Donepezil has significant efficacy in the treatment of neuropsychiatric symptoms in patients with mild to moderate AD.

[(11)C]-PK11195 Positron Emission Tomography imaging revealed neuroinflammation in dementia with Lewy bodies and Parkinson's disease, mirroring, even at a single subject level, the common and the different topographical distribution of neuropathological changes, yet in the earliest stages of the disease process. Focusing on those events that characterize parkinsonisms and Parkinson's disease may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection.

VAF347 is a low-molecular-weight compound, which activates the aryl hydrocarbon receptor (AhR). Herein, we report that oral administration of a water-soluble derivative of VAF347 (VAG539) IntroductionDendritic cells (DCs) induce and regulate adaptive immune responses by presenting antigens in an immunogenic or tolerogenic context. [1][2][3] The capacity of DCs to induce specific effector functions in naive T cells designates them as attractive means to stimulate beneficial and suppress detrimental immune responses. [4][5][6] However, specific in vivo modulation of DC function is a complex task because DCs encounter and respond to numerous stimuli, and may modify their function accordingly. 7 Various factors have been suggested to render DCs tolerogenic by enhancing their capacity to promote the induction and/or activation of regulatory T (Tr) cells. 3,6,8,9 Antigen presentation in the absence of costimulation can result in clonal deletion, or in the induction of an anergic and suppressive T-cell phenotype. 10 Indeed, both in human tissue culture and in mice, DCs have been shown to expand IL-10-producing type 1 (Tr1) regulatory T (Tr) cells. 5,11,12 Furthermore, specific DC subsets, such as plasmacytoid DCs and CD8 ϩ splenic DCs, have been shown to selectively expand CD4 ϩ CD25 ϩ Tr cells. [13][14][15][16] Recent evidence also suggests that LPS-activated mature DCs are capable of expanding CD4 ϩ CD25 ϩ Tr cells as well. 3,17 Conversely, in inflammatory conditions, DCs present antigens to effector T cells in the context of proinflammatory cytokines and costimulatory surface molecules, and initiate adaptive immune responses by promoting activation and proliferation of antigen-specific naive T cells. 1,4 In the context of organ transplantation, it has been demonstrated that activated DCs indeed initiate immune responses toward allogeneic antigens, which result in allograft rejection. 18 However, the nature of the maturation signal that activates DCs to initiate an allogeneic immune response remains unclear. 19,20 Several preclinical strategies for the prevention of allograft rejection target DCs, in an attempt to abrogate costimulation and T-cell activation, and to promote the expansion of alloantigenspecific Tr cells. [21][22][23] Islet transplantation offers patients with type 1 diabetes mellitus freedom from long-term insulin therapy and a degree of metabolic control that is far superior to injected insulin. 24 However, the therapeutic efficacy of this strategy is compromised by the necessity to use robust immunosuppressive regimens to prevent islet allograft rejection. 25,26 Therefore, a significant amount of research effort is presently dedicated to the development of novel strategies for the induction of islet donor-specific tolerance. 27 VAF347 is a low-molecular-weight compound that has been shown to modify immune responses through a dual mode of action, namely inhibition of DC-mediated T-cell proliferation and cytokine production and isotype-specific inhibition of IgE class switching by human B lymphocytes...

Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.

Mitochondrial ferritin (FtMt) is a novel ferritin type specifically targeted to mitochondria. It is highly expressed in the human testis and in sideroblasts from patients with sideroblastic anemia, but other organs have not been studied. To study its expression in the main organs of the mouse, we first used RT-PCR and then produced recombinant mouse FtMt and specific antibodies. Immunohistochemistry analyses confirmed that FtMt is highly expressed in mouse testis, particularly in spermatocytes and interstitial Leydig cells. The protein was also identified in other organs including heart, brain, spinal cord, kidney, and pancreatic islet of Langerhans but not in liver and splenocytes, which have iron storage function and express high levels of cytosolic ferritins. Results indicate that the primary function of ferritin FtMt is not involved in storing cellular or body iron, but its association with cell types characterized by high metabolic activity and oxygen consumption suggests a role in protecting mitochondria from iron-dependent oxidative damage.