HPA axis is disturbed, while the GC level is elevated. This causes the dendrites of hippocampal neurons to atrophy,lose, regenerate, and eventually cognitive decline occurs.At the same time, the high level of GC makes the APP hydrolyze faster, and increases the accumulation of Aβ larger. Conversely, the deposition of Aβ is likely to increase the level of GC, form Aβ vicious circle, and aggravate the condition of AD. The high concentration of GC in the brain stimulates the activation of GSK3 kinase and increases the abnormal phosphorylation of tau protein[36].

A Research Perspective in Nootropics of Herbal Medicine

As mentioned above, abnormal glucose metabolism and its related hormone have closely bonds with the occurrence and development of AD. Although the main theories of AD pathogenesis have been proposed, which are cholinergic hypothesis and beta amyloid cascade hypothesis, the mechanism still needs to be elucidated.Clinically, the drugs to treat AD mainly include the anti-cholinesterase drug donepezil, lith’s amine,galanthamine and glutamate receptor antagonist memantine. However, AD still cannot be effectively prevented or cured. Meanwhile, these medications have many side effects besides the length of therapy. Emerged evidences indicate that the intervention of herbal medicines has the characteristics of small side effect and high safety, which makes that it possess certain advantages in the treatment of AD.

One of herbal medicine research groups found in their previous research that curcumin reduced Aβ aggregation in the AD mouse brain, and improved the symptoms of memory impairment. Furtherly, they used immunohistochemistry and western blot techniques to detect the glucose metabolism and insulin pathway in the APP transgenic mice. The results showed that curcumin ameliorated the deficiency of insulin signaling pathway and improved the spatial learning and memory ability by up-regulating the expression of insulin-like growth factor protein[37]. Durairajanet al. suggested that berberine inhibitted amyloid precursor protein phosphorylation to prevent Aβ deposition [38]. A study has shown that DanHong Injection can improve the memory ability of diabetic patients [39]. In a clinical trial, taking DanShenDiWan can reduce Aβ deposition and enhance cognitive function in diabetic patients [40]. ZhengSunetalhas found that ZiBuPiYin recipe can prevent brain damage in diabetic rats. The mechanisms may be affiliated with improving aberrant mitochondrial function,insulin resistance and reducing Aβ lesion [41].Chinese medicine is based on the collection of complex interactions, in other words, more research is needed on the synergistic effects of herbal combinations to better understand the mechanisms for disease [42].

A substantial epidemiological study has established clearly association between metabolic and neurodegenerative disorders in general [43]. It has also been found that the pathologic changes of insulin resistance and glucose metabolism disorder in AD are similar with that in diabetes. Therefore, it is promising to find a new pathway to consider the research strategy on exploring the nootropics candidates rooting in herbal medicine and its formula.