Articles

Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependence

Extensive genetic, biochemical, and histological evidence has implicated the amyloid-β peptide (Aβ) in Alzheimer's disease pathogenesis, and several mechanisms have been suggested, such as metal binding, react...

Authors: Dale E Bredesen

Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy

It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria supply the adenosine triphosphate (ATP) needed to support ...

Authors: Patricia A Trimmer, Kathleen M Schwartz, M Kathleen Borland, Luis De Taboada, Jackson Streeter and Uri Oron

Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation

Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains e...

Authors: Javorina Milosevic, Sigrid C Schwarz, Vera Ogunlade, Anne K Meyer, Alexander Storch and Johannes Schwarz

Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle

While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Alt...

Authors: Kristen A Malkus, Elpida Tsika and Harry Ischiropoulos

Dissembled DJ-1 high molecular weight complex in cortex mitochondria from Parkinson's disease patients

The PARK7 gene encodes a protein, DJ-1, with several functions such as protection of cells from oxidative stress, sperm maturation and fertilization, and chaperone activity. Mutations in the PARK7 gene are ass...

Authors: Hikmet Nural, Ping He, Thomas Beach, Lucia Sue, Weiming Xia and Yong Shen

An exo-cell assay for examining real-time γ-secretase activity and inhibition

γ-Secretase is an aspartyl protease that cleaves multiple substrates that are involved in broad biological processes ranging from stem cell development to neurodegeneration. The investigation of γ-secretase ha...

Authors: Christopher C Shelton, Yuan Tian, Mark G Frattini and Yue-Ming Li

ApoE isoform-dependent changes in hippocampal synaptic function

The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenera...

Authors: Kimberly M Korwek, Justin H Trotter, Mary Jo LaDu, Patrick M Sullivan and Edwin J Weeber

Calcium signaling in neurodegeneration

Calcium is a key signaling ion involved in many different intracellular and extracellular processes ranging from synaptic activity to cell-cell communication and adhesion. The exact definition at the molecular...

Authors: Philippe Marambaud, Ute Dreses-Werringloer and Valérie Vingtdeux

Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575

The γ-secretase complex is a major therapeutic target for the prevention and treatment of Alzheimer's disease. Previous studies have shown that treatment of young APP mice with specific inhibitors of γ-secreta...

Authors: Monica Garcia-Alloza, Meenakshi Subramanian, Diana Thyssen, Laura A Borrelli, Abdul Fauq, Pritam Das, Todd E Golde, Bradley T Hyman and Brian J Bacskai

GSK-3β phosphorylation of functionally distinct tau isoforms has differential, but mild effects

Tau protein exists as six different isoforms that differ by the inclusion or exclusion of exons 2, 3 and 10. Exon 10 encodes a microtubule binding repeat, thereby resulting in three isoforms with three microtu...

Authors: Kellen Voss and T Chris Gamblin

LRP1 shedding in human brain: roles of ADAM10 and ADAM17

The low-density lipoprotein receptor-related protein 1 (LRP1) plays critical roles in lipid metabolism, cell survival, and the clearance of amyloid-β (Aβ) peptide. Functional soluble LRP1 (sLRP1) has been dete...

Authors: Qiang Liu, Juan Zhang, Hien Tran, Marcel M Verbeek, Karina Reiss, Steven Estus and Guojun Bu

All-you-can-eat: autophagy in neurodegeneration and neuroprotection

Autophagy is the major pathway involved in the degradation of proteins and organelles, cellular remodeling, and survival during nutrient starvation. Autophagosomal dysfunction has been implicated in an increas...

Authors: Philipp A Jaeger and Tony Wyss-Coray

Calnuc plays a role in dynamic distribution of Gαi but not Gβ subunits and modulates ACTH secretion in AtT-20 neuroendocrine secretory cells

In AtT-20 cells ACTH secretion is regulated by both Ca²⁺ and G proteins. We previously demonstrated that calnuc, an EF-hand Ca²⁺ binding protein which regulates Alzheimer's β-amyloid precursor protein (APP) bioge...

Authors: Ping Lin, Thierry Fischer, Christine Lavoie, Haining Huang and Marilyn Gist Farquhar

The PI3K-Akt-mTOR pathway regulates Aβ oligomer induced neuronal cell cycle events

Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a g...

Authors: Kiran Bhaskar, Megan Miller, Alexandra Chludzinski, Karl Herrup, Michael Zagorski and Bruce T Lamb

The role of tau in neurodegeneration

Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, ...

Authors: Tania F Gendron and Leonard Petrucelli

Increased DJ-1 expression under oxidative stress and in Alzheimer's disease brains

Mutations in the DJ-1 gene have been linked to autosomal recessive familial Parkinson's disease. To understand the function of DJ-1, we determined the DJ-1 expression in both zebrafish and post mortem human br...

Authors: Stéphanie Baulac, Hope Lu, Jennifer Strahle, Ting Yang, Matthew S Goldberg, Jie Shen, Michael G Schlossmacher, Cynthia A Lemere, Qun Lu and Weiming Xia

Inducible mutant huntingtin expression in HN10 cells reproduces Huntington's disease-like neuronal dysfunction

Expansion of a polyglutamine repeat at the amino-terminus of huntingtin is the probable cause for Huntington's disease, a lethal progressive autosomal-dominant neurodegenerative disorders characterized by impa...

Authors: Andreas Weiss, Ana Roscic and Paolo Paganetti

PGC-1alphaas modifier of onset age in Huntington disease

Although there is a strong correlation between CAG repeat length and age at onset (AO) of motor symptoms, individual Huntington disease (HD) patients may differ dramatically in onset age and disease manifestat...

Authors: Elahe Taherzadeh-Fard, Carsten Saft, Jürgen Andrich, Stefan Wieczorek and Larissa Arning

α-Synuclein and neuronal cell death

α-Synuclein is a small protein that has special relevance for understanding Parkinson disease and related disorders. Not only is α-synuclein found in Lewy bodies characteristic of Parkinson disease, but also m...

Authors: Mark R Cookson

The therapeutic importance of understanding mechanisms of neuronal cell death in neurodegenerative disease

Despite major advances in our understanding of the initiating factors that trigger many neurodegenerative disorders, to date, no novel disease-modifying therapies have been shown to provide significant benefit...

Authors: Todd E Golde

"What kills neurons in neurodegenerative diseases?", a review series in an open access journal

Authors: Todd E Golde and Leonard Petrucelli

Linkage of cDNA expression profiles of mesencephalic dopaminergic neurons to a genome-wide in situ hybridization database

Midbrain dopaminergic neurons are involved in control of emotion, motivation and motor behavior. The loss of one of the subpopulations, substantia nigra pars compacta, is the pathological hallmark of one of th...

Authors: Kambiz N Alavian and Horst H Simon

Independent component analysis of Alzheimer's DNA microarray gene expression data

Gene microarray technology is an effective tool to investigate the simultaneous activity of multiple cellular pathways from hundreds to thousands of genes. However, because data in the colossal amounts generat...

Authors: Wei Kong, Xiaoyang Mou, Qingzhong Liu, Zhongxue Chen, Charles R Vanderburg, Jack T Rogers and Xudong Huang

Insulin-degrading enzyme is exported via an unconventional protein secretion pathway

Insulin-degrading enzyme (IDE) is a ubiquitously expressed zinc-metalloprotease that degrades several pathophysiologically significant extracellular substrates, including insulin and the amyloid β-protein (Aβ)...

Authors: Ji Zhao, Lilin Li and Malcolm A Leissring

The gene coding for PGC-1α modifies age at onset in Huntington's Disease

Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabol...

Authors: Patrick Weydt, Selma M Soyal, Cinzia Gellera, Stefano DiDonato, Claus Weidinger, Hannes Oberkofler, G Bernhard Landwehrmeyer and Wolfgang Patsch

Intracellular amyloid formation in muscle cells of Aβ-transgenic Caenorhabditis elegans: determinants and physiological role in copper detoxification

The amyloid β-peptide is a ubiquitous peptide, which is prone to aggregate forming soluble toxic oligomers and insoluble less-toxic aggregates. The intrinsic and external/environmental factors that determine A...

Authors: Alicia N Minniti, Daniela L Rebolledo, Paula M Grez, Ricardo Fadic, Rebeca Aldunate, Irene Volitakis, Robert A Cherny, Carlos Opazo, Colin Masters, Ashley I Bush and Nibaldo C Inestrosa

Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on β-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells

Activation of the liver × receptors (LXRs) by exogenous ligands stimulates the degradation of β-amyloid 1–42 (Aβ42), a peptide that plays a central role in the pathogenesis of Alzheimer's disease (AD). The oxi...

Authors: Jaya RP Prasanthi, Amber Huls, Sarah Thomasson, Alex Thompson, Eric Schommer and Othman Ghribi

Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aβ and insulin degradation

Insulin degrading enzyme (IDE) is implicated in the regulation of amyloid β (Aβ) steady-state levels in the brain, and its deficient expression and/or activity may be a risk factor in sporadic Alzheimer's dise...

Authors: Ayelén Bulloj, María C Leal, Ezequiel I Surace, Xue Zhang, Huaxi Xu, Maria D Ledesma, Eduardo M Castaño and Laura Morelli

Chronic, low-dose rotenone reproduces Lewy neurites found in early stages of Parkinson's disease, reduces mitochondrial movement and slowly kills differentiated SH-SY5Y neural cells

Parkinson's disease, the most common adult neurodegenerative movement disorder, demonstrates a brain-wide pathology that begins pre-clinically with alpha-synuclein aggregates ("Lewy neurites") in processes of ...

Authors: M Kathleen Borland, Patricia A Trimmer, Jeremy D Rubinstein, Paula M Keeney, KP Mohanakumar, Lei Liu and James P Bennett Jr

Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

Mutations in the presenilin (PSEN) genes are associated with early-onset familial Alzheimer's disease (FAD). Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase ...

Authors: Chera L Maarouf, Ian D Daugs, Salvatore Spina, Ruben Vidal, Tyler A Kokjohn, R Lyle Patton, Walter M Kalback, Dean C Luehrs, Douglas G Walker, Eduardo M Castaño, Thomas G Beach, Bernardino Ghetti and Alex E Roher

In vivo silencing of alpha-synuclein using naked siRNA

Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA cont...

Authors: Jada Lewis, Heather Melrose, David Bumcrot, Andrew Hope, Cynthia Zehr, Sarah Lincoln, Adam Braithwaite, Zhen He, Sina Ogholikhan, Kelly Hinkle, Caroline Kent, Ivanka Toudjarska, Klaus Charisse, Ravi Braich, Rajendra K Pandey, Michael Heckman…

NG2 cells response to axonal alteration in the spinal cord white matter in mice with genetic disruption of neurofilament light subunit expression

Chondroitin sulphate proteoglycan (NG2) expressing cells, morphologically characterized by multi-branched processes and small cell bodies, are the 4^th commonest cell population of non-neuronal cell type in the ce...

Authors: Ya Jun Wu, Ya Fang Tang, Zhi Cheng Xiao, Zhen Min Bao and Bei Ping He

Optimisation of region-specific reference gene selection and relative gene expression analysis methods for pre-clinical trials of Huntington's disease

Transcriptional dysregulation is an early, key pathogenic mechanism in Huntington's disease (HD). Therefore, gene expression analyses have biomarker potential for measuring therapeutic efficacy in pre-clinical...

Authors: Caroline L Benn, Helen Fox and Gillian P Bates

Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD), age-related macular degeneration (AMD), atherosclerosis, systemic amyloidoses, and glomerulonephri...

Authors: Thuzar M Shin, J Mario Isas, Chia-Ling Hsieh, Rakez Kayed, Charles G Glabe, Ralf Langen and Jeannie Chen

Evaluation of Dimebon in cellular model of Huntington's disease

Dimebon is an antihistamine compound with a long history of clinical use in Russia. Recently, Dimebon has been proposed to be useful for treating neurodegenerative disorders. It has demonstrated efficacy in ph...

Authors: Jun Wu, Qin Li and Ilya Bezprozvanny

Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice

Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in ...

Authors: Károly Mirnics, Eric M Norstrom, Krassimira Garbett, Se Hoon Choi, Xiaoqiong Zhang, Philip Ebert and Sangram S Sisodia

Expression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease

Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized by progressive memory loss. Pathological markers of AD include neurofibrillary tangles, accumulation of amyloid-β plaques, ne...

Authors: Kathryn J Bryan, Xiongwei Zhu, Peggy L Harris, George Perry, Rudy J Castellani, Mark A Smith and Gemma Casadesus

Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional role

Regulated intramembrane proteolysis of the β-amyloid precursor protein by the γ-secretase yields two peptides. One, amyloid-β, is the major component of the amyloid plaques found in Alzheimer's disease patient...

Authors: Luca Giliberto, Dawang Zhou, Richard Weldon, Elena Tamagno, Pasquale De Luca, Massimo Tabaton and Luciano D'Adamio

Prion protein lacks robust cytoprotective activity in cultured cells

The physiological function of the cellular prion protein (PrP^C) remains unknown. However, PrP^C has been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic s...

Authors: Heather M Christensen and David A Harris

MicroRNAs can regulate human APP levels

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including A...

Authors: Neha Patel, David Hoang, Nathan Miller, Sara Ansaloni, Qihong Huang, Jack T Rogers, Jeremy C Lee and Aleister J Saunders

The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease

Recent evidence supports a neuroprotective role for Wnt signaling in neurodegenerative disorders such as Alzheimer's Disease (AD). In fact, a relationship between amyloid-β-peptide (Aβ)-induced neurotoxicity and ...

Authors: Nibaldo C Inestrosa and Enrique M Toledo

Tau exon 10 alternative splicing and tauopathies

Abnormalities of microtubule-associated protein tau play a central role in neurofibrillary degeneration in several neurodegenerative disorders that collectively called tauopathies. Six isoforms of tau are expr...

Authors: Fei Liu and Cheng-Xin Gong

Autoimmune-induced preferential depletion of myelin-associated glycoprotein (MAG) is genetically regulated in relapsing EAE (B6 × SJL) F1 mice

Experimental autoimmune encephalomyelitis (EAE) is commonly used to investigate mechanisms of autoimmune-mediated damage to oligodendrocytes, myelin, and axons in multiple sclerosis (MS). Four distinct autoimm...

Authors: Dusanka S Skundric, Rujuan Dai, Vaagn L Zakarian and Weili Zhou

Changes in γ-secretase activity and specificity caused by the introduction of consensus aspartyl protease active motif in Presenilin 1

Presenilin (PS1 or PS2) is an essential component of the active γ-secretase complex that liberates the Aβ peptides from amyloid precursor protein (APP). PS1 is regarded as an atypical aspartyl protease harbori...

Authors: Donald B Carter, Edwige Dunn, Adele M Pauley, Denise D McKinley, Timothy J Fleck, Brenda R Ellerbrook, Nancy C Stratman, Xiangdong Zhou, Carol S Himes, Jeffrey S Nye, Alfredo Tomasselli and Riqiang Yan

Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein

Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived...

Authors: Celina V Zerbinatti, Joanna M Cordy, Ci-Di Chen, Maria Guillily, Sokreine Suon, William J Ray, Guy R Seabrook, Carmela R Abraham and Benjamin Wolozin

A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation

Alterations in multiple cellular pathways contribute to the development of chronic neurodegeneration such as a sporadic Alzheimer's disease (AD). These, in turn, involve changes in gene expression, amongst whi...

Authors: Qing Yan Liu, Joy X Lei, Marianna Sikorska and Rugao Liu

Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons

Parkinson's disease (PD) is the most prevalent incurable neurodegenerative movement disorder. Mutations in LRRK2 are associated with both autosomal dominant familial and sporadic forms of PD. LRRK2 encodes a larg...

Authors: Danling Wang, Beisha Tang, Guohua Zhao, Qian Pan, Kun Xia, Rolf Bodmer and Zhuohua Zhang

Presenilins are required for maintenance of neural stem cells in the developing brain

The early embryonic lethality of mutant mice bearing germ-line deletions of both presenilin genes precluded the study of their functions in neural development. We therefore employed the Cre-loxP technology to gen...

Authors: Woo-Young Kim and Jie Shen

Ginkgolides protect against amyloid-β_1–42-mediated synapse damage in vitro

The early stages of Alzheimer's disease (AD) are closely associated with the production of the Aβ_1–42 peptide, loss of synapses and gradual cognitive decline. Since some epidemiological studies showed that EGb 76...

Authors: Clive Bate, Mourad Tayebi and Alun Williams

Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding

Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such ...

Authors: Annat F Ikin, Mirsada Causevic, Steve Pedrini, Lyndsey S Benson, Joseph D Buxbaum, Toshiharu Suzuki, Simon Lovestone, Shigeki Higashiyama, Tomas Mustelin, Robert D Burgoyne and Sam Gandy