Retinoic acid isomers protect hippocampal neurons from amyloid-beta induced neurodegeneration.
ABSTRACT Attenuating amyloid-beta mediated neurodegeneration is of major therapeutic consideration in the potential treatment of Alzheimer disease. Previously, we found that a high dietary consumption of retinoic acid was associated with a reduced incidence of Alzheimer disease. Therefore, in this study, we investigated whether amyloid-beta mediated cell death in primary hippocampal neurons could be prevented by retinoic acid isomers. Our results suggest that retinoic acid isomers, including all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid, may play an important role in protecting neurons from amyloid-beta -induced cell death. Retinoic acid may therefore afford a novel therapeutic mechanism for the treatment and prevention of Alzheimer disease.
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ABSTRACT: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with profound medical and social consequences. The pathogenesis of AD is a complex and heterogeneous process which classical neuropathological hallmarks found in the brain are extracellular deposits of beta-amyloid (A)-containing plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. Mutation of presenilin-1 (PS-1), presenilin-2 (PS-2), and altered amyloid precursor protein (APP) genes has been reported to cause inherited AD. In addition, other genes such as apolipoprotein E-4 (APOE), endothelial nitric oxide synthase-3, and alpha-2-macroglubulin have also been associated with AD. A further number of hypothesis have been proposed for AD mechanism, which include: the amyloid cascade, vascular damage, excitotoxicity, deficiency of neurotrophic factors, mitochondrial dysfunction, trace element neurotoxicity, inflammation and oxidative stress hypothesis. The oxidative stress (OS) hypothesis of aging postulated by Dr. Denham Harman in 1956 proposed that brain aging is associated to a progressive imbalance between the anti-oxidant defenses and the pro-oxidant species that can occur as a result of either an increase in free radical production or a decrease in antioxidant defence. The fact that age is the main risk factor for AD development provides considerable support to the OS hypothesis since the effects produced by reactive oxygen species (ROS) can accumulate over the years (Nunomura et al., 2001). The link between AD and OS is additionally supported by the finding of decreased levels of antioxidant enzymes, increased protein, lipid and DNA oxidation and advanced glycation end products (AGEs) and ROS formation in neurons of AD patients (Perry et al., 2000; Barnham et al., 2004). It has been reported that the accumulation of the oligomeric form of A, the most toxic form of the peptide, induces OS in neurons (Butterfield, 2002), supporting the hypothesis and suggesting that OS plays a causative role in the development of AD. Then, a large amount of literature has demonstrated that OS is an important feature in AD pathogenesis that deserves to be deeply studied (Perry et al, 2002: Markesbery et al, 1999). In this Chapter, we address the main factors involved in the generation of oxidative stress and provide an overview of the oxidative stress biomarkers status in Alzheimer’s disease. The Chapter concludes with a revision of the controversial efficacy of antioxidants as potential treatment in AD therapy as well as an update of the main antioxidant compounds found to have a beneficial effect in AD.09/2011; , ISBN: 978-953-307-690-4
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ABSTRACT: Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5), respectively, and peroxisome-localized TSC functioned as a Rheb GTPase-activating protein (GAP) to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, and abrogated peroxisome localization, Rheb GAP activity and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS, and peroxisome-localization-deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for the TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signalling organelle involved in regulation of mTORC1.Nature Cell Biology 08/2013; · 20.76 Impact Factor
Article: Vitamin A and Alzheimer's disease.[Show abstract] [Hide abstract]
ABSTRACT: The deposition of amyloid β-protein (Aβ) in the brain is an invariant feature of Alzheimer's disease (AD). Vitamin A, which has been traditionally considered an anti-oxidant compound, plays a role in maintaining higher function in the central nervous system. Plasma or cerebrospinal fluid concentrations of vitamin A and β-carotene have been reported to be lower in AD patients, and these vitamins have been clinically shown to slow the progression of dementia. Vitamin A (retinol, retinal and retinoic acid) and β-carotene have been shown in in vitro studies to inhibit the formation, extension and destabilizing effects of β-amyloid fibrils. Recently, the inhibition of the oligomerization of Aβ has been suggested as a possible therapeutic target for the treatment of AD. We have recently shown the inhibitory effects of vitamin A and β-carotene on the oligomerization of Aβ40 and Aβ42 in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brain Aβ deposition and tau phosphorylation in transgenic mouse models of AD, attenuated neuronal degeneration, and improved spatial learning and memory. Thus, vitamin A and β-carotene could be key molecules for the prevention and therapy of AD.Geriatrics & Gerontology International 12/2011; 12(2):180-8.