**1. Introduction**

#### **1.1. Metabolic syndrome, pre-Alzheimer's disease, and brain mitochondria**

According to the consensus statement of the International Diabetes Federation, metabolic syndrome (MetS) is defined as abdominal obesity plus any two of four factors including raised triglycerides, reduced high-density lipoprotein (HDL) cholesterol, raised blood pressure, and elevated fasting plasma glucose [1]. The risk factors of MetS include genetic factors, physical inactivity, and too high a calorie intake or poor diet [2, 3]. It has been postulated that insulin

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

resistance is the main contributor toward MetS. Insulin resistance is a pathological condition, in which target tissues cannot take up glucose into the cells at the physiological insulin level. It is characterized by hyperinsulinemia with euglycemia. MetS is often represented by an obese-insulin-resistant condition. It can lead to the development of not only cardiovascular diseases but also stroke [4] and neurodegeneration [5]. In addition, data from clinical trials have indicated that hyperinsulinemia during insulin resistance is related to cognitive decline in elderly adults [6, 7]. MetS has been induced in several animal models to enable the investigation of the mechanisms responsible for the adverse effects of the MetS condition on cognitive impairment. MetS has been induced in animal models by using high-fat/high-calorie diet consumption. Interestingly, previous studies have investigated the effects of long-term high-fat diet (HFD) consumption on metabolic and brain dysfunction [8, 9]. Those data demonstrated that the consumption of a HFD for 8 weeks caused obese-insulin resistance or MetS, as indicated by central obesity, hyperinsulinemia, dyslipidemia, and raised blood pressure [8, 9]; however, cognitive impairment and brain insulin resistance were observed later at the end of 12 weeks of HFD consumption [8, 10]. Those findings suggest that the metabolic disturbance preceded cognitive dysfunction in induced MetS

**2. The implications of metabolic syndrome on brain mitochondria and its association with the development of AD:** *in vivo* **studies and** 

**2.1. MetS condition from a high-fat diet-induced obese-insulin-resistant model**

the effects of a HFD on brain mitochondrial function still need to be elucidated.

There are several studies which have shown that brain mitochondrial damage could impair cognitive function and synaptic plasticity [20–22, 31, 33, 34]. Various cognitive tests have been used such as the Morris water maze (MWM), novel object recognition (NOR), novel object smelling (NOS), and Y-maze test. The MWM and Y-maze are tests for hippocampal-dependent learning process, including the acquisition of spatial memory and long-term spatial memory [36]. NOR and NOS are used to assess non-force driving and spontaneous memory [35, 37].

Rats and mice fed on a HFD for 16–20 weeks had an increased time to reach the platform and a decreased time in the target quadrant and crossing target number, compared with normal diet (ND)-fed animals, when cognitive function was assessed using the MWM [20–22, 31, 34]. Furthermore, recognition index was decreased in HFD-fed mice, compared to ND-fed mice [34]. Mice fed on a HFD for 12 months did not indicate an impaired discrimination index following the NOS test, but there were decreased percentage correction alterations in the Y-maze test [33]. These accumulative data suggested that the consumption of a HFD caused obese-insulin resistance, brain mitochondrial dysfunction, and synaptic dysplasticity, possibly leading to cognitive dysfunction. However, no study has demonstrated brain mitochondrial dysfunction with elevated AD markers such as Aβ levels and hyperphosphorylated tau in HFD-fed animals. This suggests that obese-insulin resistance can lead to the development of brain mitochondrial dysfunction and cognitive impairment or MCI or pre-AD without AD symptoms. Data regarding the effects of HFD-induced obese-insulin resistance on brain mitochondria and its association with the development of AD are shown in **Table 1** and are summarized in **Figure 1**.

Obese-insulin resistance is characterized by body weight gain and peripheral insulin insensitivity [20–22, 31–34]. These characteristics are similar to those seen in the MetS condition in humans. In addition to peripheral insulin resistance, brain insulin resistance has also been reported in the obese condition in rats [20–22, 31, 34]. A diet containing 60% E from fat is considered to be a high-fat diet (HFD), and it has been widely used to induce obese-insulin resistance in rodents [20–22, 31–33]. In some studies, it has been found that HFD consumption increased plasma cholesterol and free fatty acid levels [20–22, 31, 32, 34]. However, the plasma glucose level was not increased, but hyperinsulinemia was observed following HFD consumption even after long-term consumption of a HFD (12 months), indicating a pre-diabetic state [20, 31–34]. HFD consumption between 16 weeks and 12 months caused brain mitochondrial damage, including an increased mitochondrial ROS production [20–22, 31, 34], a reduced mitochondrial membrane potential [19, 31, 34–36], and an impaired mitochondrial morphology as indicated by an increased mitochondrial swelling [20–22, 31, 33]. Furthermore, HFD reduced adenosine triphosphate (ATP) production [34]. Although several studies suggested that HFD caused brain mitochondrial dysfunction, Jorgensen et al. reported that HFD did not impair brain mitochondrial function even when the rats were given a HFD for 12 months. Therefore,

Mitochondrial Link Between Metabolic Syndrome and Pre-Alzheimer's Disease

http://dx.doi.org/10.5772/intechopen.75306

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**clinical studies**

Pre-Alzheimer's disease or mild cognitive impairment (MCI) is a condition of memory decline but does not significantly affect the normal function of a person's life [11]; however, Alzheimer's disease (AD) is an irreversible chronic neurodegenerative disease and it is the most common type of dementia [12]. The presence of neurofibrillary tangles and amyloid beta deposition in the brain is hallmarks of AD [12]. Recent studies have shown that the incidence of AD has increased in MetS subjects [13–15]. Those findings suggest that there is a possible connection in the pathogenesis between MetS and AD. Data from a clinical study suggest that oxidative stress is a key component that regulates the development of AD in MetS subjects [15]

Mitochondria are known as the major source of oxidative stress [16]. Brain mitochondrial dysfunction was observed in several pathological conditions, including MetS and AD [17–22]. That dysfunction causes increased oxidative stress [10] and leads to the activation of several stress kinases [19]. Subsequently, a raised oxidative stress impaired brain insulin receptor function [23], inhibited insulin-degrading enzymes and increased beta-secretase activity [23, 24], resulting in increased hyperphosphorylated tau and amyloid beta deposition in the brain [19]. Therefore, brain mitochondrial dysfunction could be an important feature in AD pathogenesis in the MetS condition. Furthermore, the elevation of oxidative stress caused the imbalance of brain mitochondrial dynamics [25]. Mitochondrial dynamics are a key process for the maintenance of cell life and death through the balancing of mitochondrial fission and fusion [26]. In the physiological status of the brain, mitochondrial dynamics enables mitochondria to recruit subcellular components, exchange substrates between mitochondria, and control mitochondrial shape [26]. Recently, it has been proposed that brain mitochondrial dynamic imbalance is another mechanism that is involved in the brain pathogenesis of MetS and AD [27, 28]. Examples from the recent research are as follows: (1) several studies have reported that levels of Dynamin-related protein 1 (Drp1) and mitochondrial fission 1 (Fis1), markers of mitochondrial fission, were increased in the brains of MetS and AD animals [29, 30], leading to neuronal apoptosis [29]; (2) mitochondrial fusion protein levels were decreased in the brains of both MetS and AD animals [29, 30]. Therefore, a mitochondrial dynamic imbalance may play an important role in cognitive dysfunction in MetS and AD [26, 30]
