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

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.

#### **2.3 Insulin resistance**

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,

Peroxisome Proliferator Activated Receptor Alpha

**2.4 Ketone production** 

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 131

Ketones are the alternative fuel for the brain when glucose availability is low to insure an optimal brain functioning. They are the product of triglycerides lipolysis, β-oxidation of fatty acids and ketogenesis (figure 5). The majoritary of ketones are synthesised in the liver. Studies have shown that astocytes have the capacity to produce ketones from fatty acids and the ketogenic system (Auestad et al. 1991; Guzman & Blazquez, 2001). Acetyl CoA resulting from the β-oxidation of fatty acids, undergo the Krebs cycle but if the metabolic context is favorable for the ketone body formation, acetyl CoA will be redirected in the ketogenesis pathway.

A B Fig. 4. A) Insulin concentration (mIU/L) during 6 hours. Breakfast was taken between time 0 and time 1 with no further meal. Before (-□- ) and after (-■-), 12 weeks on bezafibrate. B) Area under the curve of the insulin curves were lower after bezafibrate treatment. Data are expressed by mean ± SEM. n=12, \* p≤0.05. (Adapted from Tremblay-Mercier, 2010)

Under normal conditions (regular meals) ketogenesis is at a low rate (ketone bodies concentration <0.1 mmol/L), because a slight rise in blood glucose and the following increase in insulin concentration inhibits lipolysis and ketogenesis. After their production, β-OHB and acetoacetate will reach skeletal muscles, brain and heart by the systemic circulation to provide energy. Ketones will then be retransformed into acetyl CoA by the reaction called ketolysis (figure 6). Liver cannot use ketones as energetic molecules because the enzyme β-ketoacyl-CoA transferase is not present in the liver, so ketolysis can not occur (figure 6). Ketones pass through the blood brain barrier (BBB) by facilitated transport following the concentration gradient by the monocarboxylate transporter 1 (MCT-1), as well as pyruvate and lactate. The rate of cerebral ketone metabolism depends primarily on the concentration in blood. Cerebral ketone metabolism is also regulated by the permeability of the BBB, which depends on the abundance of MCT-1. An increase in ketone body concentration up regulates the expression of

In vitro experiments show that β-OHB protects hippocampal neurons in culture against the toxicity of the protein β-amyloid 1-42, found in the senile plaques in AD patients. This protective effect may be partly due to the fact that the ketone metabolism does not require the action of the enzyme pyruvate dehydrogenase (PDH) which is affected by the toxic

MCT-1 transporter (Leino et al. 2001; Pifferi et al., 2011).

consequence of a pancreatic cell stress and damage, and insulin level will gradually drop and glucose will stay high: type II diabetes is then diagnose. If not treated well, diabetic patient will present high circulating glucose level that can causes deleterious effects including cardiovascular disease, kidney disease, nerve damage, retinopathy, etc. This condition will also lead to deficits in cellular energy production, increased oxidative stress and reduced neuronal survival.

For a long period of time, brain glucose metabolism was known to be independent of insulin action since brain glucose transporters (GLUT-1 and GLUT-3) are insensitive to insulin. Recent literature shows that GLUT-4 responds to insulin and that insulin is produce within the brain in various regions especially in the hippocampus which is associated with learning and memory. Insulin receptors are also presents in the brain (de la Monte et al., 2006). Given that brain cells are dependent on a high glucose supply, brain and peripheral insulin may then play an essential role in brain glucose homeostasis.

Evidences showed a physiological link between insulin and cognition. Reports have documented that brain insulin receptor signaling is reduced in AD brain (reviewed in Rupinder K et al., 2011). Production as well as neuronal insulin receptors was also greatly lower in AD brain compared to age-matched controls (Zhu et al., 2005). Interestingly, in AD patients, peripheral administration of insulin improved memory and cognition, reduced brain atrophy and dementia severity (Burns et al., 2007). In an experimental animal model, intracerebral streptozotocine injection was used to deplete brain insulin, but not pancreatic insulin. This brain specific depletion was associated with progressive neurodegeneration with similar features of AD. This same experiment demonstrates that early treatment with PPARα agonist can effectively prevent this experimentally induced neurodegeneration and the related deficits in learning and memory. This same research team also showed that AD is associated with major impairements in insulin gene expression and that abnormality increase with the severity of dementia. They suggest that AD brain may represent a brain specific form of diabetes; type 3 diabetes (de la Monte et al, 2006).

Hyperlipidemia and fatty acids overload (lipotoxicity) contribute to insulin resistance phenomenon (Reviewed in Carpentier, 2008). By their reducing action on triglycerides and their role in enhancement of fatty acids β-oxidation, PPARα activators should improve insulin sensibility. At human level, findings from a study deriving from Bezafibrate Infarction Prevention trial (BIP) suggest that treatment with fibrate reduce the incidence by 30% and delay the onset of type II diabetes. However, there is not a clear consensus regarding the direct impact of fibrate on insulin sensibility, but from studies reviewed, 10 showed an improvement (Tenenbaum et al., 2007, Cree et al., 2007, Kim et al., 2003, Damci et al., 2003, Jonkers et al., 2001, Idzio-Wallus, 2001, Yong et al., 1999, Kobayashi et al., 1988, Murakami et al. 1984, Ferrari et al., 1977) and 6 a reduction in sensibility or no change (Anderlova et al., 2007, Rizos et al., 2002, Whitelaw et al., 2002, Asplund-Carlson, 1996, Sane et al., 1995, Skrha et al., 1994) . In a recent study (2010) bezafibrate treatment for 12 weeks in a mild hypertriglyceridemic population showed a postprandial insulin response 26% lower after bezafibrate, suggesting the beneficial impact of fibrate on insulin sensitivity (figure 4; Tremblay-Mercier et al., 2010). Further clinical studies measuring insulin sensibility are warranted to confirm the real insulin-sensitizing potential of fibrates and the subsequent impact on brain glucose metabolism and further impact on cognition.

#### **2.4 Ketone production**

130 Pharmacology

consequence of a pancreatic cell stress and damage, and insulin level will gradually drop and glucose will stay high: type II diabetes is then diagnose. If not treated well, diabetic patient will present high circulating glucose level that can causes deleterious effects including cardiovascular disease, kidney disease, nerve damage, retinopathy, etc. This condition will also lead to deficits in cellular energy production, increased oxidative stress

For a long period of time, brain glucose metabolism was known to be independent of insulin action since brain glucose transporters (GLUT-1 and GLUT-3) are insensitive to insulin. Recent literature shows that GLUT-4 responds to insulin and that insulin is produce within the brain in various regions especially in the hippocampus which is associated with learning and memory. Insulin receptors are also presents in the brain (de la Monte et al., 2006). Given that brain cells are dependent on a high glucose supply, brain and peripheral insulin

Evidences showed a physiological link between insulin and cognition. Reports have documented that brain insulin receptor signaling is reduced in AD brain (reviewed in Rupinder K et al., 2011). Production as well as neuronal insulin receptors was also greatly lower in AD brain compared to age-matched controls (Zhu et al., 2005). Interestingly, in AD patients, peripheral administration of insulin improved memory and cognition, reduced brain atrophy and dementia severity (Burns et al., 2007). In an experimental animal model, intracerebral streptozotocine injection was used to deplete brain insulin, but not pancreatic insulin. This brain specific depletion was associated with progressive neurodegeneration with similar features of AD. This same experiment demonstrates that early treatment with PPARα agonist can effectively prevent this experimentally induced neurodegeneration and the related deficits in learning and memory. This same research team also showed that AD is associated with major impairements in insulin gene expression and that abnormality increase with the severity of dementia. They suggest that AD brain may represent a brain

Hyperlipidemia and fatty acids overload (lipotoxicity) contribute to insulin resistance phenomenon (Reviewed in Carpentier, 2008). By their reducing action on triglycerides and their role in enhancement of fatty acids β-oxidation, PPARα activators should improve insulin sensibility. At human level, findings from a study deriving from Bezafibrate Infarction Prevention trial (BIP) suggest that treatment with fibrate reduce the incidence by 30% and delay the onset of type II diabetes. However, there is not a clear consensus regarding the direct impact of fibrate on insulin sensibility, but from studies reviewed, 10 showed an improvement (Tenenbaum et al., 2007, Cree et al., 2007, Kim et al., 2003, Damci et al., 2003, Jonkers et al., 2001, Idzio-Wallus, 2001, Yong et al., 1999, Kobayashi et al., 1988, Murakami et al. 1984, Ferrari et al., 1977) and 6 a reduction in sensibility or no change (Anderlova et al., 2007, Rizos et al., 2002, Whitelaw et al., 2002, Asplund-Carlson, 1996, Sane et al., 1995, Skrha et al., 1994) . In a recent study (2010) bezafibrate treatment for 12 weeks in a mild hypertriglyceridemic population showed a postprandial insulin response 26% lower after bezafibrate, suggesting the beneficial impact of fibrate on insulin sensitivity (figure 4; Tremblay-Mercier et al., 2010). Further clinical studies measuring insulin sensibility are warranted to confirm the real insulin-sensitizing potential of fibrates and the subsequent

and reduced neuronal survival.

may then play an essential role in brain glucose homeostasis.

specific form of diabetes; type 3 diabetes (de la Monte et al, 2006).

impact on brain glucose metabolism and further impact on cognition.

Ketones are the alternative fuel for the brain when glucose availability is low to insure an optimal brain functioning. They are the product of triglycerides lipolysis, β-oxidation of fatty acids and ketogenesis (figure 5). The majoritary of ketones are synthesised in the liver. Studies have shown that astocytes have the capacity to produce ketones from fatty acids and the ketogenic system (Auestad et al. 1991; Guzman & Blazquez, 2001). Acetyl CoA resulting from the β-oxidation of fatty acids, undergo the Krebs cycle but if the metabolic context is favorable for the ketone body formation, acetyl CoA will be redirected in the ketogenesis pathway.

Fig. 4. A) Insulin concentration (mIU/L) during 6 hours. Breakfast was taken between time 0 and time 1 with no further meal. Before (-□- ) and after (-■-), 12 weeks on bezafibrate. B) Area under the curve of the insulin curves were lower after bezafibrate treatment. Data are expressed by mean ± SEM. n=12, \* p≤0.05. (Adapted from Tremblay-Mercier, 2010)

Under normal conditions (regular meals) ketogenesis is at a low rate (ketone bodies concentration <0.1 mmol/L), because a slight rise in blood glucose and the following increase in insulin concentration inhibits lipolysis and ketogenesis. After their production, β-OHB and acetoacetate will reach skeletal muscles, brain and heart by the systemic circulation to provide energy. Ketones will then be retransformed into acetyl CoA by the reaction called ketolysis (figure 6). Liver cannot use ketones as energetic molecules because the enzyme β-ketoacyl-CoA transferase is not present in the liver, so ketolysis can not occur (figure 6). Ketones pass through the blood brain barrier (BBB) by facilitated transport following the concentration gradient by the monocarboxylate transporter 1 (MCT-1), as well as pyruvate and lactate. The rate of cerebral ketone metabolism depends primarily on the concentration in blood. Cerebral ketone metabolism is also regulated by the permeability of the BBB, which depends on the abundance of MCT-1. An increase in ketone body concentration up regulates the expression of MCT-1 transporter (Leino et al. 2001; Pifferi et al., 2011).

In vitro experiments show that β-OHB protects hippocampal neurons in culture against the toxicity of the protein β-amyloid 1-42, found in the senile plaques in AD patients. This protective effect may be partly due to the fact that the ketone metabolism does not require the action of the enzyme pyruvate dehydrogenase (PDH) which is affected by the toxic

Peroxisome Proliferator Activated Receptor Alpha

Fig. 6. Ketolysis pathway. β-OHB: β-hydroxybutyrate

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 133

Several human studies show that a slight raise in ketones concentration can maintain normal brain function even when plasma glucose would normally be low enough to result in acute cognitive and functional deficits. For example, Page and colleagues in 2009, administered MCTs to type 1 diabetics patient in hypoglycemic crisis and they observed an acute improvement in cognitive functions. Levels of ketones after the ingestion of MCTs were about 0.3-0.4 mM and were sufficient to have an impact on cognitive functioning (Page et al. 2009). Another team showed that a daily supplementation with MCTs for 90 days increased the ketogenic response to 400% and showed a score improvement at different cognitive tests in AD patients (Henderson et al, 2009). In 2004, Reger and colleagues conducted a study with 20 AD patients and showed that high β-OHB concentrations obtained after MCTs administration are positively correlated with ameliorations in the

Ketogenic diet and MCT ingestion, provides low glucose, low insulin environment and/or susbtrates for ketogenesis and are effective in raising ketones concentrations but need a change in eating habits. Another way to increase ketone bodies production without modifying eating habits is to up regulate the enzymes implicated in the pathway. As mentioned earlier fibrate drugs, via PPARα, stimulates the transcription of genes encoding for triglyceride lipolysis and fatty acid β-oxidation. As well, fibrate increase the transcription for the key enzyme in the ketogenesis which is the HMG CoA synthase. This enzyme catalyses the reaction between acetoacetyl CoA and acetyl CoA to form HMG-CoA (figure 4). Few studies on rats have demonstrated an increase in the production of ketone

paragraph recall test which is involving memory cognitive function (figure 7).

effect of β-amyloid protein and essential for the conversion of glucose into energy (Kashiwaya et al., 2000). Rats and human studies also showed that ketones decreased damages associated with free radical (Sullivan et al., 2004)

Ketone production can be stimulated by fasting but also by the administration of a ketogenic diet. This classic ketogenic diet contains a 4:1 ratio by weight of lipids to combined glucose and protein; this high fat intake forces the body to burn fatty acids rather than glucose. The therapeutic ketogenic diet was developed for treatment of pediatric epilepsy refractory to anticonvulsant in the 1920s. This diet is very effective to treat epilepsy in 30-50% of cases but is very hard to apply in a daily basis and causes significant side effects (Cross et al., 2007). Another dietary way to stimulate ketogenesis is by the ingestion of medium chain triglycerides (MCTs), which provokes an acute elevation in ketone body concentration. Those triglycerides are composed of saturated fatty acids from 6 to 12 carbons and are absorbed across the intestinal barrier and directly enter the portal vein. This allows for much quicker absorption and utilization of MCTs compared to long chain triglycerides. MCTs are transported into the mitochondria independent of the carnitine palmitoyltransferase (CPT), which is necessary for the mitochondrial absorption of long chain fatty acids. After a single dose of MCTs, a significant raise (176%) in ketone bodies concentration occur within one hour but rapidly drops to baseline values (within 2 hours) so the effect is transient (Courchesne-Loyer et al., in preparation).

Fig. 5. Ketogenesis pathway. CPT-1: Carnitine palmitoyltransferase 1.

effect of β-amyloid protein and essential for the conversion of glucose into energy (Kashiwaya et al., 2000). Rats and human studies also showed that ketones decreased

Ketone production can be stimulated by fasting but also by the administration of a ketogenic diet. This classic ketogenic diet contains a 4:1 ratio by weight of lipids to combined glucose and protein; this high fat intake forces the body to burn fatty acids rather than glucose. The therapeutic ketogenic diet was developed for treatment of pediatric epilepsy refractory to anticonvulsant in the 1920s. This diet is very effective to treat epilepsy in 30-50% of cases but is very hard to apply in a daily basis and causes significant side effects (Cross et al., 2007). Another dietary way to stimulate ketogenesis is by the ingestion of medium chain triglycerides (MCTs), which provokes an acute elevation in ketone body concentration. Those triglycerides are composed of saturated fatty acids from 6 to 12 carbons and are absorbed across the intestinal barrier and directly enter the portal vein. This allows for much quicker absorption and utilization of MCTs compared to long chain triglycerides. MCTs are transported into the mitochondria independent of the carnitine palmitoyltransferase (CPT), which is necessary for the mitochondrial absorption of long chain fatty acids. After a single dose of MCTs, a significant raise (176%) in ketone bodies concentration occur within one hour but rapidly drops to baseline values (within 2 hours) so the effect is transient

damages associated with free radical (Sullivan et al., 2004)

(Courchesne-Loyer et al., in preparation).

Fig. 5. Ketogenesis pathway. CPT-1: Carnitine palmitoyltransferase 1.

Fig. 6. Ketolysis pathway. β-OHB: β-hydroxybutyrate

Several human studies show that a slight raise in ketones concentration can maintain normal brain function even when plasma glucose would normally be low enough to result in acute cognitive and functional deficits. For example, Page and colleagues in 2009, administered MCTs to type 1 diabetics patient in hypoglycemic crisis and they observed an acute improvement in cognitive functions. Levels of ketones after the ingestion of MCTs were about 0.3-0.4 mM and were sufficient to have an impact on cognitive functioning (Page et al. 2009). Another team showed that a daily supplementation with MCTs for 90 days increased the ketogenic response to 400% and showed a score improvement at different cognitive tests in AD patients (Henderson et al, 2009). In 2004, Reger and colleagues conducted a study with 20 AD patients and showed that high β-OHB concentrations obtained after MCTs administration are positively correlated with ameliorations in the paragraph recall test which is involving memory cognitive function (figure 7).

Ketogenic diet and MCT ingestion, provides low glucose, low insulin environment and/or susbtrates for ketogenesis and are effective in raising ketones concentrations but need a change in eating habits. Another way to increase ketone bodies production without modifying eating habits is to up regulate the enzymes implicated in the pathway. As mentioned earlier fibrate drugs, via PPARα, stimulates the transcription of genes encoding for triglyceride lipolysis and fatty acid β-oxidation. As well, fibrate increase the transcription for the key enzyme in the ketogenesis which is the HMG CoA synthase. This enzyme catalyses the reaction between acetoacetyl CoA and acetyl CoA to form HMG-CoA (figure 4). Few studies on rats have demonstrated an increase in the production of ketone

Peroxisome Proliferator Activated Receptor Alpha

**2.6 Cardiovascular condition /inflammation** 

reported to correlate with an increased incidence of AD.

preserving cognitive functioning during aging.

target to consider.

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 135

perturbations are also seen in normal aging. Those perturbations decrease activities of complex I and IV of the electron transport chain which lead to an elevated reactive oxygen species production. Increased free radicals and peroxidative damage is also seen in AD (Cunnane et al., 2011). Mitchondria dysfunction seems to contribute to the early stage and to the development of various neurodegenerative diseases (Gibson et al., 2010). Numerous studies have suggested that the activation of PPAR may improve mitochondrial functions. PPARγ stimulation is likely to be more effective than PPARα in inducing mitochondrial biogenesis and seems to be effective to potentiate glucose utilization leading to improved cellular and cognitive function (Rupinder et al., 2011). Fibrates are more selective to PPARα but they also have an action on PPARγ. PPARα play a role in the oxidative stress observed in aging. Effectively, level of PPARα correlated negatively with lipid peroxide levels which are actually reduced following a bezafibrate administration (Pineda Torra et al., 1999). Therapeutic strategies targeted at preventing, delaying or treating mitochondrial dysfunction should contribute to the prevention or treatment of age related neurodegeneratives diseases (Atamna & Frey, 2007), and fibrates may be an interesting

There is a close link between cardiovascular condition and cognitive status. High blood pressure, obesity, hyperlipidemia and diabetes are among the principal risk factors for cardiovascular disease. Having those conditions also increase the risk of developing cognitive decline. Vascular risk factors may impair cognitive functions and are related to the occurrence of AD, hypertension and type II diabetes present the strongest association, especially when these factors are assessed in middle age. Atherosclerosis is also believed to be involved in development of dementia, particularly, vascular dementia. Some investigations have shown the importance of inflammation in the pathogenesis of AD, (Akiyama et al., 2000). Hypercholesterolemia, oxidative stress and inflammation have emerged as the dominant mechanism in the development of both atherosclerosis and AD (Steinberg, 2002).Genetic studies and epidemiological observations strongly suggest a relationship between dyslipidemia and AD. Elevated serum cholesterol levels have been

Based on its efficiency to reduce plasma triglycerides and to increase HDL cholesterol and it lowering action on LDL-cholesterol, major randomized intervention trials involving fibrate therapy were done to evaluate the drug efficiency to prevent cardiac events. These studies showed that a treatment with a fibrate has beneficial effects by reducing myocardial infarction and coronary event (Goldenberg et al., 2008). The Bezafibrate Infarction Prevention (BIP) trial in 2000 showed that bezafibrate also prevent atherosclerosis and significantly attenuates the risk of long term major cadiovascular events (Tennenbaum et al., 2005). PPARα is also involved in the anti-inflammatory response by his inhibition of NFкB transcription and by decreasing the production of pro-inflammatory IL-6, prostaglandins and C- reactive protein. Fibrates are known to be efficient molecules to prevent cardiovascular disease, knowing that cardiovascular disease and cognitive decline share the same risk factors, preventing cardiovascular disease with fibrate therapy should help

Fig. 7. Relationship between β-hydroxybutyrate (β-OHB) levels at the time of cognitive testing and the change in paragraph recall; *r* = 0*.*50, *P* = 0*.*02 (Reger et al., 2004).

bodies by the liver following a fibrate treatment which concord with studies on hepatocytes. In rats treated with clofibrate, PPARα stimulation leads to an upregulation of MCT-1 (König et al., 2008). At the human level the first study to investigate ketone metabolism following a fibrate therapy was done at the Research Center on Aging in Sherbrooke, Quebec, Canada. This study suggests that treatment with bezafibrate has a mild ketogenic potential; postprandial β-OHB response was 58% higher after bezafibrate treatment for 12 weeks. With bezafibrate treatment, the level of ketones (β-OHB) was low during fasting (early in the morning) but was rising during the experimental day to reach 0.3-0.4 mM β-OHB at the end of the day (Tremblay-Mercier et al., 2010). Perhaps in conjunction with a fibrate, joint administration of a dose of MCT, would maintain a moderate level of circulating ketones to insure the delivery to the brain to maintain the energetic homeostasis (Tremblay-Mercier et al., 2010). Preliminary results concerning cerebral ketone metabolism with the tracer 11Cacetoacetate shows that brain ketones uptake is proportional to physiologic plasma ketones concentration as expected by anterior studies (Cunnane et al,. 2011). Further studies with this tracer will help to better understand the impact of fibrate on ketogenesis and the repercussion on brain metabolism in elderly and in cognitively impaired patients.

#### **2.5 Mitochondrial function**

Mitochondria are the central organelle in the generation of cellular energy via the Krebs cycle and the electron transport chain. They may be a key players in the cerebral low glucose metabolism observed in AD. Effectively, in the diseased brain, the numbers of neuronal mitochondria are greatly reduced. Several studies have demonstrated aberrations in the electron transport complexes and Krebs cycle in AD (Atamna & Frey, 2007). Mitochondrial

Fig. 7. Relationship between β-hydroxybutyrate (β-OHB) levels at the time of cognitive

bodies by the liver following a fibrate treatment which concord with studies on hepatocytes. In rats treated with clofibrate, PPARα stimulation leads to an upregulation of MCT-1 (König et al., 2008). At the human level the first study to investigate ketone metabolism following a fibrate therapy was done at the Research Center on Aging in Sherbrooke, Quebec, Canada. This study suggests that treatment with bezafibrate has a mild ketogenic potential; postprandial β-OHB response was 58% higher after bezafibrate treatment for 12 weeks. With bezafibrate treatment, the level of ketones (β-OHB) was low during fasting (early in the morning) but was rising during the experimental day to reach 0.3-0.4 mM β-OHB at the end of the day (Tremblay-Mercier et al., 2010). Perhaps in conjunction with a fibrate, joint administration of a dose of MCT, would maintain a moderate level of circulating ketones to insure the delivery to the brain to maintain the energetic homeostasis (Tremblay-Mercier et al., 2010). Preliminary results concerning cerebral ketone metabolism with the tracer 11Cacetoacetate shows that brain ketones uptake is proportional to physiologic plasma ketones concentration as expected by anterior studies (Cunnane et al,. 2011). Further studies with this tracer will help to better understand the impact of fibrate on ketogenesis and the

testing and the change in paragraph recall; *r* = 0*.*50, *P* = 0*.*02 (Reger et al., 2004).

repercussion on brain metabolism in elderly and in cognitively impaired patients.

Mitochondria are the central organelle in the generation of cellular energy via the Krebs cycle and the electron transport chain. They may be a key players in the cerebral low glucose metabolism observed in AD. Effectively, in the diseased brain, the numbers of neuronal mitochondria are greatly reduced. Several studies have demonstrated aberrations in the electron transport complexes and Krebs cycle in AD (Atamna & Frey, 2007). Mitochondrial

**2.5 Mitochondrial function** 

perturbations are also seen in normal aging. Those perturbations decrease activities of complex I and IV of the electron transport chain which lead to an elevated reactive oxygen species production. Increased free radicals and peroxidative damage is also seen in AD (Cunnane et al., 2011). Mitchondria dysfunction seems to contribute to the early stage and to the development of various neurodegenerative diseases (Gibson et al., 2010). Numerous studies have suggested that the activation of PPAR may improve mitochondrial functions. PPARγ stimulation is likely to be more effective than PPARα in inducing mitochondrial biogenesis and seems to be effective to potentiate glucose utilization leading to improved cellular and cognitive function (Rupinder et al., 2011). Fibrates are more selective to PPARα but they also have an action on PPARγ. PPARα play a role in the oxidative stress observed in aging. Effectively, level of PPARα correlated negatively with lipid peroxide levels which are actually reduced following a bezafibrate administration (Pineda Torra et al., 1999). Therapeutic strategies targeted at preventing, delaying or treating mitochondrial dysfunction should contribute to the prevention or treatment of age related neurodegeneratives diseases (Atamna & Frey, 2007), and fibrates may be an interesting target to consider.

#### **2.6 Cardiovascular condition /inflammation**

There is a close link between cardiovascular condition and cognitive status. High blood pressure, obesity, hyperlipidemia and diabetes are among the principal risk factors for cardiovascular disease. Having those conditions also increase the risk of developing cognitive decline. Vascular risk factors may impair cognitive functions and are related to the occurrence of AD, hypertension and type II diabetes present the strongest association, especially when these factors are assessed in middle age. Atherosclerosis is also believed to be involved in development of dementia, particularly, vascular dementia. Some investigations have shown the importance of inflammation in the pathogenesis of AD, (Akiyama et al., 2000). Hypercholesterolemia, oxidative stress and inflammation have emerged as the dominant mechanism in the development of both atherosclerosis and AD (Steinberg, 2002).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.

Based on its efficiency to reduce plasma triglycerides and to increase HDL cholesterol and it lowering action on LDL-cholesterol, major randomized intervention trials involving fibrate therapy were done to evaluate the drug efficiency to prevent cardiac events. These studies showed that a treatment with a fibrate has beneficial effects by reducing myocardial infarction and coronary event (Goldenberg et al., 2008). The Bezafibrate Infarction Prevention (BIP) trial in 2000 showed that bezafibrate also prevent atherosclerosis and significantly attenuates the risk of long term major cadiovascular events (Tennenbaum et al., 2005). PPARα is also involved in the anti-inflammatory response by his inhibition of NFкB transcription and by decreasing the production of pro-inflammatory IL-6, prostaglandins and C- reactive protein. Fibrates are known to be efficient molecules to prevent cardiovascular disease, knowing that cardiovascular disease and cognitive decline share the same risk factors, preventing cardiovascular disease with fibrate therapy should help preserving cognitive functioning during aging.

Peroxisome Proliferator Activated Receptor Alpha

*Aging*, Vol. 2, No. 3, pp. 383-421.

type 2 diabetes. *Physiol Res* Vol. 56 pp. 579-86.

hypertriglyceridaemia. *J Cardiovasc Risk,* Vol.3, pp.385-390.

**5. References** 

7249

1991) pp. 1376-1386.

2006) pp. 387-403.

*Ageing Dev* Vol.128, pp.558-565.

1-11, ISSN 1384-2877.

1094-1101

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 137

Akiyama, H. Barger, S. Barnum, S. (2000) Inflammation and Alzheimer's disease. *Neurobiol* 

Anderlova, K. Dolezalova, R. Housova, J. Bosanska, L. Haluzikova, D. Kremen, J. Skrha, J.

Asplund-Carlson, A. (1996) Effects of gemfibrozil therapy on glucose tolerance, insulin

Atamna, H. Frey, WH. (2007) Mechanism of mitochondrial dysfunction and energy

Auestad, N. Korsak, R. A. Morrow, J.W. Edmond J. (1991). Fatty acid oxidation and

Blennow, K., M. J. de Leon, et al. (2006). Alzheimer's disease, *Lancet*, Vol. 368 No. 9533 (July

Burns, J.M. Donnelly, J.E. Anderson, H.S. Mayo, M.S. Spencer-Gardner, L. Thomas, G.

Carpentier, A. (2008) Postprandial fatty acid metabolism in the development of lipotoxicity and type 2 diabetes, *Diabetes & Metabolism,* Vol. 34. Pp. 697-107 ISSN 1262-3636 Colcombe, S. Erikson, K. Raz, N. Webb, A.G. Cohen, N.J. McAuley, E. Kramer, A.F. (2003)

Cree, M.G. Newcomer, B.R. Read, L.K. Sheffield-Moore, M. Paddon-Jones, D. Chinkes, D.

Cross, H. Ferrie, C. Lascelles, K. Livingstone, J. Mewasingh, L. (2007) Old versus new anti-

Cunnane, S. Nugent, S. Roy, M., Courchesne-Loyer, A. Croteau, E., Tremblay, S. Castellano,

and Alzheimer's disease. *Nutrition* Vol. 27, No.1, pp. 3-20, ISSN 0899-9007. D'Alton S.,George D. (2011) Changing perspectives on Alzheimer's Disease: Thinking

Damci, T. Tatliagac, S. Osar, Z. Ilkova, H. (2003) Fenofibrate treatment is associated with

Alzheimer's disease. *Journal of Alzheimers Disease,* Vol. 10, No. 1, pp.89-109.

patients with hypertriglyceridemia. *Eur J Intern Med*, Vol.14: 357-360. de la Monte, S.M. Tong, M. Lester-Coll, N. Plater, M. Jr. Wands, J.R. (2006) Therapeutics

Vol. 58, pp. 176-180. Courchesne-Loyer et al., in preparation

epileptic drug; the SANAD study. *Lancet,* Vol. 370, pp. 314-16.

Haluzik, M. (2007) Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with

sensitivity and plasma plasminogen activator inhibitor activity in

deficiency in Alzheimer's disease. *Mitochondrion,* Vol. 7, pp. 297-310, ISSN 1567-

ketogenesis by astrocytes in primary culture. *J Neurochem,*Vol. 56, No. 4, (April

Cronk, B.B. Haddad, Z. Klima, D. Hansen, D. Brooks, W.M. (2007) Peripheral insulin and brain structure in early Alzheimer disease. Neurology, Vol. 969, pp.

Aerobic fitness reduces brain tissue loss in ageing humans*. Journal of Gerontology*,

Aarsland, A. Wolfe, R.R. (2007) Plasma triglycerides are not related to tissue lipids and insulin sensitivity in elderly following PPAR-alpha agonist treatment. *Mech* 

A. Pifferi, F. Bocti, C. Paquet, N. Begdouri, H. Bentourkia, M. Turcotte, E. Allard, M. Barbeger-Gateau, P. Fulop, T. Rapoport, S. (2011). Brain fuel metabolism, aging,

outside the amyloid Box, *Journal of Alzheimer's Disease,* Vol. 24, (February 2011) pp.

better glycemic control and lower serum leptin and insulin levels in type 2 diabetic

rescue of neurodegeneration in experimental type 3 diabetes: relevance to
