Файл: Extracellular and Intracellular Signaling (книга).pdf

emerged in some cases.35 Tau is considered today a novel attractive target in AD.36,37 While targeting tau production and aggregation is more theoretical, the possibility to a ect tau phosphorylation has been tested using GSK3b and other tau kinase inhibitors. Compounds able to regulate tau aggregation and folding, to stimulate its clearance and to stabilize microtubules are also being explored as therapeutic agents. Finally, tau immunotherapy has recently been considered and preclinical studies have provided some comforting data.35

Although much is on the way, available treatments are still poor and, in some cases, initial results from early phase clinical trials have been discouraging. Furthermore, there is no absolute certainty that the course of the disease can be modified simply by altering Ab concentrations and/or that results obtained in transgenic animal models of overproduction of Ab can be reproduced in patients with AD. In addition, as mentioned, early intervention may be critical for e cacy of treatment. This requires the development and identification of biomarkers that can be monitored even before the onset of clinical signs of AD. In this respect, according to Montine and co-authors,38 it appears necessary to broaden our current view of potential therapeutic/ preventive approaches to AD and cognitive impairments to include selection of specific biomarkers and a multi-faceted approach to these conditions. In this line, the possibility to place AD in a more global scenario and/or to relate

it to metabolic disorders such as diabetes, hyperinsulinemia, insulin resistance and obesity has to be taken into account.39,40

8.2 AD and Metabolic Dysfunction

8.2.1Impaired Glucose Metabolism

Although still debated, an association between diabetes and the risk of AD has recently found solid support from data provided by several studies with longer follow-up. The association based on several epidemiological studies mainly relates hyperinsulinemia and increased risk of AD. Hence, peripheral

hyperinsulinemia and insulin resistance represent the key elements of the increased risk of AD reported in patients with diabetes mellitus.39–43 Avail-

able epidemiological and clinical data have provided a solid support in this sense, underlying the potential connection between a peripheral metabolic disorder and a disease of the CNS. Under conditions of hyperinsulinemia, in fact, brain insulin levels are decreased due to the impaired transport of peripheral insulin across the blood-brain barrier (BBB).39 The concentrations of insulin in the cerebrospinal fluid are also low in AD patients and this correlates with a lower expression of insulin receptors and insulin receptor substrate (IRS). At the CNS, insulin is known to exert a physiological role in Ab production and clearance. Hence, low brain insulin concentrations result in Ab accumulation since low insulin and impaired insulin signaling a ect APP processing. At the same time, in the CNS, insulin becomes a substrate for insulin degrading enzyme (IDE), thus competing with Ab and decreasing its

clearance.31 Changes in Ab levels under these conditions are accompanied by increased tau phosphorylation due to reduced phosphatidylinositol-3-kinase (PI3K)/AKT signaling and increased glycogen synthase kinase 3b (GSK3b) activity. All these events contribute to AD pathogenesis. To confirm this hypothesis, increases in peripheral insulin levels produce a rise of Ab 1–42 in cerebrospinal fluid, and administration of intranasal insulin that reaches the CNS yields beneficial e ect in AD.

8.2.2Lipid Disorders

More recently, the view of AD in a context of metabolic disorders has been broadened including as a background scenario di erent aspects of disturbances in lipid metabolism. The first association in this regard comes from the demonstrated link between AD and apoE that, as mentioned, represents the main risk factor for the late onset form of the disease. In particular, the presence of two e4 alleles increases the risk of AD by approximately 12-fold and lowers the age of onset of the disease by about 15 years.19 ApoE is a 35 kDa protein that exists in three isoforms, E2, E3 and E4, di ering in only one amino acid. Cholesterol metabolism in the brain is regulated independently of peripheral cholesterol. It is synthesized mainly by astrocytes and microglia or recycled from degenerating neurons.44 Its transport in the brain depends on lipoproteins that are similar to HDL and contain mainly ApoE4 and to a lesser extent ApoE1.45 ApoE in brain is expressed in all types of glial cells, astrocytes, microglia and oligodendrocytes, and under conditions of neuronal damage its main role is the transport of cholesterol and phospholipids from glia to neurons where regeneration and remyelination occur.46,47 Although an exact correlation between the e4 allele and the risk of AD has not been clarified, ApoE is known to play a major role in modulating Ab production and clearance together with its receptors, LDL receptor (LDLR) and LDL receptor related protein (LRP). Accordingly, increased amyloid deposition and impaired cognitive behavior have been reported in transgenic mice lacking LDLR.48 ApoE co-localizes with amyloid deposits in the brain49 and its lipi-

dation state increases its ability to bind Ab.50 ApoE4 is more e cient in inducing Ab synthesis and fibrillogenesis19,51,52 and a ects Ab clearance

though several mechanisms. It causes retention of Ab within the brain, impeding its crossing the blood-brain barrier, thus reducing its tra cking toward the periphery.53,54 A correlation between the E4 isoform and increased tau hyperphosphorylation as well as the formation of neurofibrillary tangles has also been demonstrated.55 Although apoE4 has been mainly related to changes in Ab metabolism, the possibility that this isoform di erently a ects neuroinflammatory processes or altered brain blood flow and metabolic function that accompany AD have also to be considered.19

Although brain cholesterol is recognized to be regulated independently of the periphery, hyperlipidemia and midlife elevation of serum cholesterol (o6.5 mmol/l) significantly augment the risk of AD.56–58 Accordingly, studies

participate in metabolic functions. Adipokines can be synthesized by fat as well as non-fat cells of the adipose tissue but they can also be synthesized at di erent sites and exert independent actions. Many of them exert proinflammatory e ects, including leptin, tumor necrosis factor-a (TNFa), interleukin-6 (IL-6) angiotensinogen, resistin, plasminogen activator inhibitor (PAI), whereas a few others exert mainly anti-inflammatory activity. Among the latter are adiponectin and transforming growth factor b (TGFb). Most of the adipokines identified to date have high circulating plasma levels in obese subjects. Some of them reflect the mild inflammatory condition that characterizes obesity in its initial phases, others have more inflammatory features and their origin is debated.86 Additional adipokines may be endowed with anti-inflammatory e ect and be at higher circulating levels in obesity because of a compensatory response to inflammatory mediators. IL-10 as well as IL-6 may be considered in this context.87,88 As a whole, adipokines are considered fundamental regulators of carbohydrate and lipid metabolism. This gains importance in terms of deposition and mobilization of fatty acids and regulation of obesity-related comorbidities.89 However, the e ect of adipokines is not restricted to the periphery since some of them can cross the BBB or modulate the function of endothelial cells.90

8.3.1Leptin

The more well known and characterized adipokine, leptin, which has allowed the identification of this large family of proteins all related to lipid metabolism, was initially recognized because of its anorexigenic and appetite suppressive e ects. Both e ects are exerted within the brain. Since then, interest in the e ects of adipokines in the brain has increased and knowledge of this specific issue has broadened. Leptin is a 16-kDa peptide that exerts its biological actions by binding to Lep-Rb (ObR, a–f), all members of the IL-6 receptor family of the class I cytokine receptor superfamily, and divided into long, short and soluble forms.91 Six di erent isoforms of the ObR have been described. The long form ObRb seems to mediate most of the actions of leptin. Short forms of the receptor such as ObRa and ObRc are abundantly expressed in cerebral vessels of the BBB suggesting a role for these short forms of receptor in the transport of leptin from the periphery into the brain. Interestingly, leptin binds also megalin/LRP2, a multi-ligand receptor

expressed in choroid plexus epithelial cells that is known to participate also in Ab clearance from the brain to the blood.92,93 Transport across the BBB

seems to be crucial although leptin is also known to be produced in very low amounts within the brain. ObRb is devoid of autophosphorylation and signals mainly through JAK2 responsible for phosphorylation of STAT, above all STAT3, that dimerizes and translocates to the nucleus to control the expression of a series of genes. Alternatively JAK2 activates the SH2/SH3 domain-containing adaptor protein growth factor receptor-bound protein 2 (GRB2), responsible for downstream involvement of the mitogen-activated

kinase (MAPK) pathway. The latter is the only signaling cascade activated by the short forms of ObR.94

Leptin via its central actions does not control exclusively food intake, but recognizes receptors also in the hippocampus where it controls cognitive processes. It in fact facilitates learning and memory events, increases long-term potentiation (LTP)95 and enhances synaptic density.96 Accordingly, impairment of LTP is reported in db/db mice, which carry a leptin receptor mutation and do not express functional leptin receptors,97 whereas leptin treatment increases hippocampal concentrations of synaptic proteins including synapsin 2A and synaptophysin.98 Leptin is also endowed with neuroprotective e ects as shown by decreased neuronal death following either serum or neurotrophic factor deprivation.99 In addition, leptin has been proven to counteract the loss of dopaminergic neurons observed in experimental models of Parkinson’s disease, to be neuroprotective against ischemic stroke and to exert anticonvulsant properties in most seizure models.100

Among various adipokines, leptin is the one that has been more convincingly related to AD. In fact, observational studies have demonstrated an inverse relationship between blood leptin levels on one side and human cognitive impairment and AD development on the other side.101 Conversely, high peripheral leptin concentrations correlate to a low incidence of dementia and AD.102 Leptin can a ect AD pathogenesis by acting at multiple sites (Figure 8.1). Evidence exists in fact to suggest that it a ects not only Ab but also NFT formation. In particular, due to its lypolitic e ect, leptin modifies lipid raft composition and a ects indirectly BACE activity, thus decreasing Ab formation.103 It increases also Ab clearance by facilitating ApoE-dependent Ab uptake through LRP1.103 These in vitro data find support in animal studies

reporting the ability of leptin to reduce Ab load in a transgenic model of AD103,104 and to improve cognitive performance in AD mice.105 The e ects of

leptin are not limited to modulation of Ab synthesis and degradation as leptin decreases also tau phosphorylation in neurons,106 through modulation

Aβ

leptin

ObRb

MAPK JAK2/STAT3

BACE = Ab synthesis

LRP1 = Ab clearance

AMPK = ptau

Figure 8.1 Mechanisms involving leptin in the pathogenesis of AD.

of AMP-activated protein kinase (AMPK)107 and ensuing inactivation of GSK-3b,108 which is known to be involved with tau hyperphosphorylation and neurofibrillary tangle formation. Of note, AMPK seems to mediate not only the e ect of leptin on tau phosphorylation, but also the reducing action of leptin on Ab production. Moreover, the e ects of leptin, through AMPK activation, involve two independent downstream signaling pathways, with peroxisome proliferator-activated receptor-g (PPAR-g) a ecting Ab formation through BACE and GSK3b modifying tau phosphorylation.107 All these experimental data have identified leptin as a novel potential therapeutic tool in AD104 and have also indicated leptin-induced intracellular signals as a potential target in the optic of novel treatments of AD.

8.3.2Adiponectin

Adiponectin is a 224 amino acid protein whose main function is decreasing glucose synthesis in the liver and enhancement of fatty acid oxidation, thus exerting in anti-atherogenic, anti-diabetic and insulin-sensitizing properties.109 Accordingly, decreased serum concentrations of adiponectin correlate with obesity, type 2 diabetes and insulin resistance. Adiponectin binds two di erent receptors, ADIPOR1 and ADIPOR2. Stimulation of both receptors leads to subsequent activation of AMPK, PPAR-a and PPAR-g. An action of adiponectin at the CNS has not been clearly demonstrated as it does not cross the BBB. However, an upregulation of adiponectin receptors has been observed in brain endothelium during fasting.110 Thus adiponectin seems to exert only indirect e ects in the CNS, such as reduced release of IL-6 observed in brain endothelial cells following treatment with adiponectin.111 To date, the ability of adiponectin to modify IL-6 (or other proinflammatory cytokines) in the brain represents the only link between this adipokine and AD. However, the possibility that adiponectin plays an indirect role by reducing insulin resistance, diabetes, obesity, all conditions considered main risk factors for AD, has also to be taken into account.

8.3.3Resistin

Resistin is a member of the resistin-like molecule (RELM) family of cysteinerich proteins, which appears to increase in obesity, type 2 diabetes and insulin resistance, although some controversies regarding its role in humans still exist.112 It is clear that resistin is upregulated in inflammatory processes and a reciprocal control exists between resistin, TNFa and IL-6. Thus, resistin has been suggested to be involved in several inflammatory conditions including inflammatory bowel disease, coronary artery disease and rheumatoid arthritis.112 Resistin is present in the brain and its expression increases under conditions of hypoxia/ischemia, traumatic brain injury or cerebral LPS injection.113 Although leptin and resistin synergize to control glucose homeostasis in diabetes, they a ect STAT3 and AMPK in an opposite way. Thus, resistin counteracts central leptin action and nullifies its signaling.114