**5. Prospects of therapy**

For developing new therapeutic strategies for atherosclerosis, it is important to understand the cause of the disease pathogenesis and its progression [33]. A number of studies have shown that cell deaths produce different patterns depending on the stage of the plaque and types of cells involved in cell death. In summary, atherosclerosis is an inflammation-related arterial intima disease. A number of pharmacologic approaches have developed the way to stabilize rupture-prone atherosclerotic lesion by applying macrophage autophagic death. For therapeutic approach in atherosclerosis, it should be implicated for plaque stability and selective depletion of macrophages by modulating sterols. This section will introduce them.

#### **5.1. Harnessing macrophagic autophagy as a therapy for atherosclerosis**

One such pathway regulating the initiating autophagy involves mammalian target of rapamycin (mTOR). Blocking mTOR using rapamycin has an effect on cell proliferation both *in vitro* and *in vivo* [87]. Inhibition of mTOR leads to autophagic cell death through some ATG protein pathways [88]. ATG13 is rapidly dephosphorylated when the mTOR pathway is inhibited. By stimulating affinity to ATG1, the ATG1-ATG13 complex is involved in autophagosome formation. When the rapamycin derivative everolimus is delivered from a stent in atherosclerotic plaques, in the lesion site of cholesterol-fed rabbits, autophagic macrophage death occurred due to macrophage reduction. In contrast, the amounts of VSMCs were sustained without change [89]. An mTOR-mediated pathway induces dephosphorylation of p70 S6 kinase, which is responsible for selective induction of macrophage death. On the other hand, the protein synthesis inhibitor cycloheximide induced selective macrophage death in plaques of cholesterol-fed rabbits. In this case, apoptosis occurred not only via autophagy, because plaque macrophages might be highly metabolic active and vulnerable to protein synthesis inhibitors relative to SMCs [90].

summit in 2013 and the WHO Ministerial Conference in 2015 decided to engage in a global action against dementia. The Atherosclerosis Risk in Communities (ARIC) study performed in 1987–1989 enrolled 15,792 individuals: they were a bi-racial group, with an age range from 45 to 64 years, from 4 US communities. Cognitive assessments were performed in the second ARIC examination in 1990–1992 [74]. A comprehensive dementia study, Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), was used as the fifth ARIC examination in 2011–2013. They evaluated what happens to participants with extensive cardiovascular disease and cognitive dysfunction after a long history of ARIC and for the participants who died. This is a longitudinal cohort depicting the association of cognitive function, cardiovascular condition, cerebrovascular condition, and mortality. In ARIC-NCS, they reported that the overall prevalence of dementia in living ARIC participants is similar to the estimate of the World Alzheimer Report 2015. Although the prevalence of MCI in ARIC-NCS and the prevalence of MCI have been reporting to be at a similar level, there is a variation in MCI prevalence because of different MCI definitions [74]. Therefore, longitudinal studies of incident dementia

From some studies, it is obvious that the prevalence of dementia is related to stroke, heart disease, hypertension, and diabetes. These results are limited because many medications used to treat cardiovascular disease and other vascular diseases have been observed to have an effect on dementia prevalence and incidence. This is why no single factor has been identified to fully explain the changes in dementia prevalence and incidence. However, it is important to identify multiple risk factors and protective factors throughout a personal whole life-course relating to physical, mental, and cognitive health. In particular, atherosclerotic and vascular

For developing new therapeutic strategies for atherosclerosis, it is important to understand the cause of the disease pathogenesis and its progression [33]. A number of studies have shown that cell deaths produce different patterns depending on the stage of the plaque and types of cells involved in cell death. In summary, atherosclerosis is an inflammation-related arterial intima disease. A number of pharmacologic approaches have developed the way to stabilize rupture-prone atherosclerotic lesion by applying macrophage autophagic death. For therapeutic approach in atherosclerosis, it should be implicated for plaque stability and selective depletion of macrophages by modulating sterols. This section will introduce them.

One such pathway regulating the initiating autophagy involves mammalian target of rapamycin (mTOR). Blocking mTOR using rapamycin has an effect on cell proliferation both *in vitro* and *in vivo* [87]. Inhibition of mTOR leads to autophagic cell death through some ATG protein pathways [88]. ATG13 is rapidly dephosphorylated when the mTOR pathway is inhibited. By stimulating affinity to ATG1, the ATG1-ATG13 complex is involved in autophagosome

risk factors need to be well-controlled for reducing the risk of dementia in later life.

**5.1. Harnessing macrophagic autophagy as a therapy for atherosclerosis**

in this cohort are required for validation of the MCI definition.

**5. Prospects of therapy**

108 Atherosclerosis - Yesterday, Today and Tomorrow

As another therapeutic case of rapamycin, inhibited translation of VSMCs leads to upregulation of smooth muscle B-actin, calponin, and myosin heavy chain, which modulates VSMCs to be differentiated, quiescent, and have a contractile phenotype. As a result, VSMCs undergo cell death. It has been suggested that restricted protein translation might selectively induce macrophage cell death rather than cell death protein expression. mTOR gene silencing is another therapeutic approach. Transfection of mTOR-specific small interfering RNA selectively induces macrophage cell death [89]. The recent evidence shows that the transcription factor TFEB works as a transcriptional activator for a network of autophagy and lysosomal genes [91]. The studies show that macrophage specific gene activator of TFEB has the ability of lysosomal biogenesis, recovering lysosomal dysfunction via atherogenic lipids. It allows some functions such as increasing cholesterol efflux, inhibiting inflammation activation, and clearing abnormal protein aggregate [16]. This study provides the possibility that overexpressed TFEB in macrophages alleviates atherosclerosis [16].

Lipid reduction is the one of the well-known ways to eradicate macrophages from atherosclerotic plaques [36]. One of recent studies using a rabbit atherosclerosis model suggested that the lower levels of lipid led not to macrophage apoptosis but instead monocyte recruiting impairment because of a decrease in macrophage replication. Statins are generally used in myocardial infarction patients. In SMCs treated with the autophagy inducer 7-ketocholesterol, fluvastatin failed to activate caspases. It has been suggested there is a possibility that activation of autophagy interferes with the statin-induced apoptotic pathway [36]. Another suggestion that has been proposed is that defective mitochondria are engulfed by autophagosomes, which limits the relocation of pro-apoptotic molecules from mitochondria into the cytosol or nucleus [36].

#### **5.2. Treating atherosclerosis as a therapy for cognitive impairment**

Currently, statin drugs are major therapeutics to prevent acute coronary events. Statins inhibit cholesterol biosynthesis, reduce LDL receptors (LDLRs), and consequently trigger a reduction in blood cholesterol levels [92]. Statins work at multiple stages in atherosclerotic plaque formation. Among these stages, statins have effects at earlier atherosclerosis development stages because they hinder cholesterol accumulation, monocyte infiltration, and inflammation in arteries [92]. Carotid atherosclerosis is measured by two distinct characteristics: carotid intimamedia thickness (cIMT) and carotid plaque burden quantified by plaque presence or localization. A recent study suggests that plaque burden may act as a predictor of cardiovascular disease other than cIMT, although cIMT has been better represented in preventative measures [68]. It has been suggested that plaque numbers and cIMT may be involved in cognitive impairment and dementia [66]. These studies report early intervention of atherosclerosis to prevent cognitive impairment [72]. It is obvious that carotid atherosclerosis can be a potential target for early intervention and risk management for those at risk for cognitive decline. A recent study was performed under the hypothesis that cognitive performance in the dominantly affected domain would be related to carotid plaque burden and cIMT, and cognitive decline would be shown differently in the racial and ethnical diverse Northern Manhattan Study (NOMAS) [93]. They indicated that elderly individuals with a larger cIMT have a higher future risk of progression to MCI or dementia. It is required to monitor patients for earlier detection of cognitive dysfunction [93]. Additionally, they identified a cutoff value for predicting cognitive impairment progression (0.825 mm of cIMT), which corresponds to the cutoff values for predicting stroke and CVD in the previous report [93].

are spilled from lipid-overloaded macrophages in the plaques. Based on previous research, future studies are focusing on therapeutic advantages of autophagic microphages in unstable

Cerebrovascular Atherosclerosis: Cognitive Dysfunction Progress and Autophagic Regression

http://dx.doi.org/10.5772/intechopen.72296

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Despite efforts to develop strong therapeutic targets, it is not feasible to establish respective contributors to degeneration and vascular disease onset and progression in each patient. Today, in our aging society, dementia has becoming an important issue in the public heath, economics, and social aspects, and also in political fields. With careful converging and treating on vascular risk factors containing atherosclerosis, it would get available therapeutic strat-

egies for prognosis and diagnosis in patients with progressive dementia.

1 Department of Life Science, Kyonggi University, Suwon, South Korea

2 Department of Neurology, Severance Hospital, Yonsei University College of Medicine,

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[2] Hansson GK, Hermansson A. The immune system in atherosclerosis. Nature Immuno-

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[4] Goldstein JL, Brown MSA. Century of cholesterol and coronaries: From plaques to genes

[5] Sergin I, Evans TD, Razani B. Degradation and beyond: The macrophage lysosome as a nexus for nutrient sensing and processing in atherosclerosis. Current Opinion in

[6] Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. The New

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\* and Gyung Whan Kim<sup>2</sup>

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

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**Author details**

Kyoung Joo Cho<sup>1</sup>

Seoul, South Korea

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**References**

Considering the role of vascular blood factors in patients with MCI, some blood factors suggested in our previous study may also influence the progression of cognitive decline [94]. However, there are currently no markers for prognostication or the risk of conversion from MCI to dementia. Therefore, it is necessary to develop noninvasive diagnostic methods for the assessment of vascular status [80]. This aspect is discussed further in the next section along with my results. Our results may provide a route for determining the most appropriate treatment strategy for patients with MCI or multiple diagnoses.

According to recent research, trends of dementia prevalence and incidence have been reported, which are based on healthcare and insurance databases, clinical records, and meta-analysis. These studies have not currently provided how to control the recent trends of cognitive function about diagnosis, clinical details, or public awareness for it. Nonetheless, researchers and clinicians are agreeing that long-term determinants are needed for both healthy and unhealthy aging in the most of society. Furthermore, it goes on the efforts to reduce risk of dementia by maintaining health with age.
