**Peroxisome Proliferator Activated Receptor Alpha (PPAR) Agonists: A Potential Tool for a Healthy Aging Brain**

Jennifer Tremblay-Mercier *Université de Sherbrooke, Research Center on Aging Canada* 

#### **1. Introduction**

122 Pharmacology

Yamamoto, S., N. Yamamoto, et al. (2001). "Proliferation of parenchymal neural

Zhang, G., W. Chen, et al. (2010). "Cannabinoid CB1 receptor facilitation of substance P

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115-127.

Eur J Neurosci 31(2): 225-237.

17(12): 2750-2754.

progenitors in response to injury in the adult rat spinal cord." Exp Neurol 172(1):

release in the rat spinal cord, measured as neurokinin 1 receptor internalization."

cord of neuropathic but not inflammatory chronic pain models." Eur J Neurosci

#### **1.1 Definitions and considerations**

Cognitive decline related to advancing age includes many sub-categories of diseases, some more or less well defined and understood. First, there is "normal" cognitive decline, which is gradual and progressive during aging and seems inevitable. When cognitive decline is large enough to disrupt the activities of daily life, a state of dementia is diagnosed. There are several types of dementia according to the etiology of cognitive decline: vascular dementia, which results from a circulatory disorder causing an obstruction of cerebral blood vessels which leads to the progressive degeneration of brain cells due to a lack of oxygen. Vascular dementia represents 20% of all cases of dementia. Lewis body dementia is an accumulation of α-synuclein protein within the cell and it represents 5 to 15% of neurodegenerative diseases. Frontotemporal dementia as the name suggests, is a degeneration of the region of the frontal and temporal anterior cortex. The reasons for this degeneration are not fully understood. Alzheimer's disease (AD) represents the majority of cases of dementia (65%) although its etiology is not known exactly, or rather multi-factorial.

The most accepted theory in the medical community to explain the origin of AD is currently the accumulation of β-amyloid protein in the form of plaques accompanied by neurofibrillary tangles of tau protein that cause neuronal death and loss of brain matter. However, this theory is challenged for many reasons. The high profile failures of antiamyloid interventions and lack of agreement on which form the β-amyloid is toxic and the mechanism by which this occurs force the scientific community to consider amyloid only as one part of a multi-factorial disease process including a variety of aggravating factors. A recent paper entitled "Changing perspectives on Alzheimer's Disease: Thinking outside the amyloid Box" resume this thinking (D'Alton & George, 2011).

#### **1.2 Alzheimer's disease diagnosis**

The clinical diagnosis of AD is based on clinical examination and confirmed by neuropsychological tests and is diagnosed through exclusion. That means if the person

Peroxisome Proliferator Activated Receptor Alpha

2011).

AD (Reiman et al., 2004).

does in a proportion of about 18% (Cunnane et al., 2011.)

**1.3 Physiopathology: Focus on brain metabolism** 

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 125

In addition to the abnormal protein (aβ, tau, α-synuclein) present in the demented brains, there is also a decrease in brain glucose metabolism in the majority of dementia. The brain is one of the most metabolically active organs. Despite representing about 2% of adult body weight, the brain uses about 23 % of the body's total energy needs. The brain gets its energy from glucose to 97% making it the main energy substrate. Every day, an average human brain consumes approximately 16% of the total oxygen consumption and metabolizes approximately 110 to 145 g of glucose. Over 90% of used glucose is oxidized to ensure the supply of ATP which is vital for the cells and maintenance of synaptic transmission (Henderson, 2008). The determination of the brain glucose metabolism pattern is used in the differential diagnosis of dementia using Position Emission Tomography (PET) imaging with an analog of glucose; 18fluorodeoxyglucose (18FDG). The cerebral glucose hypometabolism in cases of AD has been known since the 1980s with the beginning of PET imaging and represents about 20% reduction but varies between 8 and 49% (reviewed in Cunnane et al.,

In the case of AD, several evidences shows that brain glucose hypometabolism is present in certain regions well before the first clinical signs of cognitive decline, so it is not simply the result of neuronal loss but rather would be responsible for this loss. For example, in a clinical study containing 20 AD patients and 20 young adults (20-39 years old) at risk of developing AD (carrier of the Apolipoprotein E4 allele; ApoE4), small areas of cortical glucose hypometabolism were present in the young participants, especially in the posterior cingulate, parietal, temporal and prefrontonal cortex. These hypometabolic regions were the same in the AD patients but in a more extensive way. This reduction in brain glucose metabolism may be the earliest brain abnormalities yet found in living persons at risk for

It is still unclear as to whether or not healthy aging (no cognitive impairment) is associated with reduction in brain glucose metabolism. Cunnane and collegues reviewed the literature on this specific question and they found out that eight studies showed that cerebral glucose metabolism does not decline with healthy aging and nine studies have demonstrated that it

The reason for this alteration in brain glucose metabolism is not clearly elucidated. It could be a problem in the glucose transport, glucose availability, or a dysfunction in the production of energy derived from glucose. Mitochondria play a central role in producing ATP as the central

The brain uses glucose as main energy source but can also use ketones as an alternative energy source in situations of glucose deprivation (fasting, intense physical activity). Ketones refer to 3 molecules: acetoacetate, β-hydroxybutyrate (β-OHB) and acetone. In starvation conditions, up to 60% of the human brain energy requirements can be met by ketones (Owen, 1967). Whether ketone brain metabolism is also decreasing in healthy aging or in AD is not yet known, but Cunnane's team developed a ketone radiotracer (11Cacetoacetate) especially to be able to study brain ketone metabolism in the elderly; studies are ongoing. Based on the fact that ketones are energetic molecules and used by the brain as an alternative to glucose, some studies have demonstrated the ability of ketones to improve some cognitive dysfunction in diabetic hypoglycemia (Page et al., 2009) and even in case

source of cellular energy, so a dysfunction at the mitochondria level is conceivable.

presents a certain profile of cognitive decline and does not match certain criteria (Table 1) the patient is put into the broad category of "probable" AD (Whitehouse, 2008). Within this category there are "typical" Alzheimer and those who are called "atypical" which means that their profile may include some features of vascular dementia or components of Lewis Body dementia. In 2011, the use of brain imaging (Positrons Emission Tomography (PET) and Magnetic Resonance Imaging (MRI)) can optimize the basic clinical diagnosis (clinical and neuropsychological data) of atypical profile, if this kind of technological platform is available. However, it is only at death that the diagnosis can be confirmed by neuropathological brain examination of the abundance of β-amyloid plaques and neurofibrillary tangle, even if the amyloid theory is increasingly questioned. Not surprisingly, neuropathological diagnosis of post-mortem brain does not always correlate with the clinical diagnosis. One classic example is the "Nun Study" from Chicago (Snowdon et al., 1997), in this study, several participants showed abundant neurofibrillary tangles and β-amyloid plaques at the post-mortem analysis, but had not received a clinical diagnosis of AD and were mentally intact during their life. The opposite was also seen i.e. that a person with a clinical AD diagnostic presented an intact brain (no neuropathology) at death.


Table 1. Alzheimer's Disease: diagnosis of exclusion (Adapted from Whitehouse, 2008)

The mismatch between clinical diagnosis and aβ and tau neuropathology at death shakes the causation link and suggests the importance of other aspects in the etiology of the cognitive decline associated with aging.

#### **1.3 Physiopathology: Focus on brain metabolism**

124 Pharmacology

presents a certain profile of cognitive decline and does not match certain criteria (Table 1) the patient is put into the broad category of "probable" AD (Whitehouse, 2008). Within this category there are "typical" Alzheimer and those who are called "atypical" which means that their profile may include some features of vascular dementia or components of Lewis Body dementia. In 2011, the use of brain imaging (Positrons Emission Tomography (PET) and Magnetic Resonance Imaging (MRI)) can optimize the basic clinical diagnosis (clinical and neuropsychological data) of atypical profile, if this kind of technological platform is available. However, it is only at death that the diagnosis can be confirmed by neuropathological brain examination of the abundance of β-amyloid plaques and neurofibrillary tangle, even if the amyloid theory is increasingly questioned. Not surprisingly, neuropathological diagnosis of post-mortem brain does not always correlate with the clinical diagnosis. One classic example is the "Nun Study" from Chicago (Snowdon et al., 1997), in this study, several participants showed abundant neurofibrillary tangles and β-amyloid plaques at the post-mortem analysis, but had not received a clinical diagnosis of AD and were mentally intact during their life. The opposite was also seen i.e. that a person

with a clinical AD diagnostic presented an intact brain (no neuropathology) at death.

Table 1. Alzheimer's Disease: diagnosis of exclusion (Adapted from Whitehouse, 2008)

cognitive decline associated with aging.

The mismatch between clinical diagnosis and aβ and tau neuropathology at death shakes the causation link and suggests the importance of other aspects in the etiology of the In addition to the abnormal protein (aβ, tau, α-synuclein) present in the demented brains, there is also a decrease in brain glucose metabolism in the majority of dementia. The brain is one of the most metabolically active organs. Despite representing about 2% of adult body weight, the brain uses about 23 % of the body's total energy needs. The brain gets its energy from glucose to 97% making it the main energy substrate. Every day, an average human brain consumes approximately 16% of the total oxygen consumption and metabolizes approximately 110 to 145 g of glucose. Over 90% of used glucose is oxidized to ensure the supply of ATP which is vital for the cells and maintenance of synaptic transmission (Henderson, 2008). The determination of the brain glucose metabolism pattern is used in the differential diagnosis of dementia using Position Emission Tomography (PET) imaging with an analog of glucose; 18fluorodeoxyglucose (18FDG). The cerebral glucose hypometabolism in cases of AD has been known since the 1980s with the beginning of PET imaging and represents about 20% reduction but varies between 8 and 49% (reviewed in Cunnane et al., 2011).

In the case of AD, several evidences shows that brain glucose hypometabolism is present in certain regions well before the first clinical signs of cognitive decline, so it is not simply the result of neuronal loss but rather would be responsible for this loss. For example, in a clinical study containing 20 AD patients and 20 young adults (20-39 years old) at risk of developing AD (carrier of the Apolipoprotein E4 allele; ApoE4), small areas of cortical glucose hypometabolism were present in the young participants, especially in the posterior cingulate, parietal, temporal and prefrontonal cortex. These hypometabolic regions were the same in the AD patients but in a more extensive way. This reduction in brain glucose metabolism may be the earliest brain abnormalities yet found in living persons at risk for AD (Reiman et al., 2004).

It is still unclear as to whether or not healthy aging (no cognitive impairment) is associated with reduction in brain glucose metabolism. Cunnane and collegues reviewed the literature on this specific question and they found out that eight studies showed that cerebral glucose metabolism does not decline with healthy aging and nine studies have demonstrated that it does in a proportion of about 18% (Cunnane et al., 2011.)

The reason for this alteration in brain glucose metabolism is not clearly elucidated. It could be a problem in the glucose transport, glucose availability, or a dysfunction in the production of energy derived from glucose. Mitochondria play a central role in producing ATP as the central source of cellular energy, so a dysfunction at the mitochondria level is conceivable.

The brain uses glucose as main energy source but can also use ketones as an alternative energy source in situations of glucose deprivation (fasting, intense physical activity). Ketones refer to 3 molecules: acetoacetate, β-hydroxybutyrate (β-OHB) and acetone. In starvation conditions, up to 60% of the human brain energy requirements can be met by ketones (Owen, 1967). Whether ketone brain metabolism is also decreasing in healthy aging or in AD is not yet known, but Cunnane's team developed a ketone radiotracer (11Cacetoacetate) especially to be able to study brain ketone metabolism in the elderly; studies are ongoing. Based on the fact that ketones are energetic molecules and used by the brain as an alternative to glucose, some studies have demonstrated the ability of ketones to improve some cognitive dysfunction in diabetic hypoglycemia (Page et al., 2009) and even in case

Peroxisome Proliferator Activated Receptor Alpha

**2.1 Mecanisms, pathways, activators** 

activate or repress (figure 2).

**2. PPAR** 

(PPAR) Agonists: A Potential Tool for a Healthy Aging Brain 127

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

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 (\_ \_).

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

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

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 relationship exist between these two entities.

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

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).
