**2. PPAR**

126 Pharmacology

AD (Henderson et al., 2009). Although brain ketone metabolism is less known in the elderly population, fundamental and clinical studies suggests that they could represents an

In addition to understanding the physiopathology underlying the cognitive decline it is important to know the factors that increase the risk of being affected by a decline in cognitive function to help prevent them. Aging is the main factor and it often say that it is inevitable. It is true that the passage of time cannot be slowing down, but individuals can play a role in modifying their "biological" age or their metabolic condition. Effectively, aging naturally tends to reduce the cognitive functioning but also worsen the metabolic condition. At advanced age, the prevalence of hypertension, dyslipidemia, inflammation, atherosclerosis and diabetes increase. To prevent these metabolic problems, it is highly documented that the adoption of a healthy lifestyle (physical activities and equilibrate diet) through the lifespan is an efficient way (Colcombe et al., 2003, Peters, 2009.) It turns out that having a bad metabolic condition raises up the risk to develop a cognitive disorder (Frisardi et al., 2010) Peripheral problems and brain disorders are often dissociated but a close

Having type II diabetes is associated with the increased risk of developing a cognitive disorder. More than 80% of AD patients have type II diabetes or present an abnormal glucose level. Insulin resistance and hyperinsulinemia, two characteristics of type II diabetes, have been shown to have a high correlation with memory impairment and risk for AD. The rising insulin level that occurs with aging is also a strong predicator of cognitive impairments, in non-diabetics. (Landreth et al., 2008). The Italian Longitudinal study on aging shows that patients with mild cognitive impairment who were also afflict by metabolic syndrome had a higher risk of progression to dementia compared with those without metabolic syndrome. Hypertriglyceridemia was the major component of metabolic syndrome related to dementia (Solfrizzi et al., 2009). Genetic studies and epidemiological observations strongly suggest a relationship between dyslipidemia and AD. Elevated serum cholesterol levels have been reported to correlate with an increased incidence of AD (Landreth et al., 2008). Longitudinal studies have reported that obesity and chronic hypertension are also associated with higher

Then, improvement in those metabolic parameters could modify the individual risk for dementia. Preventive activities during the lifespan are primordial but changing individual behaviour is a long term challenge for the public health. The use of metabolic regulator as a secondary prevention may become essential in individuals at middle age who presents a poor metabolic condition (high blood glucose, deteriorated lipids profile, hypertension, etc.) not only to prevent heart diseases but precisely to delay the first signs of cognitive decline. Given that tertiary prevention of AD dementia which refers to anticholinesterase drugs is known to modestly delay progression of dementia because its probaby too late to correct the existing damage, primary and secondary prevention are essentials (Haan & Wallace 2004) (figure 1). It is well known that if you want to avoid a pulmonary cancer you should not smoke cigarettes, but the population feels armed less in front of neurodegenerative disorders and should not: progression to dementia can be prevented or modified (Haan et Wallace 2004).

interesting therapeutic potential for cognitive decline (reviewed in Veech et al., 2001)

**1.4 Risk factors: Importance of the metabolic condition** 

relationship exist between these two entities.

risk of cognitive decline (reviewed in Frisardi et al., 2010).

## **2.1 Mecanisms, pathways, activators**

Peroxisome Proliferator Activated Receptor alpha (PPARα) is a nuclear receptor present in tissues where fatty acids catabolism is at elevated rate, especially in liver but also in heart, kidney, skeletal muscles, enterocytes and astrocytes. This receptor is activated by fatty acids and their derivates and among the synthetic ligands; by compounds of the fibrate family. PPARα regulates gene expression by associating with his ligand in the cytoplasm of cells; the complex then migrates into the nucleus and binds with the 9-cis retinoic acid receptor (RXR). The heterodimer (PPARα/RXR) recognizes specific response elements (peroxisome proliferator response element; PPRE) presents in the promoter regions of genes and binds to activate or repress (figure 2).

Fig. 1. Schematic cognitive capacity during life. Primordial and secondary preventions, by regulating metabolic condition, may maintain cognitive capacity above the clinical threshold of cognitive decline. Tertiary prevention can modestly help to delays progression of dementia once it is installed. Progression of cognitive capacity in Alzheimer's disease (\_\_\_) and in cognitively healthy elderly (\_ \_).

Peroxisome Proliferator Activated Receptor Alpha

Fig. 3. Structures of clofibrate, fenofibrate and bezafibrate.

**2.3 Insulin resistance** 

**2.2 How can PPARα stimulation help cognitive functioning?** 

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 129

Clofibrate is a first generation fibrate and was used for numerous years before the arrival of the second generation comprising bezafibrate and fenofibrate which are more selective and causes fewer side effects (figure 3). Clofibric acid and fenobibric acid (active metabolites of clofibrate and fenofibrate) activate PPARα and PPARγ but they are 10 times more selective

The impact of PPARα agonists on cognition was not deeply investigated at a large scale level but some observational studies are interesting. In a large Europeean study (8582 subjects) fibrate use tended (p=0.07) to be associated with a reduction in the prevalence of dementia. Dementia included AD (65%), vascular dementia (12%), mixed dementia (11%) and other form of dementia (11.7%). Prevalence of dementia was 1.5% among fibrates user and 2.3% among non-user (Dufouil et al., 2005). In another observational study Rodriguez et al, showed that in a population of 845 individuals, 20.1% of the cohort were demented (based on Clinical dementia Rating) and the proportion of lipid lowering drugs user within the demented population was lower compared to the non-demented (3.5% versus 10.8%) which suggest that lipid lowering drugs may be protective (Rodriguez et al., 2002). In an older study, reducing triglycerides with gemfibrozil (a fibrate) appeared to improve cerebral perfusion and cognitive performance compared to untreated group (Rogers RL et al., 1989). Next sections will focused on how fibrates intake can be protective for the aging brain.

Insulin is produce by the pancreas and control blood glucose level by allowing the transport of glucose molecules from the circulation into cells. Insulin resistance occur when the cells (insulin receptors) are progressively unable to have a proper insulin response resulting in an inadequate entry of glucose in the cells. By a compensatory mechanism, pancreas will secretes more insulin. If the higher amount of insulin is still inefficient to control blood glucose, the person with high insulin and high glucose level will present a situation of prediabetes and insulin resistance. Eventually, pancreas will decrease the insulin secretion,

to PPARα. Bezafibrate activates PPARα but can also be linked to PPARγ and PPARδ.

Fig. 2. Following activation with the ligand, PPARα binds a specific DNA sequence (PPRE) in the promoter region of target genes.

PPARα regulates gene associated with lipids, glucose and energy metabolism and exert an anti-inflammatory activity (table 2). Fibrates are first-line drugs used for over 40 years to treat hypertriglyceridemia and their mode of action is entirely via the activation of PPARα. Effectively, fibrates reduces plasma level of triglycerides by 30-50%, slightly increase HDLcholesterol by up to 5-15 % and usually reduces LDL-cholesterol by 15 to 20% (Chapman et al., 2006). By the activation of PPARα, fibrates are effective to stimulate lipolysis, to increase cellular and mitochondrial fatty acid uptake, to promote fatty acid oxidation, to reduce TG production by the liver, to increase the VLDL clearance and to increase the HDL-cholesterol synthesis.


Table 2. Target genes regulated by PPARα (Goldenberg et al., 2008). Abbreviations: VLDL: very low density lipoprotein. SR-BI/CLA1: class B scavenger receptor. VCAM-1: vascular cell adhesion molecule 1.

Fig. 2. Following activation with the ligand, PPARα binds a specific DNA sequence (PPRE)

PPARα regulates gene associated with lipids, glucose and energy metabolism and exert an anti-inflammatory activity (table 2). Fibrates are first-line drugs used for over 40 years to treat hypertriglyceridemia and their mode of action is entirely via the activation of PPARα. Effectively, fibrates reduces plasma level of triglycerides by 30-50%, slightly increase HDLcholesterol by up to 5-15 % and usually reduces LDL-cholesterol by 15 to 20% (Chapman et al., 2006). By the activation of PPARα, fibrates are effective to stimulate lipolysis, to increase cellular and mitochondrial fatty acid uptake, to promote fatty acid oxidation, to reduce TG production by the liver, to increase the VLDL clearance and to increase the HDL-cholesterol

in the promoter region of target genes.

Genes Expression Functions

Lipoprotein Lipase Lipolysis

Apolipoprotein CIII VLDL clearance inhibition

Apolipoprotein AI AII HDL cholesterol synthesis

Fatty Acid Binding Protein Fatty acids entry into the cell

Cyclooxygenase-2 Arachidonic acid metabolism

AcylCoA Synthase Fatty acids entry into the mitochondria

Table 2. Target genes regulated by PPARα (Goldenberg et al., 2008). Abbreviations: VLDL: very low density lipoprotein. SR-BI/CLA1: class B scavenger receptor. VCAM-1: vascular

SR-BI/CLA-1 receptor Cholesterol efflux

AcetylCoA carboxylase Fatty acids synthesis Fibrinogen Blood clotting C reactive protein Inflammation Interleukin 6 Inflammation

VCAM-1 Adhesion molecules

synthesis.

cell adhesion molecule 1.

Clofibrate is a first generation fibrate and was used for numerous years before the arrival of the second generation comprising bezafibrate and fenofibrate which are more selective and causes fewer side effects (figure 3). Clofibric acid and fenobibric acid (active metabolites of clofibrate and fenofibrate) activate PPARα and PPARγ but they are 10 times more selective to PPARα. Bezafibrate activates PPARα but can also be linked to PPARγ and PPARδ.
