**3. The implications of high-calorie diet consumption on brain mitochondrial function and brain function in an AD model:** *in vivo* **studies**

In the T2DM model, brain mitochondrial markers were evaluated along with the changes in AD markers. It is interesting that T2DM rats developed AD signs, specifically that the levels of AD markers, including Aβ42 and hyperphosphorylated tau, were significantly increased in T2DM rats, when compared with non-T2DM rats [39, 41]. In addition, acetylcholine esterase enzyme activity was increased, and ACh levels were decreased in the brains of T2DM mice [39]. These data suggested that T2DM rats had impaired brain mitochondrial dysfunction and synaptic plasticity, leading to cognitive dysfunction and showed increased AD markers. Interestingly, those findings indicated that AD was developing in the T2DM condition. Contrary to the findings from animal studies, when Loo et al. investigated the effect of T2DM on mitochondrial function in human mononuclear cells, their data showed that T2DM did

**Study model Major findings Refs**

*MWM*

*MWM*

**Cognitive function AD** 

• ↑Escape latency • ↓Crossing target number

• ↑Escape latency • ↓Time in target quadrant *Y-maze test* • ↓% Correct alterations • ↓Total distance

*Synaptic plasticity* • ↓PSD95 *SNAP25*

• ↔Synaptophysin

Abbreviations: BW, body weight; STZ, streptozotocin; T2DM, type 2 diabetes mellitus; HFD, high-fat diet; ND, normal diet; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; Ach, acetylcholine; AChE, acetylcholine esterase; ATP, adenosine triphosphate; RCR, respiratory control ratio; NRF, nuclear respiratory factor; MWM, Morris

**Table 2.** Implications of type 2 diabetes mellitus (T2DM) on brain mitochondria and its association with the development

**marker**

• ↑pTau/ Tau • ↑AChE activity • ↓ACh

N/A N/A T2DM is not

N/A T2DM causes

mitochondrial dysfunction and impairs synaptic plasticity.

associated with mitochondrial dysfunction.

**Interpretation**

T2DM causes brain mitochondrial dysfunction, increases levels of AD marker, and cognitive dysfunction.

[41]

[39]

[38]

[40]

• ↑Aβ42 T2DM causes brain mitochondrial dysfunction, increases levels of AD markers, and cognitive dysfunction.

**Mitochondrial parameters**

• ↓Mito number • ↑ROS • ↓MMP

• ↓MMP • ↓ATP

• ↓RCR • ↓MMP • ↓ATP • ↓NRF2

• ↔MMP • ↔ATP

**Animal/diet/ duration**

SD rats/HFD (60% E fat) + STZ (30 mg/kg, i.p.) or ND + citrate buffer/11 weeks

C57BL/6 mice/ HFD (60% E fat) or ND (10% E fat)/10 weeks

Wild-type mice/ sucrose(20%) solution or control (water)/7 months

T2DM patients compared to healthy controls

water maze; N/A, not assessed.

of Alzheimer's disease.

**Metabolic parameters**

64 Alzheimer's Disease - The 21st Century Challenge

• ↑BW, insulin, glucose • ↓Peripheral insulin sensitivity • ↓Brain insulin signaling

• ↑BW, insulin, HbA1c

N/A • ↔ROS

• ↑Glucose • ↑ROS

Two AD animal models, including 3xTg AD mice and APPswe/PS1dE9 mice, have been used to investigate the implications of high-calorie diet consumption on brain mitochondrial function



**4. Therapeutic approaches on rats with the MetS condition specific to brain mitochondrial dysfunction and its association with the** 

Several studies have used various interventions on brain mitochondria and described their associations with the development of pre-AD. In this report, we have separated these interventions into three categories: (1) antidiabetic drugs, (2) traditional medicine, and (3) other drugs.

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

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

67

Several studies have demonstrated the beneficial effects of antidiabetic drugs on insulin sensitivity and brain mitochondrial function [21, 31, 45]. Our previous study found that the sodium glucose cotransporter 2 (SGLT2) inhibitor, which is a new antidiabetic drug, could decrease metabolic disturbance, brain mitochondrial ROS production, brain mitochondrial membrane potential change, brain mitochondrial swelling, synaptic dysplasticity and cognitive decline in HFD-fed rats [21]. In addition, the incretin-based drugs such as sitagliptin and vildagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors, also had beneficial effects on the improvement of insulin sensitivity, brain mitochondrial function and cognitive function in HFD-fed rats [21, 31, 45]. Another incretin-based drug, liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, also improved insulin sensitivity and decreased brain mitochondrial swelling [45]. All of these findings indicated that the antidiabetic drugs could reduce peripheral and brain insulin resistance, leading to improvement in cognitive function and synaptic plasticity and were associated with improved brain mitochondrial function. However, there is still lack of evidence showing the effects of antidiabetic drugs on AD markers. Data pertinent to the effect of antidiabetic drugs on brain mitochondrial dysfunction and their association with the devel-

Several studies have shown the beneficial effects of traditional medicine on brain mitochondrial function in HFD-fed, T2DM and AD rat models [20, 34, 39, 41]. Naringin, a citrus flavonoid, can improve insulin sensitivity and decrease brain mitochondrial ROS production, brain mitochondrial membrane potential change, brain mitochondrial ATP production, and cognitive decline in HFD-fed mice [34]. Furthermore, our previous studies found that garlic extract reduced peripheral and brain insulin resistance, brain mitochondrial ROS production, brain mitochondrial membrane potential change, and brain mitochondrial swelling, leading to improved cognitive function in HFD-fed rats [20]. The ZiBuPiYin recipe (ZBPYR), a traditional Chinese medicine, reduced brain mitochondrial ROS production, increased brain mitochondrial membrane potential change, increased brain mitochondrial number, and decreased cortical insoluble Aβ42, leading to improved cognitive function in T2DM mice [41]. *Dendropanax morbifera* (Araliaceae), a herbal medicine in Asia, improved peripheral and brain insulin sensitivity, decreased brain mitochondrial ROS

opment of pre-AD in the MetS condition are shown in **Table 4**.

**development of AD**

**4.1. Antidiabetic drugs**

**4.2. Traditional medicine**

Abbreviations: AD, Alzheimer's disease; HFD, high-fat diet; ND, normal diet; BW, body weight; PGC, peroxisome proliferator-activated receptor gamma; NRF, nuclear respiratory factor; TFAM, mitochondrial transcription factor A; RCR, respiratory control ratio; MMP, mitochondrial membrane potential; ATP, adenosine triphosphate; PSD, postsynaptic density protein; SNAP, synaptosomal-associated protein; NOR, novel object recognition; N/A, not assessed.

**Table 3.** Implications of high-calorie diet consumption on brain mitochondria and brain function in an Alzheimer's disease model.

and brain function. 3xTg AD mice cells with the mutations Thy-1.2-driven APP-Swedish and tau P301L were co-injected into a homozygous PS1M146V knock-in background. This type of AD mice had parenchymal plaque by 6 months of age combined with tau pathology by 12 months of age [44]. In APPswe/PS1dE9 mice, APP/PS1 animals co-express a Swedish (K594 M/N595 L) mutation of a chimeric mouse/human APP (Mo/HuAPP695swe), together with the human exon-9-deleted variant of PS1 (PS1-dE9), which leads to an increase in human Aβ peptide secretion in the brain of APPswe/PS1dE9 mice [17, 18].

There is only one study that has compared the brain mitochondrial function between T2DM and AD animal models. The investigators reported that both T2DM and AD mice had similar degrees of brain mitochondrial dysfunction, decreased synaptic plasticity proteins levels, and raised AD markers [38]. Those findings indicated that AD pathology was developed in T2DM animals, with an involvement of brain mitochondrial dysfunction.

The provision of a HFD to AD mice resulted in a different outcome depending on a genetic background of the AD mice. In 3xTg AD mice, the provision of a HFD led to increased body weight, but did not alter plasma glucose and insulin levels, compared to 3xTg AD mice given an ND [33]. In addition, the brain mitochondrial number and brain mitochondrial morphology, as well as cognitive function and AD markers were not affected by the HFD [33]. The data from this study suggested that T2DM did not alter brain mitochondria, cognitive function, or AD markers in 3xTgAD mice. By contrast, the consumption of a HFD led to a markedly decreased brain mitochondrial biogenesis and aggravated cognitive impairment in APPswe/ PS1dE9 mice [17, 18]. Furthermore, a HFD aggravated AD pathogenesis in APPswe/PS1dE9 mice, as indicated by increased cortical soluble and insoluble Aβ, and decreased insulindegrading enzymes [17, 18]. Data regarding the effects of consumption of a high-calorie diet on brain mitochondrial function and brain function in the AD model are shown in **Table 3** and are summarized in **Figure 1**.
