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Chapter 8 |
Although direct information is missing, what is known to date, which includes the indirect proinflammatory action exerted through upregulation of inflammatory cytokines, increased expression under several inflammatory brain states and the antagonism of leptin e ects in the CNS, seems to indicate an unfavorable action of resistin in AD.
8.3.4Visfatin
Visfatin, also known as pre-B cell colony enhancing factor (PBEF) and nicotinamide phosphoribosyl transferase (Nampt), in most species, is a 491 amino acids protein with several functions including enhancement of cell proliferation, maturation of B cells, biosynthesis of nicotinamide monoand di-nucleotide and hypoglycemic e ects derived from reduction of glucose release from liver
and stimulation of glucose utilization in adipocytes and myocytes. Serum levels of visfatin are elevated in obesity and type 2 diabetes115,116 and visfatin mimics
insulin binding to its receptor at a site di erent from that of insulin.
Visfatin is recognized as a proinflammatory agent, stimulating inflammatory cytokine expression, such as TNFa, IL-6 and promoting smooth muscle cell maturation. High visfatin serum levels have been associated with inflammatory conditions and ischemic stroke,117 but a protective e ect of visfatin in cerebral ischemia has also been shown.118 One interesting aspect that may help in identifying a specific role for visfatin in AD resides in its nicotinamide phosphoribosyl transferase activity. NAD originates in fact from nicotinamide, substrate for visfatin, which is converted to nicotinamide mononucleotide (NMN) and then to NAD, and further reduced to NADH. The latter is a substrate for NADH oxidase that forms superoxides. Ab seems to be endowed with NADH oxidase activity to form oxygen radicals from extracellular NADH. Hence, an enhanced production of visfatin, in the presence of Ab, results in increased formation of free oxygen species that can contribute to an increased damage to neurons and the BBB.119 It is suggested that visfatin represents the central factor of a vicious cycle in which enhanced oxygen radicals cause damage to the brain vasculature, increasing chemotaxis of blood cells that contribute to produce visfatin with ensuing proinflammatory cytokines. As visfatin levels may increase with age, an excessive accumulation, with other concomitant factors, may be responsible for a cumulative brain damage that characterizes AD or other neurodegenerative conditions.
8.3.5Plasminogen Activator Inhibitor
Plasminogen activator inhibitors (PAI-1 and -2) are protease inhibitors belonging to the serpin family. PAI regulates the plasminogen activator (PA)/ plasmin system that is involved in a variety of functions including cell migration, invasive growth, neuronal migration and plasticity. Overexpression of PAI causes adipocyte hypotrophy whereas mice deficient in
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PAI-1 have faster weight gain in diet-induced obesity indicating a protective role of PAI-1 in this condition.120 However, increased PAI-1 concentrations are considered a risk factor for thrombotic diseases. Elevated PAI levels correlate also with the metabolic syndrome and insulin resistance. PAI-1 is positively controlled by TGF-b both in the periphery and in the CNS where TGF-b exerts its neuroprotective e ect by stimulating production of PAI-1 in astrocytes.
PAI is expressed in the human brain in both neurons and astrocytes121 and has been reported to exert anti-apoptotic and neurotrophic activities in the CNS.122 Evidence also exists to suggest a role for PAI-1 in AD. Plasmin in fact contributes to Ab clearance, cleaving both monomeric and fibrillar Ab and its protein levels are reduced in AD.123 In addition PA activity in the frontal cortex of AD patients is dramatically reduced, although PAI-1 concentrations are not changed.124 These data confirm results obtained in animal models of AD in which elevated Ab correlates with inhibition of PA/plasmin system and upregulation of PAI-1. Moreover, in mice lacking PA or plasminogen, but not in wild-type mice, injection of Ab causes PAI expression and neuronal damage.125 Available data seem to suggest that inhibition of the PA/plasmin system by PAI-1 contrasts with clearance of Ab favoring its accumulation. However, controversies still exist in this regard as the increased PAI-1 levels observed in the AD mouse model have also been considered neuroprotective against Ab-induced neuronal damage.122
8.3.6Interleukin-6
IL-6 is a pleiotropic proinflammatory cytokine produced by adipocytes whose plasma levels correlate with insulin resistance and obesity. In obese patients about 30% of total IL-6 can originate from adipocytes. Although IL-6 is
produced both in the periphery and centrally, its levels have been reported to be elevated in plasma, CSF and brains of AD patients.126,127 As cerebral inflam-
matory processes may play a main role in AD, several inflammatory molecules including IL-6, either produced by resident cells surrounding the plaque, such as microglia, or periphery-derived cells, are elevated in AD patients.128 However, although peripheral IL-6 can cross the BBB, its real contribution to the cerebral inflammatory process is not clear. Despite this, peripheral blood levels of IL-6 have been suggested as potential biomarkers of AD severity.129 Although the upregulation of IL-6 in the AD brain might suggest a detrimental role on neuronal viability, a recent report very elegantly supports a protective function of IL-6 with reduction of Ab deposition consequent to enhanced Ab clearance.130
8.3.7Transforming Growth Factor-b1
TGF-b1, a 25-kDa protein, is a potent anti-inflammatory molecule produced by adipocytes as well as other tissues. The ratio of TGF-b1 mRNA produced in
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fat cells to that in non-fat cells is, however, very low and this, together with its low ability to cross the BBB, makes it di cult to look at TGF-b1 as an adipokine of fat-cell origin acting in the CNS. TGF-b1 is instead produced in the CNS mainly by astrocytes and microglia in response to injury or during aging. TGF-b1 is elevated in the CSF, but not in plasma, of AD patients whereas a defect in TGF-b1 signaling facilitates Ab deposition and reduces
neuronal viability in a mouse model of AD and negatively correlates with neurofibrillary tangle formation in humans.131,132 Among the mechanisms
involved in the neuroprotective actions of TGF-b1 in AD it is plausible to consider the release of neurotrophic factors as well as the reduction of microglia
activation with ensuing lower release of the inflammatory cytokines IL-1b, TNFa, IL-6 and enhanced degradation of Ab.133
8.4 Conclusions
In summary, interest in adipokines cannot remain restricted to their functions in adipose tissue or in metabolic disturbances. This actively growing family of proteins is in fact produced in di erent tissues exerting various actions. It remains to be established whether actions in the CNS, or specifically in AD, can be reconnected to their peripheral origin or should be considered absolutely independent of the adipose tissue. It has to be remembered in this regard that some of them do not cross or barely cross the BBB. On the other hand, some adipokines may represent promising molecules as biomarkers to follow the disease state. Unfortunately, no data are available to correlate with the actions of most adipokines in AD pathogenesis or to understand their real roles in the synthesis, action and degradation of Ab or hyperphosphorylation of tau. When more profound information is provided, it is hard to believe that a direct connection exists between adipose tissue and CNS. This, for instance, can be the case of TGF-b1. Much has to be done to clarify these aspects.
However, in a broader view of AD on a background scenario of metabolic disorders that include also lipid dysregulation and glucose homeostasis dysfunction, a profound characterization of the role of adipokines in the pathogenesis of AD or their consideration as target of focused interventions in the treatment of the disease certainly deserves great attention and may provide useful tools to help relate AD to main metabolic disorders. Leptin may represent the leading molecule in this sense but several other adipokines seem promising and require further investigation.
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