Role of Synucleins in Alzheimer’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-β protein (Aβ) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Aβ and Tau; however, recent studies suggest that α-syn might also play a role in the pathogenesis of AD. For example, fragments of α-syn can associate with amyloid plaques and Aβ promotes the aggregation of α-syn in vivo and worsens the deficits in α-syn tg mice. Moreover, α-syn has also been shown to accumulate in limbic regions in AD, Down’s syndrome, and familial AD cases. Aβ and α-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Aβ and α-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Aβ and α-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD

Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

Background: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid b protein (Ab) oligomers has been identified as one of the central toxic events in AD, accumulation of a-synuclein (a-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Ab promotes a-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. Methodology/Principal Findings: In order to understand the molecular mechanisms involved in potential Ab/a-syn interactions, immunoblot, molecular modeling, and in vitro studies with a-syn and Ab were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Ab and a-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Ab binds a-syn monomers, homodimers, and trimers, forming hybrid ringlike pentamers. Interactions occurred between the N-terminus of Ab and the N-terminus and C-terminus of a-syn. Interacting a-syn and Ab dimers that dock on the membrane incorporated additional a-syn molecules, leading to th

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1 alpha and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell-cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1 alpha treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1 alpha release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1 alpha and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation. Oncogene (2012) 31, 992-1000; doi:10.1038/onc.2011.298; published online 18 July 201

Associated factors in modulating aflatoxin B1-albumin adduct level in three Chinese populations

10.1007/s10620-005-2468-1Digestive Diseases and Sciences503525-532DDSC