Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Neurodegenerative diseases, exemplified by Alzheimer's disease and Huntington's disease, are characterized by progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Although there are differences in the exact sites of pathology, and the clinical profiles of these two conditions only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of exploiting common therapeutic targets for drug development. As Huntington's disease has a monogenic cause, it is possible to accurately identify individuals who carry the Huntington's disease mutation but do not yet manifest symptoms. These individuals could act as a model for Alzheimer's disease to test therapeutic interventions that target shared pathogenic pathways.

[1]  C. Paúl,et al.  Education, leisure activities and cognitive and functional ability of Alzheimer's disease patients: A follow-up study , 2013, Dementia & neuropsychologia.

[2]  F. Tagliavini,et al.  NEURONAL COUNTS IN BASAL NUCLEUS OF MEYNERT IN ALZHEIMER DISEASE AND IN SIMPLE SENILE DEMENTIA , 1983, The Lancet.

[3]  J. Penney,et al.  Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington's disease. , 1990, The New England journal of medicine.

[4]  P. Chiaravelli Variations on a theme. , 1990, Journal of the American Dental Association.

[5]  C. Cotman,et al.  Exercise and brain neurotrophins , 1995, Nature.

[6]  R. Faull,et al.  Brain-derived neurotrophic factor is reduced in Alzheimer's disease. , 1997, Brain research. Molecular brain research.

[7]  Gloria Dal Forno,et al.  Cognitive decline strongly correlates with cortical atrophy in Alzheimer’s dementia , 1998, Neurobiology of Aging.

[8]  Y. Agid,et al.  An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease , 1999, Neuroscience.

[9]  H. Lehrach,et al.  Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  I. Ferrer,et al.  Brain-derived neurotrophic factor in Huntington disease , 2000, Brain Research.

[11]  P. Brachet,et al.  Intracerebral Implantation of NGF-Releasing Biodegradable Microspheres Protects Striatum against Excitotoxic Damage , 2000, Experimental Neurology.

[12]  M. J. Wade,et al.  Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. , 2001, Archives of neurology.

[13]  O. Andreassen,et al.  Mice Overexpressing 70-kDa Heat Shock Protein Show Increased Resistance to Malonate and 3-Nitropropionic Acid , 2002, Experimental Neurology.

[14]  Fabrice P Cordelières,et al.  The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. , 2002, Developmental cell.

[15]  W. Friedman,et al.  Mechanisms of p75-mediated Death of Hippocampal Neurons , 2002, The Journal of Biological Chemistry.

[16]  M. Riva,et al.  Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease , 2002, Molecular Psychiatry.

[17]  D. Rubinsztein,et al.  Glycogen Synthase Kinase-3β Inhibitors Prevent Cellular Polyglutamine Toxicity Caused by the Huntington's Disease Mutation* , 2002, The Journal of Biological Chemistry.

[18]  Erich E Wanker,et al.  The hunt for huntingtin function: interaction partners tell many different stories. , 2003, Trends in biochemical sciences.

[19]  Leslie M Thompson,et al.  Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Carla Perrone-Capano,et al.  Chronic activation of ERK and neurodegenerative diseases , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[21]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[22]  C. Parsons,et al.  Expression of Polyglutamine-expanded Huntingtin Induces Tyrosine Phosphorylation of N-Methyl-D-aspartate Receptors* , 2003, Journal of Biological Chemistry.

[23]  L. Thompson,et al.  Autophagy regulates the processing of amino terminal huntingtin fragments. , 2003, Human molecular genetics.

[24]  N. Robakis An Alzheimer's disease hypothesis based on transcriptional dysregulation , 2003, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[25]  C. Ross,et al.  Protein aggregation and neurodegenerative disease , 2004, Nature Medicine.

[26]  M. Gerlach,et al.  The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. , 2004, Journal of neural transmission. Supplementum.

[27]  S. Albrecht,et al.  Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. , 2004, The American journal of pathology.

[28]  M. Göttlicher Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. , 2004, Annals of hematology.

[29]  Toshiharu Suzuki,et al.  Suppression of the caspase cleavage of β‐amyloid precursor protein by its cytoplasmic phosphorylation , 2004, FEBS letters.

[30]  Mark R. Segal,et al.  Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death , 2004, Nature.

[31]  Francesco Scaravilli,et al.  Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease , 2004, Nature Genetics.

[32]  M. Los,et al.  Caspases and cancer: mechanisms of inactivation and new treatment modalities. , 2004, Experimental oncology.

[33]  S. Sorbi,et al.  Brain‐derived neurotrophic factor genetic variants are not susceptibility factors to Alzheimer's disease in Italy , 2004, Annals of neurology.

[34]  Fabrice P Cordelières,et al.  Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules , 2004, Cell.

[35]  O. Combarros,et al.  Polymorphism at Codon 66 of the Brain-Derived Neurotrophic Factor Gene Is Not Associated with Sporadic Alzheimer’s Disease , 2004, Dementia and Geriatric Cognitive Disorders.

[36]  Zhenxin Zhang,et al.  Association analysis of brain-derived neurotrophic factor (BDNF) gene 196 A/G polymorphism with Alzheimer's disease (AD) in mainland Chinese , 2005, Neuroscience Letters.

[37]  Steven G Potkin,et al.  A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease , 2005, Nature Medicine.

[38]  S. DeKosky,et al.  Investigation of the effect of brain-derived neurotrophic factor (BDNF) polymorphisms on the risk of late-onset Alzheimer's disease (AD) and quantitative measures of AD progression , 2005, Neuroscience Letters.

[39]  L. Tjernberg,et al.  Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease , 2005, The Journal of cell biology.

[40]  K. Ono,et al.  Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease , 2006, Cellular and Molecular Life Sciences CMLS.

[41]  A. Young,et al.  A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  E. Muñoz,et al.  Association between BDNF Val66Met polymorphism and age at onset in Huntington disease , 2005, Neurology.

[43]  T. Gillis,et al.  Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington’s disease , 2006, Neurobiology of Disease.

[44]  N. Herrmann,et al.  A Placebo-Controlled Trial of Valproate for Agitation and Aggression in Alzheimer’s Disease , 2006, Dementia and Geriatric Cognitive Disorders.

[45]  Hong Liu,et al.  Expression and localization of estrogenic type 12 17β-hydroxysteroid dehydrogenase in the cynomolgus monkey , 2007, BMC Biochemistry.

[46]  J. Rothman,et al.  Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway , 2006, The Journal of cell biology.

[47]  L. Raymond,et al.  Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and Degeneration Due to Mutant Huntingtin , 2006, Cell.

[48]  D. Bredesen,et al.  Correction for Galvan et al., Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664 , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Xiao-Jiang Li,et al.  Interaction of Huntingtin-associated Protein-1 with Kinesin Light Chain , 2006, Journal of Biological Chemistry.

[50]  Lu Gan,et al.  Palmitoylation of huntingtin by HIP14is essential for its trafficking and function , 2006, Nature Neuroscience.

[51]  Susan Lindquist,et al.  Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. , 2006, Human molecular genetics.

[52]  K. Blennow,et al.  Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study , 2006, The Lancet Neurology.

[53]  Alexei Degterev,et al.  Regulation of Intracellular Accumulation of Mutant Huntingtin by Beclin 1* , 2006, Journal of Biological Chemistry.

[54]  J. Biernat,et al.  N-phenylamine derivatives as aggregation inhibitors in cell models of tauopathy. , 2007, Current Alzheimer research.

[55]  E. Masliah,et al.  Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3β Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation , 2007, The Journal of Neuroscience.

[56]  W. Ondo,et al.  A pilot study of the clinical efficacy and safety of memantine for Huntington's disease. , 2007, Parkinsonism & related disorders.

[57]  G. Collingridge,et al.  LTP Inhibits LTD in the Hippocampus via Regulation of GSK3β , 2007, Neuron.

[58]  A. Kelly,et al.  Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection. , 2007, Biochemical Society transactions.

[59]  D. Bennett,et al.  Activation of caspase-6 in aging and mild cognitive impairment. , 2007, The American journal of pathology.

[60]  M. Michaelis,et al.  Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers. , 2007, European journal of pharmacology.

[61]  G. Pigino,et al.  Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1 , 2007, The Journal of Neuroscience.

[62]  S. Jones,et al.  Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington’s disease , 2007, Neuroscience.

[63]  N. Déglon,et al.  Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[64]  S. Schreiber,et al.  Small Molecule Enhancers of Rapamycin-Induced TOR Inhibition Promote Autophagy, Reduce Toxicity in Huntington’s Disease Models and Enhance Killing of Mycobacteria by Macrophages , 2007, Autophagy.

[65]  D. Rubinsztein,et al.  The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias , 2007, BMC Biochemistry.

[66]  Fabrice P Cordelières,et al.  Histone Deacetylase 6 Inhibition Compensates for the Transport Deficit in Huntington's Disease by Increasing Tubulin Acetylation , 2007, The Journal of Neuroscience.

[67]  S. Oddo,et al.  The ubiquitin-proteasome system in Alzheimer's disease , 2008, Journal of cellular and molecular medicine.

[68]  Ram Dixit,et al.  Differential Regulation of Dynein and Kinesin Motor Proteins by Tau , 2008, Science.

[69]  D. Ehrnhoefer,et al.  EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers , 2008, Nature Structural &Molecular Biology.

[70]  D. Rubinsztein,et al.  Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. , 2008, Nature chemical biology.

[71]  A. Orr,et al.  Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice , 2008, The Journal of cell biology.

[72]  H. Hou,et al.  Green tea epigallocatechin-3-gallate (EGCG) reduces β-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice , 2008, Brain Research.

[73]  F. Mouliere,et al.  Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats , 2008, Neurobiology of Disease.

[74]  R. Ferrante,et al.  Evidence of Oxidant Damage in Huntington's Disease: Translational Strategies Using Antioxidants , 2008, Annals of the New York Academy of Sciences.

[75]  R. Hellweg,et al.  Neurotrophins: from pathophysiology to treatment in Alzheimer's disease. , 2008, Current Alzheimer research.

[76]  Hong Qing,et al.  Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models , 2008, The Journal of Experimental Medicine.

[77]  Antonius M. J. VanDongen,et al.  Biology of the NMDA receptor , 2008 .

[78]  J. Bilbao [Lights and shadows]. , 2008, Radiologia.

[79]  M. MacDonald,et al.  RESEARCH ARTICLE: Systematic Assessment of BDNF and Its Receptor Levels in Human Cortices Affected by Huntington's Disease , 2007, Brain pathology.

[80]  D. Praticò,et al.  Evidence of Oxidative Stress in Alzheimer's Disease Brain and Antioxidant Therapy , 2008, Annals of the New York Academy of Sciences.

[81]  M. Garabedian,et al.  Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect , 2008, Proceedings of the National Academy of Sciences.

[82]  Shaun S. Sanders,et al.  Neuronal palmitoyl acyl transferases exhibit distinct substrate specificity , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[83]  E. Masliah,et al.  Beclin 1 Gene Transfer Activates Autophagy and Ameliorates the Neurodegenerative Pathology in α-Synuclein Models of Parkinson's and Lewy Body Diseases , 2009, The Journal of Neuroscience.

[84]  M. Eshraghi,et al.  Apoptosis and cancer: mutations within caspase genes , 2009, Journal of Medical Genetics.

[85]  E. Arama,et al.  Can’t live without them, can live with them: roles of caspases during vital cellular processes , 2009, Apoptosis.

[86]  G. Egea,et al.  Mutant huntingtin impairs post-Golgi trafficking to lysosomes by delocalizing optineurin/Rab8 complex from the Golgi apparatus. , 2009, Molecular biology of the cell.

[87]  L. Raymond,et al.  NMDA Receptors and Huntington’s Disease , 2009 .

[88]  H. Basun,et al.  Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. , 2009, Journal of Alzheimer's disease : JAD.

[89]  Ronald C Petersen,et al.  Early diagnosis of Alzheimer's disease: is MCI too late? , 2009, Current Alzheimer research.

[90]  M. Ehlers,et al.  The Effects of Amyloid Precursor Protein on Postsynaptic Composition and Activity* , 2009, Journal of Biological Chemistry.

[91]  Wenjun Gao,et al.  Dopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons , 2010, Molecular Brain.

[92]  Shihua Li,et al.  Huntingtin-associated Protein-1 Interacts with Pro-brain-derived Neurotrophic Factor and Mediates Its Transport and Release* , 2009, The Journal of Biological Chemistry.

[93]  Cunxian Song,et al.  Recombinant human NGF-loaded microspheres promote survival of basal forebrain cholinergic neurons and improve memory impairments of spatial learning in the rat model of Alzheimer's disease with fimbria-fornix lesion , 2009, Neuroscience Letters.

[94]  Danielle A. Simmons,et al.  Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice , 2009, Proceedings of the National Academy of Sciences.

[95]  F. Müller,et al.  Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease , 2009, Proceedings of the National Academy of Sciences.

[96]  D. Ehrnhoefer,et al.  Mouse models of Huntington disease: variations on a theme , 2009, Disease Models & Mechanisms.

[97]  D. Geschwind,et al.  Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease , 2009, Nature Medicine.

[98]  Steven Finkbeiner,et al.  Single Neuron Ubiquitin-Proteasome Dynamics Accompanying Inclusion Body Formation in Huntington Disease* , 2009, Journal of Biological Chemistry.

[99]  H. Möller,et al.  Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. , 2009, The Journal of clinical psychiatry.

[100]  D. Bredesen,et al.  Selective vulnerability in Alzheimer's disease: Amyloid precursor protein and p75NTR interaction , 2009, Annals of neurology.

[101]  T. Gómez-Isla,et al.  A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo , 2009, Neurobiology of Disease.

[102]  M. Hayden,et al.  Phosphorylation of huntingtin reduces the accumulation of its nuclear fragments , 2009, Molecular and Cellular Neuroscience.

[103]  P. Wong,et al.  S-Palmitoylation of γ-Secretase Subunits Nicastrin and APH-1* , 2009, Journal of Biological Chemistry.

[104]  Michael R. Hayden,et al.  Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin , 2009, Nature Medicine.

[105]  A. García-Osta,et al.  Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model , 2009, Neuropsychopharmacology.

[106]  Marc Tessier-Lavigne,et al.  APP binds DR6 to trigger axon pruning and neuron death via distinct caspases , 2009, Nature.

[107]  S. Capsoni,et al.  Development of a non invasive NGF-based therapy for Alzheimer's disease. , 2009, Current Alzheimer research.

[108]  J. Geddes,et al.  What is a randomised controlled trial? , 2009, Epidemiologia e Psichiatria Sociale.

[109]  P. Bickford,et al.  Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer's disease. , 2010, International journal of pharmaceutics.

[110]  R. Xavier,et al.  Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease , 2010, Proceedings of the National Academy of Sciences.

[111]  H. Manji,et al.  Novel Insights into Lithium’s Mechanism of Action: Neurotrophic and Neuroprotective Effects , 2010, Neuropsychobiology.

[112]  D. Kaplan,et al.  p75NTR-dependent, myelin-mediated axonal degeneration regulates neural connectivity in the adult brain , 2010, Nature Neuroscience.

[113]  H. Katus,et al.  Effects of the main green tea polyphenol epigallocatechin-3-gallate on cardiac involvement in patients with AL amyloidosis , 2010, Clinical Research in Cardiology.

[114]  W. M. van der Flier,et al.  Translational research in genomics of Alzheimer's disease: a review of current practice and future perspectives. , 2010, Journal of Alzheimer's disease : JAD.

[115]  L. Raymond,et al.  Cleavage at the 586 Amino Acid Caspase-6 Site in Mutant huntingtin Influences Caspase-6 Activation In Vivo , 2010, The Journal of Neuroscience.

[116]  R. Pautler,et al.  Convergence of Presenilin- and Tau-Mediated Pathways on Axonal Trafficking and Neuronal Function , 2010, The Journal of Neuroscience.

[117]  M. Racchi,et al.  Phosphorylation of APP‐CTF‐AICD domains and interaction with adaptor proteins: signal transduction and/or transcriptional role – relevance for Alzheimer pathology , 2010, Journal of neurochemistry.

[118]  Min Jae Lee,et al.  Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of Usp14 , 2010, Nature.

[119]  B. Walker,et al.  From sentencing to execution – the processes of apoptosis , 2010, The Journal of pharmacy and pharmacology.

[120]  C. Matrone,et al.  Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease , 2010, Developmental neurobiology.

[121]  P. Marks The clinical development of histone deacetylase inhibitors as targeted anticancer drugs , 2010, Expert opinion on investigational drugs.

[122]  R. E. Hughes,et al.  Neurobiology of Huntington's Disease : Applications to Drug Discovery , 2010 .

[123]  D. Bennett,et al.  Identification of Caspase-6-Mediated Processing of the Valosin Containing Protein (p97) in Alzheimer's Disease: A Novel Link to Dysfunction in Ubiquitin Proteasome System-Mediated Protein Degradation , 2010, The Journal of Neuroscience.

[124]  Jayanta Debnath,et al.  Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease , 2010, PloS one.

[125]  B. Leavitt,et al.  Phosphorylation of Huntingtin at Ser421 in YAC128 Neurons Is Associated with Protection of YAC128 Neurons from NMDA-Mediated Excitotoxicity and Is Modulated by PP1 and PP2A , 2010, The Journal of Neuroscience.

[126]  E. Masliah,et al.  Molecular mechanisms of neurodegeneration in Alzheimer's disease. , 2010, Human molecular genetics.

[127]  Jürgen Götz,et al.  Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models , 2010, Cell.

[128]  M. Fukata,et al.  Protein palmitoylation in neuronal development and synaptic plasticity , 2010, Nature Reviews Neuroscience.

[129]  T. Wyss-Coray,et al.  Beclin 1 complex in autophagy and Alzheimer disease. , 2010, Archives of neurology.

[130]  M. Sheng,et al.  Caspase-3 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization , 2010, Cell.

[131]  L. Raymond,et al.  Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington's Disease Mice , 2010, Neuron.

[132]  X. Bi Alzheimer Disease: Update on Basic Mechanisms , 2010, The Journal of the American Osteopathic Association.

[133]  M. Fardilha,et al.  The physiological relevance of protein phosphatase 1 and its interacting proteins to health and disease. , 2012, Current medicinal chemistry.

[134]  J. Trojanowski,et al.  Epothilone D Improves Microtubule Density, Axonal Integrity, and Cognition in a Transgenic Mouse Model of Tauopathy , 2010, The Journal of Neuroscience.

[135]  R. Riek,et al.  Biology of amyloid: structure, function, and regulation. , 2010, Structure.

[136]  Harald Hampel,et al.  Advances and perspectives from genetic research: development of biological markers in Alzheimer’s disease , 2010, Expert review of molecular diagnostics.

[137]  D. Westaway,et al.  Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations , 2010, Cell.

[138]  A. Yaron,et al.  Axonal Degeneration Is Regulated by the Apoptotic Machinery or a NAD+-Sensitive Pathway in Insects and Mammals , 2010, The Journal of Neuroscience.

[139]  Steven Finkbeiner,et al.  A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model , 2010, Proceedings of the National Academy of Sciences.

[140]  A. Buisson,et al.  Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production , 2010, The Journal of Neuroscience.

[141]  A. Cuervo,et al.  Autophagy gone awry in neurodegenerative diseases , 2010, Nature Neuroscience.

[142]  Reid L Skeel,et al.  Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington's disease , 2010, Behavioural Brain Research.

[143]  Amedeo Caflisch,et al.  Complete Phenotypic Recovery of an Alzheimer's Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor , 2010, PloS one.

[144]  N. Aronin,et al.  Mutant huntingtin and glycogen synthase kinase 3‐β accumulate in neuronal lipid rafts of a presymptomatic knock‐in mouse model of Huntington's disease , 2010, Journal of neuroscience research.

[145]  Elena Cattaneo,et al.  Molecular mechanisms and potential therapeutical targets in Huntington's disease. , 2010, Physiological reviews.

[146]  G. McKhann,et al.  Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model , 2010, Proceedings of the National Academy of Sciences.

[147]  Sami Mahrus,et al.  Activation of Specific Apoptotic Caspases with an Engineered Small-Molecule-Activated Protease , 2010, Cell.

[148]  Sarah J Tabrizi,et al.  Huntington’s disease , 2010, BMJ : British Medical Journal.

[149]  N. Inestrosa,et al.  Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease , 2010, Molecular Psychiatry.

[150]  G. Collingridge,et al.  Aβ1–42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β , 2011, Nature Neuroscience.

[151]  L. Mucke,et al.  Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease , 2011, The Journal of Neuroscience.

[152]  P. Patterson,et al.  Gene Therapy in Mouse Models of Huntington Disease , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[153]  P. Hemachandra Reddy,et al.  Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. , 2011, Human molecular genetics.

[154]  W. Klein,et al.  Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo , 2011, Journal of neuroscience research.

[155]  I. Law,et al.  Huntington's disease: effect of memantine on FDG-PET brain metabolism? , 2011, The Journal of neuropsychiatry and clinical neurosciences.

[156]  W. Thies Stopping a thief and killer: Alzheimer's disease crisis demands greater commitment to research , 2011, Alzheimer's & Dementia.

[157]  A. Kurz,et al.  Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial. , 2011, Journal of Alzheimer's disease : JAD.

[158]  James Lowe,et al.  Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets , 2010, Nature Reviews Drug Discovery.

[159]  Rudi D'Hooge,et al.  Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant , 2011, The Journal of Neuroscience.

[160]  D. Selkoe Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[161]  D. Goldsmith,et al.  Mammalian Target of Rapamycin (mTOR) Inhibitors , 2011, Drug safety.

[162]  J. Trojanowski,et al.  The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies. , 2011, Pharmacological research.

[163]  Lucia Pagani,et al.  Amyloid-Beta Interaction with Mitochondria , 2011, International journal of Alzheimer's disease.

[164]  Morgan Sheng,et al.  Deconstruction for Reconstruction: The Role of Proteolysis in Neural Plasticity and Disease , 2011, Neuron.

[165]  A. Messer,et al.  Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease , 2011, Neurobiology of Disease.

[166]  O. Forlenza,et al.  Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial , 2011, British Journal of Psychiatry.

[167]  Shaun S. Sanders,et al.  Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14. , 2011, Human molecular genetics.

[168]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[169]  Shaomin Li,et al.  Soluble Aβ Oligomers Inhibit Long-Term Potentiation through a Mechanism Involving Excessive Activation of Extrasynaptic NR2B-Containing NMDA Receptors , 2011, The Journal of Neuroscience.

[170]  B. Pollock,et al.  The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. , 2011, Archives of general psychiatry.

[171]  H. Goto,et al.  A Phase II Multi-Center Study of Triple Therapy with Paclitaxel, S-1 and Cisplatin in Patients with Advanced Gastric Cancer , 2011, Oncology.

[172]  R Mark Henkelman,et al.  Altered palmitoylation and neuropathological deficits in mice lacking HIP14. , 2011, Human molecular genetics.

[173]  M. Ohno,et al.  Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. , 2011, Brain : a journal of neurology.

[174]  D. Chuang,et al.  Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington's Disease , 2011, Neuropsychopharmacology.

[175]  Chris Frost,et al.  Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis , 2011, The Lancet Neurology.

[176]  Anne Corbett,et al.  Alzheimer's disease , 2011, The Lancet.

[177]  S. Rivest,et al.  Subchronic memantine administration on spatial learning, exploratory activity, and nest-building in an APP/PS1 mouse model of Alzheimer’s disease , 2011, Neuropharmacology.

[178]  R. Schwarcz,et al.  Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration , 2011, Cell.

[179]  Hui-li Liu,et al.  Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation , 2011, Behavioural Brain Research.