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

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.

### **4.1. Antidiabetic drugs**

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

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

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.

**Study model Major findings Refs**

*Synaptic plasticity* • ↔PSD95, synaptophysin, SNAP25

**Cognitive function AD marker Interpretation**

N/A T2DM and AD

mice exhibited similar phenotypes as regards brain synaptic plasticity and brain mitochondrial function.

[38]

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

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

the brain of APPswe/PS1dE9 mice [17, 18].

**Animal/diet/ duration**

Sucrose (20% sucrose) fed mice or 3xTgAD mice fed with ND

disease model.

**Metabolic parameters**

66 Alzheimer's Disease - The 21st Century Challenge

N/A • ↔RCR

**Mitochondrial parameters**

• ↔MMP • ↔ATP • ↔NRF2

are summarized in **Figure 1**.

animals, with an involvement of brain mitochondrial dysfunction.

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

### **4.2. Traditional medicine**

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


**Study model Major findings Refs**

*NOR*

*MWM* • ↓Time to reach platform • ↑Time in target quadrant

*MWM*

*Y-maze*

*MWM*

Abbreviations: HFD, high-fat diet; ND, normal diet; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial

**Table 5.** Potential effects of traditional medicine on brain mitochondria and its association with the development of

membrane potential; NOR, novel object recognition; MWM, Morris water maze; NA, not assessed.

• ↑Time in target quadrant

• ↑Alternation behavior • ↑Total distance

• ↑Time in target quadrant • ↑Crossing target number

**Cognitive function**

• ↑Recognition index *MWM*

• ↑Time in target quadrant • ↑Crossing target number **AD marker Interpretation**

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

N/A Naringin reduced

rats.

rats.

rats.

rats.

• ↓Cortical insoluble Aβ42

N/A *Dendropanax* 

N/A Garlic extract

peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function in obeseinsulin-resistant

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

reduced peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function in obeseinsulin-resistant

*morbifera* reduced peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function in obeseinsulin-resistant

Although Chinese medicine did not improve peripheral insulin resistance, it improved brain mitochondrial function, improved cognitive function, and reduced AD marker in T2DM

[34]

69

[20]

[41]

[39]

**Mitochondrial parameters**

• ↓ROS • ↑MMP • ↑ATP

• ↓ROS • ↑MMP • ↓Swelling

• ↓ROS • ↑MMP • ↑ATP

• ↓ROS • ↑MMP • ↑Mito number

**Animal/ interventions/ duration**

HFD-fed rats/ naringin (100 mg/kg) or vehicle/20 weeks

HFD-fed rats/garlic extract (200, 500 mg/kg) or vehicle/3 weeks

HFD-fed rats/*Dendropanax morbifera* (20 and 50 mg/kg) or vehicle/10 weeks

HFD-fed mice + low-dose STZ/Chinese medicine ZiBu PiYin recipe or vehicle

Alzheimer's disease.

**Metabolic parameters**

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


• ↑Peripheral insulin sensitivity

• ↔ BW • Peripheral insulin sensitivity

Abbreviations: HFD, high-fat diet; ND, normal diet; DPP-4, dipeptidyl peptidase 4; SGLT2, sodium glucose transporter 2; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; MWM, Morris water maze; NA, not assessed.

**Table 4.** Potential effects of antidiabetic drugs on brain mitochondria and their association with the development of Alzheimer's disease.

production, increased brain mitochondrial membrane potential change, and increased brain mitochondrial ATP production, leading to a decrease in cognitive decline in HFD-fed mice [39]. All of these traditional medicines contain flavonoid and phenolic compounds which have antioxidant properties, and it is thought that these properties may play an important role in the improvement of insulin sensitivity and brain mitochondrial function, leading to improved cognitive function. Data regarding the effect of traditional medicine on brain mitochondrial dysfunction and its association with a delay in the development of pre-AD in association with MetS are shown in **Table 5**.


Abbreviations: HFD, high-fat diet; ND, normal diet; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; NOR, novel object recognition; MWM, Morris water maze; NA, not assessed.

production, increased brain mitochondrial membrane potential change, and increased brain mitochondrial ATP production, leading to a decrease in cognitive decline in HFD-fed mice [39]. All of these traditional medicines contain flavonoid and phenolic compounds which have antioxidant properties, and it is thought that these properties may play an important role in the improvement of insulin sensitivity and brain mitochondrial function, leading to improved cognitive function. Data regarding the effect of traditional medicine on brain mitochondrial dysfunction and its association with a delay in the development of

**Table 4.** Potential effects of antidiabetic drugs on brain mitochondria and their association with the development of

Abbreviations: HFD, high-fat diet; ND, normal diet; DPP-4, dipeptidyl peptidase 4; SGLT2, sodium glucose transporter 2; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; MWM, Morris water

**Study model Major findings Refs**

*MWM* • ↓Time to reach platform • ↑Time in target quadrant *Synaptic plasticity* • ↑LTP

*MWM* • ↓Time to reach platform • ↑Time in target quadrant

*MWM* - ↓ Time to reach platform - ↑ Time in target quadrant

• ↓Swelling N/A N/A Liraglutide reduced

**Cognitive function**

**AD marker** **Interpretation**

N/A SGLT2 inhibitor reduced

N/A DPP-4 inhibitor reduced

N/A DPP-4 inhibitor reduced

peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function and synaptic plasticity in obese-insulin-resistant rats.

peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function in obese-insulin-resistant rats.

peripheral and brain insulin resistance, improved brain mitochondrial function, and improved cognitive function in obese-insulin-resistant rats.

peripheral resistance and improved brain mitochondrial function in obese-insulin-resistant rats. [21]

[31]

[31, 45]

[45]

**Mitochondrial parameters**

• ↓ROS • ↑MMP • ↓Swelling

• ↓ROS • ↑MMP • ↓Swelling

• ↓ROS • ↑MMP • ↓Swelling

**Animal/ interventions/ duration**

HFD-fed rats/ SGLT2 inhibitor (1 mg/kg) or vehicle/4 weeks

HFD-fed rats/ vildagliptin (3 mg/kg) or vehicle/3 weeks

HFD-fed rats/ sitagliptin (30 mg/kg) or vehicle/3–4 weeks

HFD-fed rats/ liraglutide (0.6 mg/kg) or vehicle/3 weeks

maze; NA, not assessed.

Alzheimer's disease.

**Metabolic parameters**

68 Alzheimer's Disease - The 21st Century Challenge

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

• ↔ BW • ↓Insulin HOMA

• ↔ BW • ↓Insulin HOMA

• ↔ BW • ↓Peripheral insulin sensitivity

pre-AD in association with MetS are shown in **Table 5**.

**Table 5.** Potential effects of traditional medicine on brain mitochondria and its association with the development of Alzheimer's disease.

#### **4.3. Other drugs**

The other therapies such as fibroblast growth factor 21 (FGF21), hydroxytyrosol 2-(3,4-dihydroxyphenyl)-ethanol, and mitochondrial fission inhibitors also had beneficial effects on brain mitochondrial function in HFD-fed, T2DM and AD models. Our previous study found that an endocrine hormone, FGF21, decreased metabolic disturbance, brain mitochondrial ROS production, brain mitochondrial membrane potential change, brain mitochondrial swelling, synaptic dysplasticity, and cognitive decline in rats with MetS induced by the consumption of a HFD [22]. Hydroxytyrosol 2-(3,4-di-hydroxyphenyl)-ethanol, a major antioxidant phenol in olive oil, ameliorated mitochondrial dysfunction, reduced mitochondrial carbonyl protein, and enhanced superoxide dismutase 2 expression in AD mice. However, this drug did not affect Aβ accumulation in these AD mice [46]. The mitochondrial fission inhibitor, mdivi-1, improved synaptic plasticity and was associated with improving brain mitochondrial function and biogenesis via increasing mitochondrial density, OXPHOS I, and ATP production in T2DM mice [30]. All of these findings indicated that the SGLT2 inhibitor, vildagliptin, liraglutide, FGF21, naringin, garlic extract, and *D. morbifera* improved not only peripheral insulin sensitivity but also brain insulin sensitivity, brain mitochondrial function, and cognitive function. Hydroxytyrosol, Mdivi-1, and ZiBuPiYin improved brain mitochondrial function and cognitive function. However, only ZiBuPiYin reduced levels of AD mark-

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

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71

Data regarding the effect of other drugs on brain mitochondrial dysfunction and the association of this dysfunction with the development of pre-AD in the MetS condition are shown in **Table 6**. The summarized therapeutic approaches on brain mitochondria and their association

In addition, previous studies showed that acetylcholine (Ach) levels of AD brain were lower than that of healthy brain [6, 12]. Therefore, acetylcholinesterase inhibitors (AChEs) are commonly used for the symptomatic treatment of AD patients. Previous *in vivo* study and *clinical study* demonstrated that AChEIs have an effect on mitochondrial function (REFs). For example, (1) Donepezil (AChEI) attenuated brain mitochondrial dysfunction by reducing calcium-induced brain mitochondrial swelling and reduced mitochondrial Aβ40 and Aβ42 accumulation in AD mice, leading to improved cognitive function in AD mice [47]. (2) A clinical study by Casademont et al. showed that rivastigmin, AChEI, enhanced mitochondrial electron transport chain function as indicated by increased complex I and complex III of mitochondrial oxidation and increased enzymatic activities of complexes II, III, and IV

**Figure 2.** Summarized therapeutic approaches on brain mitochondria and their association with the development of Alzheimer's disease. Abbreviations: SGLT2, sodium-glucose transporter 2; PI3K, phosphoinositide 3 kinase; Akt, protein

ers, possibly resulting in improved cognitive function.

with the development of AD are shown in **Figure 2**.

kinase B; FGF 21, fibroblast growth factor 21.


Abbreviations: HFD, high-fat diet; ND, normal diet; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; OXPHOS, oxidative phosphorylation; PGC, peroxisome proliferator activated receptor gamma; ATP, adenosine triphosphate; LTP, long-term potentiation; N/A, not assessed.

**Table 6.** Potential interventions on brain mitochondria and their association with the development of Alzheimer's disease.

mitochondrial function and biogenesis via increasing mitochondrial density, OXPHOS I, and ATP production in T2DM mice [30]. All of these findings indicated that the SGLT2 inhibitor, vildagliptin, liraglutide, FGF21, naringin, garlic extract, and *D. morbifera* improved not only peripheral insulin sensitivity but also brain insulin sensitivity, brain mitochondrial function, and cognitive function. Hydroxytyrosol, Mdivi-1, and ZiBuPiYin improved brain mitochondrial function and cognitive function. However, only ZiBuPiYin reduced levels of AD markers, possibly resulting in improved cognitive function.

**4.3. Other drugs**

70 Alzheimer's Disease - The 21st Century Challenge

**Animal/interventions/**

HFD-fed rats/FGF21 (0.1 mg/kg) or vehicle/20 weeks

*APP/PS1* mice/ hydroxytyrosol (50 mg/kg) or vehicle/8 weeks

*db/db* mice/mdivi-1 (50 mg/kg) or vehicle/2 weeks

**Metabolic parameters**

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

**duration**

The other therapies such as fibroblast growth factor 21 (FGF21), hydroxytyrosol 2-(3,4-dihydroxyphenyl)-ethanol, and mitochondrial fission inhibitors also had beneficial effects on brain mitochondrial function in HFD-fed, T2DM and AD models. Our previous study found that an endocrine hormone, FGF21, decreased metabolic disturbance, brain mitochondrial ROS production, brain mitochondrial membrane potential change, brain mitochondrial swelling, synaptic dysplasticity, and cognitive decline in rats with MetS induced by the consumption of a HFD [22]. Hydroxytyrosol 2-(3,4-di-hydroxyphenyl)-ethanol, a major antioxidant phenol in olive oil, ameliorated mitochondrial dysfunction, reduced mitochondrial carbonyl protein, and enhanced superoxide dismutase 2 expression in AD mice. However, this drug did not affect Aβ accumulation in these AD mice [46]. The mitochondrial fission inhibitor, mdivi-1, improved synaptic plasticity and was associated with improving brain

**Study model Major findings Refs**

**Cognitive function**

N/A ↔ Aβ

*Synaptic plasticity* • ↑ LTP levels

*MWM* • ↓ Time to reach platform • ↑ Time in target quadrant *Synaptic plasticity* • ↑ LTP

**AD marker** **Interpretation**

[22]

[46]

[30]

N/A FGF21 reduced peripheral and brain insulin resistance, improved brain mitochondrial function and cognitive function in obeseinsulin-resistant

rats.

N/A Mitochondrial

Hydroxytyrosol improved mitochondrial function and increased mitochondrial biogenesis in T2DM mice.

fission inhibitor improved brain mitochondrial function and brain synaptic plasticity in T2DM mice.

**Mitochondrial parameters**

• ↓ ROS • ↑ MMP • ↓ Swelling

I, IV • ↑ PGC1-α

• ↑OXPHOSI • ↑ ATP

Abbreviations: HFD, high-fat diet; ND, normal diet; BW, body weight; ROS, reactive oxygen species; MMP, mitochondrial membrane potential; OXPHOS, oxidative phosphorylation; PGC, peroxisome proliferator activated receptor gamma;

**Table 6.** Potential interventions on brain mitochondria and their association with the development of Alzheimer's disease.

N/A • ↑OXPHOS

N/A • ↑Mito density

ATP, adenosine triphosphate; LTP, long-term potentiation; N/A, not assessed.

Data regarding the effect of other drugs on brain mitochondrial dysfunction and the association of this dysfunction with the development of pre-AD in the MetS condition are shown in **Table 6**. The summarized therapeutic approaches on brain mitochondria and their association with the development of AD are shown in **Figure 2**.

In addition, previous studies showed that acetylcholine (Ach) levels of AD brain were lower than that of healthy brain [6, 12]. Therefore, acetylcholinesterase inhibitors (AChEs) are commonly used for the symptomatic treatment of AD patients. Previous *in vivo* study and *clinical study* demonstrated that AChEIs have an effect on mitochondrial function (REFs). For example, (1) Donepezil (AChEI) attenuated brain mitochondrial dysfunction by reducing calcium-induced brain mitochondrial swelling and reduced mitochondrial Aβ40 and Aβ42 accumulation in AD mice, leading to improved cognitive function in AD mice [47]. (2) A clinical study by Casademont et al. showed that rivastigmin, AChEI, enhanced mitochondrial electron transport chain function as indicated by increased complex I and complex III of mitochondrial oxidation and increased enzymatic activities of complexes II, III, and IV

**Figure 2.** Summarized therapeutic approaches on brain mitochondria and their association with the development of Alzheimer's disease. Abbreviations: SGLT2, sodium-glucose transporter 2; PI3K, phosphoinositide 3 kinase; Akt, protein kinase B; FGF 21, fibroblast growth factor 21.


information regarding the role of mitochondria in the underlying mechanisms of pre-AD in MetS and offer important insights for future research on interventions that aim to improve the

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

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73

In this study, the accumulated data led to the conclusion that although cognitive decline and brain mitochondrial dysfunction were observed in obese-insulin-resistant rats, AD was not developed during the pre-diabetic state. In addition, markers indicating the presence of AD were observed in T2DM subjects. Treatment with antidiabetic drugs, traditional medicine, FGF21, and mitochondrial fission inhibitors effectively improved brain mitochondrial func-

This work was supported by Thailand Research Fund Grants TRF-Senior Research Scholar RTA6080003(SCC), MRG5980198 (WP), and TRG6080005 (NA), an NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand (NC), and a

quality of life in MetS patients with AD.

tion and cognitive function in rats with induced MetS.

Chiang Mai University Center of Excellence Award (NC).

The authors declare that there are no conflicts of interest.

\*Address all correspondence to: scchattipakorn@gmail.com

Training Center, Chiang Mai University, Chiang Mai, Thailand

Nattayaporn Apaijai1,2, Wasana Pratchayasakul1,2,3, Nipon Chattipakorn1,2,3 and

1 Neurophysiology Unit, Faculty of Medicine, Cardiac Electrophysiology Research and

2 Center of Excellence in Cardiac Electrophysiology Research, Faculty of Medicine, Chiang

3 Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang

4 Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai

**6. Conclusion**

**Acknowledgements**

**Declaration of interest**

Siriporn C. Chattipakorn1,2,4\*

Mai University, Chiang Mai, Thailand

Mai University, Chiang Mai, Thailand

University, Chiang Mai, Thailand

**Author details**

Abbreviations: AChE, acetylcholinesterase; APP, amyloid beta precursor; AD, Alzheimer's disease; Ca2+, calcium; Aβ, amyloid beta; N/A, not assessed.

**Table 7.** The effects of acetylcholine esterase inhibitors (AChEIs), the standard drugs for AD treatment, on brain mitochondrial function and their association with the development of Alzheimer's disease.

in the lymphocytes from AD patients [48]. (3) By contrast, tacrine, AChEI, impaired brain mitochondrial respiratory complex I, IV, and V activities in XX model [49]. Therefore, further studies are required to provide more evidence to support the effects of AChE inhibitor on brain mitochondrial function in AD patients as well as in the metabolic syndrome subjects. Those findings of AChEIs on brain mitochondrial function and their association with the development of Alzheimer's disease are summarized in **Table 7**.
