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Etiopathology and Alzheimer

Izabela Sadowska-Bartosz, Grzegorz Bartosz
Vast evidence supports the view that glycation of proteins is one of the main factors contributing to aging and is an important element of etiopathology of age-related diseases, especially type 2 diabetes mellitus, cataract and neurodegenerative diseases. Counteracting glycation can therefore be a means of increasing both the lifespan and healthspan. In this review, accumulation of glycation products during aging is presented, pathophysiological effects of glycation are discussed and ways of attenuation of the effects of glycation are described, concentrating on prevention of glycation...
September 23, 2016: Mechanisms of Ageing and Development
Charlotte Delay, Benjamin Grenier-Boley, Philippe Amouyel, Julie Dumont, Jean-Charles Lambert
BACKGROUND: A growing body of evidence suggests that microRNAs (miRNAs) are involved in Alzheimer's disease (AD) and that some disease-associated genetic variants are located within miRNA binding sites. In the present study, we sought to characterize functional polymorphisms in miRNA target sites within the loci defined in earlier genome-wide association studies (GWAS). The main objectives of this study were to (1) facilitate the identification of the gene or genes responsible for the GWAS signal within a locus of interest and (2) determine how functional polymorphisms might be involved in the AD process (e...
2016: Alzheimer's Research & Therapy
Juan Yang, Song Li, Xi-Biao He, Cheng Cheng, Weidong Le
Alzheimer's disease (AD) is the most common cause of dementia in those over the age of 65. While a numerous of disease-causing genes and risk factors have been identified, the exact etiological mechanisms of AD are not yet completely understood, due to the inability to test theoretical hypotheses on non-postmortem and patient-specific research systems. The use of recently developed and optimized induced pluripotent stem cells (iPSCs) technology may provide a promising platform to create reliable models, not only for better understanding the etiopathological process of AD, but also for efficient anti-AD drugs screening...
2016: Molecular Neurodegeneration
Federica Prati, Angela De Simone, Andrea Armirotti, Maria Summa, Daniela Pizzirani, Rita Scarpelli, Sine Mandrup Bertozzi, Daniel I Perez, Vincenza Andrisano, Ana Perez-Castillo, Barbara Monti, Francesca Massenzio, Letizia Polito, Marco Racchi, Piera Sabatino, Giovanni Bottegoni, Ana Martinez, Andrea Cavalli, Maria L Bolognesi
One of the main obstacles toward the discovery of effective anti-Alzheimer drugs is the multifactorial nature of its etiopathology. Therefore, the use of multitarget-directed ligands has emerged as particularly suitable. Such ligands, able to modulate different neurodegenerative pathways, for example, amyloid and tau cascades, as well as cognitive and neurogenic functions, are fostered to come. In this respect, we report herein on the first class of BACE-1/GSK-3β dual inhibitors based on a 3,4-dihydro-1,3,5-triazin-2(1H)-one skeleton, whose hit compound 1 showed interesting properties in a preliminary investigation...
October 21, 2015: ACS Chemical Neuroscience
Ping Sun, Ana Knezovic, Milena Parlak, Jacqueline Cuber, Margherita M Karabeg, Jürgen Deckert, Peter Riederer, Qian Hua, Melita Salkovic-Petrisic, Angelika G Schmitt
Altered adult hippocampal neurogenesis (AN) plays a role in the etiopathology of Alzheimer's disease (AD), a disorder characterized by a progressive loss of memory and spatial orientation impairment. Diabetes is shown to be one risk factor for the development of the sporadic form of AD (sAD), which affects >95% of AD patients. Streptozotocin intracerebroventricularily (STZ icv) treated rats, which develop an insulin-resistant brain state and learning and memory deficits preceding amyloid beta and tau pathology, may act as an appropriate animal model for sAD...
2015: Current Alzheimer Research
Michelle M Mielke, Norman J Haughey
Understanding the etiopathological processes of Alzheimer's disease (AD) in the preclinical and early clinical stages will be important in developing new therapeutic targets and biomarkers. There is growing consensus that nonamyloid targets will be necessary to reverse or slow AD progression. Lipidomic, metabolomic and targeted approaches have identified pathways and products of sphingolipid metabolism that are altered early in the course of AD and contribute to the neuropathological alterations associated with AD, including amyloid-β production, tau formation and neurodegeneration...
October 2012: Clinical Lipidology
P Russo, A Frustaci, A Del Bufalo, M Fini, A Cesario
The etiopathology of Alzheimer's disease (AD) is extremely complex and heterogeneous, often associated with comorbidities. As a result it may be unlikely that AD may be mitigated by drug acting on a single specific target. The current tendency in drug design and discovery in AD is the rational design or "serendipitous" discovery of new drug entities challenging multiple targets. Since two of the presently approved drugs for AD are based on natural products (galantamine and the physostigmine-derivative rivastigmine), many plants are now under investigation as a potential source of new drugs...
2013: Current Medicinal Chemistry
J R Walton
The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis...
2013: Journal of Alzheimer's Disease: JAD
Stavros J Baloyannis, Ioannis S Baloyannis
Although the etiopathological background of Alzheimer's disease (AD) is mostly associated with the deposition of Αβ-peptide, the hyperphosphorylation of τ protein, the synaptic pathology and the mitochondrial alterations, the vascular factor may play substantial role in plotting the multifactorial pattern of the disease. We attempted to study the blood capillaries in the hippocampus, the acoustic, the visual and the parietal cortex in twelve early cases of Alzheimer's disease. Samples were processed for Golgi silver impregnation technique and electron microscopy...
November 15, 2012: Journal of the Neurological Sciences
Matthew A Lalli, Gloria Garcia, Lucia Madrigal, Mauricio Arcos-Burgos, Mary Luz Arcila, Kenneth S Kosik, Francisco Lopera
Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years...
December 2012: Human Mutation
Tara M Weitz, Terrence Town
Neuroinflammation is now regarded as both an early event and prime mover in the pathobiology of Alzheimer disease (AD), a neurodegenerative disease that represents a growing public health threat. As the resident innate immune cells within the central nervous system, microglia are centrally positioned as key orchestrators of brain inflammation. It is now accepted that numerous forms of activated microglia exist. Furthermore, while some types of reactive microglia are detrimental, others can actually be beneficial...
2012: International Journal of Alzheimer's Disease
Peizhong Mao, Maria Manczak, Marcus J Calkins, Quang Truong, Tejaswini P Reddy, Arubala P Reddy, Ulziibat Shirendeb, Herng-Hsiang Lo, Peter S Rabinovitch, P Hemachandra Reddy
The purpose of this study was to investigate the protective effects of the mitochondria-targeted antioxidant catalase (MCAT) and lifespan extension in mice that express amyloid beta (Aβ). Using immunoblotting and immunostaining analyses, we measured the production of full-length amyloid precursor protein (APP), soluble APPα, C-terminal fragments CTF99 and CTF83, monomeric and oligomeric Aβ, Aβ deposits and beta site amyloid precursor protein cleaving enzyme 1 (BACE1), in different stages of disease progression in MCAT/AβPP and AβPP mice...
July 1, 2012: Human Molecular Genetics
Walter J Lukiw
Introduction: Alzheimer's disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing "amyloid cascade hypothesis," which maintains that the aberrant proteolysis of beta-amyloid precursor protein (βAPP) into neurotoxic amyloid beta (Aβ) peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42 peptide generation in an effort to ameliorate the tragedy of AD...
March 23, 2012: Expert Opinion on Emerging Drugs
K Kume, M Kikukawa, H Hanyu, Y Takata, T Umahara, H Sakurai, H Kanetaka, K Ohyashiki, J H Ohyashiki, T Iwamoto
BACKGROUND AND PURPOSE: Shortened telomere length has been considered to be associated with various age-related diseases, especially in dementia such as Alzheimer's disease and vascular dementia. However, changes in telomere length in dementia with Lewy bodies (DLB) remain unclear. To elucidate these changes, we set out to determine telomere length in peripheral leukocytes as well as the level of urinary 8-hydroxy-deoxyguanosine (8-OHdG) as a marker of oxidative stress in DLB. METHODS: Blood samples were obtained from 33 patients with a clinical diagnosis of probable DLB and 35 age-matched, non-demented elderly controls (NEC)...
June 2012: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Cornelis J Van der Schyf, Werner J Geldenhuys
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing...
2011: International Review of Neurobiology
Werner J Geldenhuys, Moussa B H Youdim, Richard T Carroll, Cornelis J Van der Schyf
The incidence of neurodegenerative diseases has seen a constant increase in the global population, and is likely to be the result of extended life expectancy brought about by better health care. Despite this increase in the incidence of neurodegenerative diseases, there has been a dearth in the introduction of new disease-modifying therapies that are approved to prevent or delay the onset of these diseases, or reverse the degenerative processes in brain. Mounting evidence in the peer-reviewed literature shows that the etiopathology of these diseases is extremely complex and heterogeneous, resulting in significant comorbidity and therefore unlikely to be mitigated by any drug acting on a single pathway or target...
September 1, 2011: Progress in Neurobiology
T Pflanzner, C R Kuhlmann, C U Pietrzik
Alzheimer's disease (AD) is the most common form of dementia in the elderly with more than 26 million people worldwide living with the disease. Besides the main neuropathological hallmarks of AD, provoked by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation, other cells and cellular systems such as microglia and the neurovascular unit establishing the blood-brain-barrier (BBB) have been implicated to play a role in AD etiopathology. Insulating the brain from the blood stream, the BBB facilitates supply and disposal of nutrients and metabolites by the expression of transporters and transcytotic receptors at the polarized endothelial cell (EC) surface...
November 2010: Current Alzheimer Research
Min Wang, Jianping Jia
Inflammatory response is involved in the etiopathology of Alzheimer's disease (AD). Interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, was reported to be associated with both increased A beta aggregation and the appearance of hyperphosphorylated tau in AD brain. To explore the association of genetic variants in the promoter of IL-6 gene with sporadic AD (SAD), a case-control study was conducted in a North Chinese Han population. A systematic screening of IL-6 promoter was performed using direct sequencing and two polymorphisms were obtained including -572C/G (rs1800796) and -384A/T (rs7802308)...
October 4, 2010: Neuroscience Letters
Szabina Szücs, Magdolna Pákáski, Agnes Domokos, János Kálmán, Sára Kálmán, Dénes Garab, Botond Penke, Gyula Szabó, Zoltán Janka, János Kálmán
Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes...
March 2010: Neuropsychopharmacologia Hungarica
Valérie Leduc, Louise Théroux, Doris Dea, Yves Robitaille, Judes Poirier
Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066)...
November 2009: European Journal of Neuroscience
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