CHAPTER 10
DNA, Nuclear Cell Signaling
and Neurodegeneration
JAMES D. ADAMS, JR., PH.D.
Associate Professor, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, PSC 716, Los Angeles, CA 90089-9121, USA
10.1 Adipokines, Toxic Lipids and the Aging Brain
Most people are born with healthy brains and could keep their brains healthy if they knew how. But many aging people become less active and adopt toxic lifestyles that alter normal physiology and muscle mass. As the body ages muscle tissue is lost and fat tends to accumulate, sometimes with the development of the metabolic syndrome. At the same time, neurons and other brain cells accumulate more fat.1,2 As ectopic and visceral fat accumulate, adipokines are secreted into the blood, including visfatin, leptin, resistin, TNFa, IL-6 and others.3 At the same time, adiponectin, the protective adipokine, decreases.3 Adipokines are secreted by visceral fat cells, macrophages and perhaps other cells. What are the consequences in the brain of these changes to the body?
Health care for stroke and Alzheimer’s disease patients is very limited and has not greatly improved for more than 40 years. The typical care for a stroke patient is to observe them in the emergency room six hours after they su ered a stroke. This is because six hours is required for the brain lesion to stabilize. Many patients are then released to return home. For most other patients, health care is supportive. For 10% or fewer patients, a blood-clot-dissolving factor may be given, which can provide a small benefit to them. Alzheimer’s disease care is
RSC Drug Discovery Series No. 10 Extracellular and Intracellular Signaling
Edited by James D. Adams, Jr. and Keith K. Parker r Royal Society of Chemistry 2011
Published by the Royal Society of Chemistry, www.rsc.org
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limited to supportive care for many patients. Ginkgo or cholinesterase inhibitors can be used with small benefit to the patients.
10.1.1Toxic Lifestyles, Adipokines and Toxic Lipids
Considerable controversy exists about lifestyle and obesity as causes of some forms of neurodegeneration. However, the most common cause of stroke is thrombosis lodged in the middle cerebral artery. Thrombosis frequently is caused by atherosclerosis, that is associated with toxic lifestyles, including alcohol consumption, smoking, the metabolic syndrome and lack of exercise.4,5 It is clear that stopping toxic lifestyles and increasing exercise can have an impact on adipokines and the metabolic syndrome.5,6 Lifestyle improvements, in clinical trials, lead to decreased leptin levels,7 increased adiponectin levels,8,9 decreased TNFa levels9 and decreased C-peptide levels.10
Alzheimer’s disease appears to be associated with, and perhaps caused by, changes in lipid metabolism in the brain, especially ceramide. Cholesterol and lipid
metabolism are altered in Alzheimer’s disease, which results in lipid accumulation in the brain and other cells.2,11–14 Ceramide increases in the brain as an early
event in the pathogenesis of Alzheimer’s disease.2,15–17 Astrocytes and cerebral cortical cells are the primary sites of increase.18–20 Ceramide accumulation clearly is caused, in part, by sphingomyelin catabolism. However, excessive triglyceride accumulation can also lead to switches in cellular biochemistry that cause an increase in ceramide synthesis as an alternative fat storage mechanism.
Apolipoprotein E isoforms appear to be risk factors for Alzheimer’s disease,20,21 and are involved in triglyceride transport and uptake. This implies that the uptake of triglycerides into the brain may be involved in the development of Alzheimer’s disease. This leads, in part, to ceramide accumulation.
A lifestyle that is good for the heart is also good for the brain. This is clearly demonstrated in the WHIMS trial where postmenopausal women with hypertension were at increased risk of developing dementia and white matter lesions.22 Another risk factor for Alzheimer’s disease is decreased muscle mass.23 Exercise is good for the muscles, heart and perhaps the brain. Diets low
in fat and high in fruit and vegetables are good for the heart and also decrease the risk of Alzheimer’s disease.24,25
What causes the changes in lipid metabolism in Alzheimer’s disease? Leptin levels may be low in Alzheimer’s disease patients,26 leading to decreased fatty acid catabolism and increased ceramide accumulation. It is not clear why leptin levels are lower in Alzheimer’s disease patients compared to non-demented, age-matched controls. Is it possible that Alzheimer’s disease patients are less obese than controls? Or is it possible that another factor causes leptin levels to decrease in people at risk of developing Alzheimer’s disease?
The e ects of lifestyle and toxic lipids are not well examined in other forms of neurodegeneration. However, half of the patients who have su ered from Parkinson’s disease for more than a few years develop Alzheimer’s disease. This suggests some commonality between the causes of Alzheimer’s disease and Parkinson’s disease.
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10.1.2Ceramide Toxicity in the Brain
During aging the brain switches from using tropomyosin related kinase A (TrkA) to p75 neurotrophin receptor (p75NTR) as the main receptor for nerve growth factor (NGF).27 Both NGF receptors regulate the processing of APP (amyloid precursor protein) in the brain. p75NTR is involved in the activation of the beta cleavage of APP. APP is an integral membrane protein that is found abundantly in synapses. Ceramide accumulation increases the interaction of p75NTR, NGF and ceramide, which activates the pathway for beta scission of APP.27 This produces amyloidb in the brain that forms extracellular plaques and deposits around arteries and arterioles. All people accumulate amyloidb plaques to a certain extent during normal aging. Alzheimer’s disease patients frequently accumulate more plaques than normal. Amyloidb causes ceramide to accumulate in the brain, in a vicious cycle, by stimulation of sphingomyelinase activity.2,28
Ceramide induces both the inducible and endothelial forms of nitric oxide synthase (iNOS and eNOS).29,30 Ceramide also causes these enzymes to dys-
function, which produces peroxynitrite, superoxide and oxygen radicals rather than the normal nitrous oxide (NO). Superoxide and oxygen radical formation lead to dismutation and hydrogen peroxide generation. NO is usually protective of endothelial cells and causes vasodilation. However, peroxynitrite,
superoxide and hydrogen peroxide damage endothelial cells and astrocytes in the brain.31,32 This leads to a leaky blood-brain barrier that may attract
monocytes and neutrophils.33 Monocytes are known to penetrate the bloodbrain barrier in Alzheimer’s disease.34
Ceramide production in the brain is a vicious cycle in which initial formation of ceramide causes more ceramide accumulation.35 Ceramide activates amyloidb formation that induces NADPH oxidase (NOX) activity, which forms extracellular hydrogen peroxide.35 Hydrogen peroxide can cross cell membranes and activates neutral sphingomyelinase that forms ceramide.35 NOX is primarily a transmembrane enzyme found in macrophages, monocytes and neutrophils. NOX is discussed in more detail below.
Ceramide decreases glycolysis in the brain.36 Alzheimer’s disease is associated with decreased glucose uptake/metabolism in the brain.37 This may involve amyloidb competition with insulin for binding to the neuronal insulin receptor, thereby causing neuronal hypoglycemia and potential neuronal death.38 This could be a critical mechanism for some populations of neurons that may rely on insulin or insulin-like growth factor to stimulate glucose uptake and use.36 However, ceramide induced decreases in glycolysis will lead to less use of glucose and perhaps more use of fats as energy sources in the brain.
10.1.3Endocannabinoids, Ceramide and Amyloidb
Endocannabinoids, 2-arachidonyl glycerol and anandamide are involved in the regulation of energy metabolism in the body, and stimulate eating.39 They are synthesized on demand and are released from neurons where they function
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as neurotransmitters.39 Endocannabinoids increase during the metabolic syndrome and when lipids accumulate in cells.39 A cannabinoid receptor, transient receptor potential cation channel vanilloid 1 (TRPV1), may be involved in inflammation in the brain.40 Amyloidb increases 2-arachidonyl glycerol levels and decreases anandamide levels.40 This may produce a vicious cycle in which endocannabinoids stimulate more eating, leading to more ceramide and amyloidb, which increases 2-arachidonyl glycerol levels.
10.2The Blood-Brain Barrier as a Target for Neurodegenerative Conditions
If adipokines are involved in neurodegeneration, it is logical that they might act at the blood-brain barrier. Adipokines are proteins that do not readily cross the blood-brain barrier. Damage to the blood-brain barrier might allow amyloid to penetrate into the brain, accumulate around blood vessels and form plaques in the brain. A recent paper suggests that protection of the blood-brain barrier may be useful in Alzheimer’s disease.41 Monocytes and other white blood cells penetrate the blood-brain barrier and infiltrate into brain tissue in Alzheimer’s disease.42 The adipokine monocyte chemoattractant protein-1 (MCP-1) causes monocytes to stick to brain endothelial cells which increases blood-brain barrier permeability.43 Monocytes induce endothelial cells to make tissue-type plasminogen activator that allows the monocytes to penetrate through endothelial tight junctions.44 How does the blood-brain barrier become damaged such that monocytes begin to stick?
10.2.1Visfatin and the Blood-Brain Barrier
Visfatin is secreted by visceral adipocytes and macrophages, and has insulin mimetic activity such that it binds to and activates the insulin receptor.45 Visfatin is also known as pre-B cell colony enhancing factor and is important in the maturation of B cells.40 Visfatin is also nicotinamide phosphoribosyl transferase and makes nicotinamide mononucleotide (NMN) from nicotinamide and ATP.46 ATP is found normally in plasma,47 as is nicotinamide. Plasma NMN is made into NAD by CD38, NADH pyrophosphatase and other extracellular enzymes located on lymphocytes and other cells.48 CD38 normally breaks down NAD. However, when NAD levels are very low, such as in normal plasma, CD38 operates in the reverse direction and synthesizes NAD. NAD is reduced to NADH by xanthine oxidoreductase and other extracellular dehydrogenases.49 NADH is a substrate for NADH oxidase, an ecto-enzyme that is
found on endothelial cells, monocytes, macrophages, neuronal plasma membranes and other cells.50–54 An NADH oxidase located on white blood cells
increases in activity during aging.55
NADH oxidase di ers from NOX.56 NOX transfers electrons from cytoplasmic NADPH through the transmembrane enzyme to extracellular oxygen, forming extracellular superoxide.57 NADH oxidase is an extracellular,