Down syndrome (DS) is a condition where a complete or segmental chromosome 21 trisomy causes variable intellectual disability, and progressive memory loss and neurodegeneration with age. Many research groups have examined development of the brain in DS individuals, but studies on age-related changes should also be considered, with the increased lifespan observed in DS. DS leads to pathological hallmarks of Alzheimer's disease (AD) by 40 or 50 years of age. Progressive age-related memory deficits occurring in both AD and in DS have been connected to degeneration of several neuronal populations, but mechanisms are not fully elucidated. Inflammation and oxidative stress are early events in DS pathology, and focusing on these pathways may lead to development of successful intervention strategies for AD associated with DS. Here we discuss recent findings and potential treatment avenues regarding development of AD neuropathology and memory loss in DS. 1. Introduction The most common cause of dementia is Alzheimer’s disease (AD), with rates of prevalence increasing steadily from 60 years of age to reach almost 40% by the age of 85 [1]. AD is defined as the presence of neuritic plaques, which are composed of extracellular deposits of amyloid beta, and neurofibrillary tangles [2]. Neurodegeneration in the later stages of AD is widespread, with massive synapse loss and an overall decline in grey matter resulting from neuronal loss in cortical and hippocampal regions. Cortical neuronal loss is preceded by degeneration of certain subcortical neuronal populations, including basal forebrain cholinergic neurons (BFCNs) [3] and noradrenergic neurons of the locus coeruleus (LC-NE) [4, 5]. While the majority of AD cases are considered sporadic, mutations in amyloid precursor protein (APP) and presenilins 1 and 2 (PS-1 and PS-2) genes are responsible for most of the cases of AD considered “familial” [6]. These mutations lead to alterations in APP metabolism that result in an overabundance of amyloid plaques. Similarly, APP processing is also affected in Down syndrome (DS), a population who exhibit histopathology consistent with AD by the 4th and 5th decades of life with near uniformity, as well as increased risk for dementia [7, 8]. Located on chromosome 21, APP is triplicated in DS, and amyloid-beta deposition is frequently profound in these individuals [9–11]. Recently, cases of familial AD resulting from duplication of only the APP locus have been discovered [12], further defining a role for APP in AD dementia. However, few studies have been able to correlate plaque
References
[1]
J. D. Woolley, B. K. Khan, N. K. Murthy, B. L. Miller, and K. P. Rankin, “The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease,” Journal of Clinical Psychiatry, vol. 72, no. 2, pp. 126–133, 2011.
[2]
M. Mancuso, D. Orsucci, A. LoGerfo, V. Calsolaro, and G. Siciliano, “Clinical features and pathogenesis of Alzheimer's disease: involvement of mitochondria and mitochondrial DNA,” Advances in Experimental Medicine and Biology, vol. 685, pp. 34–44, 2010.
[3]
R. Schliebs and T. Arendt, “The cholinergic system in aging and neuronal degeneration,” Behavioural Brain Research, vol. 221, no. 2, pp. 555–563, 2011.
[4]
A. Grudzien, P. Shaw, S. Weintraub, E. Bigio, D. C. Mash, and M. M. Mesulam, “Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease,” Neurobiology of Aging, vol. 28, no. 3, pp. 327–335, 2007.
[5]
M. Haglund, M. Sj？beck, and E. Englund, “Locus ceruleus degeneration is ubiquitous in Alzheimer's disease: possible implications for diagnosis and treatment,” Neuropathology, vol. 26, no. 6, pp. 528–532, 2006.
[6]
C. Shepherd, H. McCann, and G. M. Halliday, “Variations in the neuropathology of familial Alzheimer's disease,” Acta Neuropathologica, vol. 118, no. 1, pp. 37–52, 2009.
[7]
J. A. Moncaster, R. Pineda, R. D. Moir et al., “Alzheimer's disease amyloid-β links lens and brain pathology in down syndrome,” PLoS ONE, vol. 5, no. 5, Article ID e10659, 2010.
[8]
I. T. Lott and M. Dierssen, “Cognitive deficits and associated neurological complications in individuals with Down's syndrome,” The Lancet Neurology, vol. 9, no. 6, pp. 623–633, 2010.
[9]
J. K. Teller, C. Russo, L. M. DeBusk et al., “Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down's syndrome,” Nature Medicine, vol. 2, no. 1, pp. 93–95, 1996.
[10]
L. D. Nelson, P. Siddarth, V. Kepe et al., “Positron emission tomography of brain β-amyloid and tau levels in adults with down syndrome,” Archives of Neurology, vol. 68, no. 6, pp. 768–774, 2011.
[11]
H. Braak and K. Del Tredici, “The pathological process underlying Alzheimer's disease in individuals under thirty,” Acta Neuropathologica, vol. 121, no. 2, pp. 171–181, 2011.
[12]
A. Rovelet-Lecrux, T. Frebourg, H. Tuominen, K. Majamaa, D. Campion, and A. M. Remes, “APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 78, no. 10, pp. 1158–1159, 2007.
[13]
G. Pepeu and M. G. Giovannini, “Cholinesterase inhibitors and memory,” Chemico-Biological Interactions, vol. 187, no. 1–3, pp. 403–408, 2010.
[14]
D. K. Lahiri, B. Maloney, M. R. Basha, W. G. Yuan, and N. H. Zawia, “How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the “LEARn” model (Latent Early-Life Associated Regulation) may explain the triggering of AD,” Current Alzheimer Research, vol. 4, no. 2, pp. 219–228, 2007.
[15]
M. Mohan, P. K. Carpenter, and C. Bennett, “Donepezil for dementia in people with Down syndrome,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD007178, 2009.
[16]
M. Mohan, C. Bennett, and P. K. Carpenter, “Rivastigmine for dementia in people with Down syndrome,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD007658, 2009.
[17]
S. A. Rasmussen, N. Whitehead, S. A. Collier, and J. L. Frías, “Setting a public health research agenda for Down syndrome: summary of a meeting sponsored by the centers for disease control and prevention and the national down syndrome society,” American Journal of Medical Genetics, Part A, vol. 146, no. 23, pp. 2998–3010, 2008.
[18]
C. Fonatsch, “The role of chromosome 21 in hematology and oncology,” Genes Chromosomes and Cancer, vol. 49, no. 6, pp. 497–508, 2010.
[19]
K. S. Rao, “Mechanisms of disease: DNA repair defects and neurological disease,” Nature Clinical Practice Neurology, vol. 3, no. 3, pp. 162–172, 2007.
[20]
G. M. Martin, “Syndromes of accelerated aging,” National Cancer Institute Monograph, vol. 60, pp. 241–247, 1982.
[21]
S. E. Antonarakis, R. Lyle, E. T. Dermitzakis, A. Reymond, and S. Deutsch, “Chromosome 21 and Down syndrome: from genomics to pathophysiology,” Nature Reviews Genetics, vol. 5, no. 10, pp. 725–738, 2004.
[22]
J. Lockrow, H. Boger, G. Gerhardt, G. Aston-Jones, D. Bachman, and A.-C. Granholm, “A noradrenergic lesion exacerbates neurodegeneration in a down syndrome mouse model,” Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 471–489, 2011.
[23]
J. Tyrrell, M. Cosgrave, M. McCarron et al., “Dementia in people with Down's syndrome,” International Journal of Geriatric Psychiatry, vol. 16, no. 12, pp. 1168–1174, 2001.
[24]
S. Lanfranchi, O. Jerman, E. Dal Pont, A. Alberti, and R. Vianello, “Executive function in adolescents with Down Syndrome,” Journal of Intellectual Disability Research, vol. 54, no. 4, pp. 308–319, 2010.
[25]
V. P. Prasher, “Review of donepezil, rivastigmine, galantamine and memantine for the treatment of dementia in Alzheimer's disease in adults with Down syndrome: implications for the intellectual disability population,” International Journal of Geriatric Psychiatry, vol. 19, no. 6, pp. 509–515, 2004.
[26]
I. T. Lott and E. Head, “Down syndrome and alzheimer's disease: a link between development and aging,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 7, no. 3, pp. 172–178, 2001.
[27]
I. T. Lott and E. Head, “Alzheimer disease and Down syndrome: factors in pathogenesis,” Neurobiology of Aging, vol. 26, no. 3, pp. 383–389, 2005.
[28]
A. M. Cataldo, P. M. Mathews, A. B. Boiteau et al., “Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects,” American Journal of Pathology, vol. 173, no. 2, pp. 370–384, 2008.
[29]
A. M. Cataldo, C. M. Peterhoff, J. C. Troncoso, T. Gomez-Isla, B. T. Hyman, and R. A. Nixon, “Endocytic pathway abnormalities precede amyloid β deposition in sporadic alzheimer's disease and down syndrome: differential effects of APOE genotype and presenilin mutations,” American Journal of Pathology, vol. 157, no. 1, pp. 277–286, 2000.
[30]
H. E. Lockstone, L. W. Harris, J. E. Swatton, M. T. Wayland, A. J. Holland, and S. Bahn, “Gene expression profiling in the adult Down syndrome brain,” Genomics, vol. 90, no. 6, pp. 647–660, 2007.
[31]
G. Lubec and E. Engidawork, “The brain in Down syndrome (Trisomy 21),” Journal of Neurology, vol. 249, no. 10, pp. 1347–1356, 2002.
[32]
J. Busciglio, A. Pelsman, C. Wong et al., “Altered metabolism of the amyloid β precursor protein is associated with mitochondrial dysfunction in Down's syndrome,” Neuron, vol. 33, no. 5, pp. 677–688, 2002.
[33]
E. G. McGeer and P. L. McGeer, “Neuroinflammation in Alzheimer's disease and mild cognitive impairment: a field in its infancy,” Journal of Alzheimer's Disease, vol. 19, no. 1, pp. 355–361, 2010.
[34]
S. Fuller, M. Steele, and G. Münch, “Activated astroglia during chronic inflammation in Alzheimer's disease-Do they neglect their neurosupportive roles?” Mutation Research, vol. 690, no. 1-2, pp. 40–49, 2010.
[35]
P. Helguera, A. Pelsman, G. Pigino, E. Wolvetang, E. Head, and J. Busciglio, “ets-2 promotes the activation of a mitochondrial death pathway in down's syndrome neurons,” Journal of Neuroscience, vol. 25, no. 9, pp. 2295–2303, 2005.
[36]
E. A. Shukkur, A. Shimohata, T. Akagi et al., “Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome,” Human Molecular Genetics, vol. 15, no. 18, pp. 2752–2762, 2006.
[37]
C. Harris-Cerruti, A. Kamsler, B. Kaplan, B. Lamb, M. Segal, and Y. Groner, “Functional and morphological alterations in compound transgenic mice overexpreszing Cu/Zn superoxide dismutaze and amyloid precursor protein,” European Journal of Neuroscience, vol. 19, no. 5, pp. 1174–1190, 2004.
[38]
I. T. Lott, E. Head, E. Doran, and J. Busciglio, “Beta-amyloid, oxidative stress and down syndrome,” Current Alzheimer Research, vol. 3, no. 5, pp. 521–528, 2006.
[39]
M. T. Davisson, C. Schmidt, and E. C. Akeson, “Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome,” Progress in Clinical and Biological Research, vol. 360, pp. 263–280, 1990.
[40]
K. Gardiner, A. Fortna, L. Bechtel, and M. T. Davisson, “Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions,” Gene, vol. 318, no. 1-2, pp. 137–147, 2003.
[41]
J. H. K. Choi, J. D. Berger, M. J. Mazzella et al., “Age-dependent dysregulation of brain amyloid precursor protein in the Ts65Dn Down syndrome mouse model,” Journal of Neurochemistry, vol. 110, no. 6, pp. 1818–1827, 2009.
[42]
A. Salehi, J. D. Delcroix, P. V. Belichenko et al., “Increased app expression in a mouse model of Down's Syndrome disrupts NGF transport and causes cholinergic neuron degeneration,” Neuron, vol. 51, no. 1, pp. 29–42, 2006.
[43]
C. L. Hunter, H. A. Bimonte-Nelson, M. Nelson, C. B. Eckman, and A. C. Granholm, “Behavioral and neurobiological markers of Alzheimer's disease in Ts65Dn mice: effects of estrogen,” Neurobiology of Aging, vol. 25, no. 7, pp. 873–884, 2004.
[44]
D. S. Kern, K. N. Maclean, H. Jiang, E. Y. Synder, J. R. Sladek, and K. B. Bjugstad, “Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn down syndrome mice,” Cell Transplantation, vol. 20, no. 3, pp. 371–379, 2011.
[45]
S. Lomoio, E. Scherini, and D. Necchi, “β-Amyloid overload does not directly correlate with SAPK/JNK activation and tau protein phosphorylation in the cerebellar cortex of Ts65Dn mice,” Brain Research, vol. 1297, pp. 198–206, 2009.
[46]
C. L. Hunter, D. Bachman, and A. C. Granholm, “Minocycline prevents cholinergic loss in a mouse model of Down's syndrome,” Annals of Neurology, vol. 56, no. 5, pp. 675–688, 2004.
[47]
M. Di Filippo, A. Tozzi, V. Ghiglieri et al., “Impaired plasticity at specific subset of striatal synapses in the Ts65Dn mouse model of down syndrome,” Biological Psychiatry, vol. 67, no. 7, pp. 666–671, 2010.
[48]
P. V. Belichenko, A. M. Kleschevnikov, E. Masliah et al., “Excitatory-inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome,” Journal of Comparative Neurology, vol. 512, no. 4, pp. 453–466, 2009.
[49]
J. D. Cooper, A. Salehi, J. D. Delcroix et al., “Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 18, pp. 10439–10444, 2001.
[50]
C. L. Hunter, O. Isacson, M. Nelson et al., “Regional alterations in amyloid precursor protein and nerve growth factor across age in a mouse model of Down's syndrome,” Neuroscience Research, vol. 45, no. 4, pp. 437–445, 2003.
[51]
H. Seo and O. Isacson, “Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice,” Experimental Neurology, vol. 193, no. 2, pp. 469–480, 2005.
[52]
H. A. Bimonte-Nelson, C. L. Hunter, M. E. Nelson, and A. C. E. Granholm, “Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome,” Behavioural Brain Research, vol. 139, no. 1-2, pp. 47–57, 2003.
[53]
A. C. E. Granholm, L. A. Sanders, and L. S. Crnic, “Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of down's syndrome,” Experimental Neurology, vol. 161, no. 2, pp. 647–663, 2000.
[54]
D. M. Holtzman, D. Santucci, J. Kilbridge et al., “Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 23, pp. 13333–13338, 1996.
[55]
A. Salehi, M. Faizi, D. Colas et al., “Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome,” Science Translational Medicine, vol. 1, no. 7, pp. 7–17, 2009.
[56]
C. L. Hunter, H. A. Bimonte, and A. C. E. Granholm, “Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory,” Behavioural Brain Research, vol. 138, no. 2, pp. 121–131, 2003.
[57]
N. P. Belichenko, P. V. Belichenko, A. M. Kleschevnikov, A. Salehi, R. H. Reeves, and W. C. Mobley, “The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome,” Journal of Neuroscience, vol. 29, no. 18, pp. 5938–5948, 2009.
[58]
L. E. Olson, R. J. Roper, C. L. Sengstaken et al., “Trisomy for the Down syndrome 'critical region' is necessary but not sufficient for brain phenotypes of trisomic mice,” Human Molecular Genetics, vol. 16, no. 7, pp. 774–782, 2007.
[59]
O. Isacson, H. Seo, L. Lin, D. Albeck, and A. C. Granholm, “Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh,” Trends in Neurosciences, vol. 25, no. 2, pp. 79–84, 2002.
[60]
R. Nardone, R. Marth, H. Ausserer, A. Bratti, and F. Tezzon, “Reduced short latency afferent inhibition in patients with Down syndrome and Alzheimer-type dementia,” Clinical Neurophysiology, vol. 117, no. 10, pp. 2204–2210, 2006.
[61]
F. Fernandez, W. Morishita, E. Zuniga et al., “Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome,” Nature Neuroscience, vol. 10, no. 4, pp. 411–413, 2007.
[62]
R. H. Reeves, N. G. Irving, T. H. Moran et al., “A mouse model for Down syndrome exhibits learning and behaviour deficits,” Nature Genetics, vol. 11, no. 2, pp. 177–184, 1995.
[63]
G. E. Demas, R. J. Nelson, B. K. Krueger, and P. J. Yarowsky, “Impaired spatial working and reference memory in segmental trisomy (Ts65Dn) mice,” Behavioural Brain Research, vol. 90, no. 2, pp. 199–201, 1998.
[64]
L. A. Hyde, D. F. Frisone, and L. S. Crnic, “Ts65Dn mice, a model for Down syndrome, have deficits in context discrimination learning suggesting impaired hippocampal function,” Behavioural Brain Research, vol. 118, no. 1, pp. 53–60, 2001.
[65]
Z. Galdzicki, R. Siarey, R. Pearce, J. Stoll, and S. I. Rapoport, “On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models,” Brain Research Reviews, vol. 35, no. 2, pp. 115–145, 2001.
[66]
M. Faizi, P. L. Bader, C. Tun et al., “Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down Syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer,” Neurobiology of Disease, vol. 43, no. 2, pp. 397–413, 2011.
[67]
Q. Chang and P. E. Gold, “Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome,” Neurobiology of Learning and Memory, vol. 89, no. 2, pp. 167–177, 2008.
[68]
A. C.S. Costa, “On the promise of pharmacotherapies targeted at cognitive and neurodegenerative components of down syndrome,” Developmental Neuroscience, vol. 33, no. 5, pp. 414–427, 2011.
[69]
A. C. S. Costa, J. J. Scott-McKean, and M. R. Stasko, “Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test,” Neuropsychopharmacology, vol. 33, no. 7, pp. 1624–1632, 2008.
[70]
J. Lockrow, H. Boger, H. Bimonte-Nelson, and A.-C. Granholm, “Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome,” Behavioural Brain Research, vol. 221, no. 2, pp. 610–622, 2011.
[71]
N. Rueda, M. Llorens-Martín, J. Flórez et al., “Memantine normalizes several phenotypic features in the Ts65Dn mouse model of down syndrome,” Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 277–290, 2010.
[72]
R. J. Siarey, A. Kline-Burgess, M. Cho et al., “Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome,” Journal of Neurochemistry, vol. 98, no. 4, pp. 1266–1277, 2006.
[73]
D. A. Devenny, S. J. Krinsky-McHale, G. Sersen, and W. P. Silverman, “Sequence of cognitive decline in dementia in adults with Down's syndrome,” Journal of Intellectual Disability Research, vol. 44, no. 6, pp. 654–665, 2000.
[74]
D. Weinshenker, “Functional consequences of locus coeruleus degeneration in Alzheimer's disease,” Current Alzheimer Research, vol. 5, no. 3, pp. 342–345, 2008.
[75]
M. T. Heneka, E. Galea, V. Gavriluyk et al., “Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 22, no. 7, pp. 2434–2442, 2002.
[76]
M. T. Heneka, F. Nadrigny, T. Regen et al., “Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 13, pp. 6058–6063, 2010.
[77]
D. Jardanhazi-Kurutz, M. P. Kummer, D. Terwel et al., “Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits,” Neurochemistry International, vol. 57, no. 4, pp. 375–382, 2010.
[78]
S. Traver, B. Salthun-Lassalle, M. Marien, E. C. Hirsch, F. Colpaert, and P. P. Michel, “The neurotransmitter noradrenaline rescues septal cholinergic neurons in culture from degeneration caused by low-level oxidative stress,” Molecular Pharmacology, vol. 67, no. 6, pp. 1882–1891, 2005.
[79]
E. Acquas, C. Wilson, and H. C. Fibiger, “Pharmacology of sensory stimulation-evoked increases in frontal cortical acetylcholine release,” Neuroscience, vol. 85, no. 1, pp. 73–83, 1998.
[80]
C. W. Harley, “Norepinephrine and the dentate gyrus,” Progress in Brain Research, vol. 163, pp. 299–318, 2007.
[81]
M. T. Heneka, M. Ramanathan, A. H. Jacobs et al., “Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice,” Journal of Neuroscience, vol. 26, no. 5, pp. 1343–1354, 2006.
[82]
S. Kalinin, V. Gavrilyuk, P. E. Polak et al., “Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease,” Neurobiology of Aging, vol. 28, no. 8, pp. 1206–1214, 2007.
[83]
D. C. Gekman, O. Nelson, F. Liang, C. L. Liang, and D. Games, “The PDAPP mouse model of Alzheimer's disease: Locus coeruleus neuronal shrinkage,” Journal of Comparative Neurology, vol. 492, no. 4, pp. 469–476, 2005.
[84]
D. C. German, K. F. Manaye, C. L. White et al., “Disease-specific patterns of locus coeruleus cell loss,” Annals of Neurology, vol. 32, no. 5, pp. 667–676, 1992.
[85]
D. M. A. Mann, P. O. Yates, and J. Hawkes, “The pathology of the human locus ceruleus,” Clinical Neuropathology, vol. 2, no. 1, pp. 1–7, 1983.
[86]
C. Zarow, S. A. Lyness, J. A. Mortimer, and H. C. Chui, “Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases,” Archives of Neurology, vol. 60, no. 3, pp. 337–341, 2003.
[87]
H. Brunnstr？m, N. Friberg, E. Lindberg, and E. Englund, “Differential degeneration of the locus coeruleus in dementia subtypes,” Clinical Neuropathology, vol. 30, no. 3, pp. 104–110, 2011.
[88]
L. Marsh, K. Biglan, M. Gerstenhaber, and J. R. Williams, “Atomoxetine for the treatment of executive dysfunction in Parkinson's disease: a pilot open-label study,” Movement Disorders, vol. 24, no. 2, pp. 277–282, 2009.
[89]
R. C. Mohs, T. M. Shiovitz, P. N. Tariot, A. P. Porsteinsson, K. D. Baker, and P. D. Feldman, “Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study,” American Journal of Geriatric Psychiatry, vol. 17, no. 9, pp. 752–759, 2009.
[90]
C. R. Dolder, L. N. Davis, and J. McKinsey, “Use of psychostimulants in patients with dementia,” Annals of Pharmacotherapy, vol. 44, no. 10, pp. 1624–1632, 2010.
[91]
W. S. T. Griffin, “Inflammation and neurodegenerative diseases,” American Journal of Clinical Nutrition, vol. 83, no. 2, pp. 470S–474S, 2006.
[92]
R. E. Mrak and W. S. T. Griffin, “Glia and their cytokines in progression of neurodegeneration,” Neurobiology of Aging, vol. 26, no. 3, pp. 349–354, 2005.
[93]
J. Kálmán, A. Juhász, G. Laird et al., “Serum interleukin-6 levels correlate with the severity of dementia in down syndrome and in Alzheimer's disease,” Acta Neurologica Scandinavica, vol. 96, no. 4, pp. 236–240, 1997.
[94]
M. McKinney, “Brain cholinergic vulnerability: relevance to behavior and disease,” Biochemical Pharmacology, vol. 70, no. 8, pp. 1115–1124, 2005.
[95]
B. Zassler, C. Weis, and C. Humpel, “Tumor necrosis factor-α triggers cell death of sensitized potassium chloride-stimulated cholinergic neurons,” Molecular Brain Research, vol. 113, no. 1-2, pp. 78–85, 2003.
[96]
D. Carnevale, R. De Simone, and L. Minghetti, “Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems,” CNS and Neurological Disorders, vol. 6, no. 6, pp. 388–397, 2007.
[97]
W. Bondareff and C. Q. Mountjoy, “Number of neurons in nucleus locus ceruleus in demented and non-demented patients: rapid estimation and correlated parameters,” Neurobiology of Aging, vol. 7, no. 4, pp. 297–300, 1986.
[98]
R. M. Zweig, C. A. Ross, J. C. Hedreen et al., “Neuropathology of aminergic nuclei in Alzheimer's disease,” Progress in Clinical and Biological Research, vol. 317, pp. 353–365, 1989.
[99]
D. L. Feinstein, M. T. Heneka, V. Gavrilyuk, C. Dello Russo, G. Weinberg, and E. Galea, “Noradrenergic regulation of inflammatory gene expression in brain,” Neurochemistry International, vol. 41, no. 5, pp. 357–365, 2002.
[100]
K. Schindowski, K. Belarbi, and L. Buée, “Neurotrophic factors in Alzheimer's disease: role of axonal transport,” Genes, Brain and Behavior, vol. 7, no. 1, pp. 43–56, 2008.
[101]
J. D. Delcroix, J. Valletta, C. Wu et al., “Trafficking the NGF signal: implications for normal and degenerating neurons,” Progress in Brain Research, vol. 146, pp. 3–23, 2004.
[102]
S. E. Counts and E. J. Mufson, “The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 4, pp. 263–272, 2005.
[103]
B. J. Williams, M. Eriksdotter-Jonhagen, and A. C. Granholm, “Nerve growth factor in treatment and pathogenesis of Alzheimer's disease,” Progress in Neurobiology, vol. 80, no. 3, pp. 114–128, 2006.
[104]
E. J. Mufson, J. M. Conner, and J. H. Kordower, “Nerve growth factor in Alzheimer's disease: defective retrograde transport to nucleus basalis,” NeuroReport, vol. 6, no. 7, pp. 1063–1066, 1995.
[105]
B. Williams, A. C. Granholm, and K. Sambamurti, “Age-dependent loss of NGF signaling in the rat basal forebrain is due to disrupted MAPK activation,” Neuroscience Letters, vol. 413, no. 2, pp. 110–114, 2007.
[106]
Y. Jiang, K. A. Mullaney, C. M. Peterhoff et al., “Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 4, pp. 1630–1635, 2010.
[107]
S. D. Ginsberg, M. J. Alldred, S. E. Counts et al., “Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression,” Biological Psychiatry, vol. 68, no. 10, pp. 885–893, 2010.
[108]
H. Koshimizu, K. Kiyosue, T. Hara et al., “Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival,” Molecular Brain, vol. 2, no. 1, article 27, 2009.
[109]
M. Fahnestock, D. Garzon, R. M.D. Holsinger, and B. Michalski, “Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule?” Journal of Neural Transmission, no. 62, supplement, pp. 241–252, 2002.
[110]
S. Navakkode and M. Korte, “Cooperation between cholinergic and glutamatergic receptors are essential to induce BDNF-dependent long-lasting memory storage,” Hippocampus, vol. 22, no. 22, pp. 335–346, 2012.
[111]
G. Dogliotti, E. Galliera, F. Licastro, and M. M. Corsi, “Age-related changes in plasma levels of BDNF in Down syndrome patients,” Immunity and Ageing, vol. 7, article 2, 2010.
[112]
O. von Bohlen and Halbach, “Involvement of BDNF in age-dependent alterations in the hippocampus,” Frontiers in Aging Neuroscience, vol. 2, article 36, 2010.
[113]
N. C. Berchtold, N. Castello, and C. W. Cotman, “Exercise and time-dependent benefits to learning and memory,” Neuroscience, vol. 167, no. 3, pp. 588–597, 2010.
[114]
N. C. Berchtold, G. Chinn, M. Chou, J. P. Kesslak, and C. W. Cotman, “Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus,” Neuroscience, vol. 133, no. 3, pp. 853–861, 2005.
[115]
H. -L. Liu, G. Zhao, K. Cai, H. -H. Zhao, and L. -D. Shi, “Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation,” Behavioural Brain Research, vol. 218, no. 2, pp. 308–314, 2011.
[116]
Y. F. Liu, H. I. Chen, L. Yu et al., “Upregulation of hippocampal TrkB and synaptotagmin is involved in treadmill exercise-enhanced aversive memory in mice,” Neurobiology of Learning and Memory, vol. 90, no. 1, pp. 81–89, 2008.
[117]
K. Nichol, S. P. Deeny, J. Seif, K. Camaclang, and C. W. Cotman, “Exercise improves cognition and hippocampal plasticity in APOE ε{lunate}4 mice,” Alzheimer's and Dementia, vol. 5, no. 4, pp. 287–294, 2009.
[118]
L. Willis, E. M. Quintero, M. Nelson, and A. C. Granholm, “Regulation of trophic factor expression by innervating target regions in intraocular double transplants,” Cell Transplantation, vol. 14, no. 1, pp. 21–29, 2005.
[119]
S. E. Counts and E. J. Mufson, “Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity,” Journal of Neurochemistry, vol. 113, no. 3, pp. 649–660, 2010.
[120]
K. A. Jellinger, “Recent advances in our understanding of neurodegeneration,” Journal of Neural Transmission, vol. 116, no. 9, pp. 1111–1162, 2009.
[121]
A. Strydom, M. J. Dickinson, S. Shende, D. Pratico, and Z. Walker, “Oxidative stress and cognitive ability in adults with Down syndrome,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 33, no. 1, pp. 76–80, 2009.
[122]
A. G. Nikonenko, L. Radenovic, P. R. Andjus, and G. G. Skibo, “Structural features of ischemic damage in the hippocampus,” Anatomical Record, vol. 292, no. 12, pp. 1914–1921, 2009.
[123]
F. F. Cruz-Sánchez, X. Gironès, A. Ortega, F. Alameda, and J. V. Lafuente, “Oxidative stress in Alzheimer's disease hippocampus: a topographical study,” Journal of the Neurological Sciences, vol. 299, no. 1-2, pp. 163–167, 2010.
[124]
A. Nunomura, G. Perry, G. Aliev et al., “Oxidative damage is the earliest event in Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 60, no. 8, pp. 759–767, 2001.
[125]
A. Nunomura, G. Perry, M. A. Pappolla et al., “Neuronal oxidative stress precedes amyloid-β deposition in down syndrome,” Journal of Neuropathology and Experimental Neurology, vol. 59, no. 11, pp. 1011–1017, 2000.
[126]
C. A. Massaad, T. M. Washington, R. G. Pautler, and E. Klann, “Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 32, pp. 13576–13581, 2009.
[127]
R. Gardner, A. Salvador, and P. Moradas-Ferreira, “Why does SOD overexpression sometimes enhance, sometimes decrease, hydrogen peroxide production? A minimalist explanation,” Free Radical Biology and Medicine, vol. 32, no. 12, pp. 1351–1357, 2002.
[128]
S. H. Kim, M. Fountoulakis, N. Cairns, and G. Lubec, “Protein levels of human peroxiredoxin subtypes in brains of patients with Alzheimer's disease and Down Syndrome,” Journal of Neural Transmission, no. 61, supplement, pp. 223–235, 2001.
[129]
D. Praticò, “Evidence of oxidative stress in Alzheimer's disease brain and antioxidant therapy: lights and shadows,” Annals of the New York Academy of Sciences, vol. 1147, pp. 70–78, 2008.
[130]
J. M. Ellis, K. T. Hooi, R. E. Gilbert et al., “Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial,” British Medical Journal, vol. 336, no. 7644, pp. 594–597, 2008.
[131]
J. Lockrow, A. Prakasam, P. Huang, H. Bimonte-Nelson, K. Sambamurti, and A. C. Granholm, “Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model,” Experimental Neurology, vol. 216, no. 2, pp. 278–289, 2009.
[132]
F. G. De Felice, P. T. Velasco, M. P. Lambert et al., “Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine,” Journal of Biological Chemistry, vol. 282, no. 15, pp. 11590–11601, 2007.
[133]
J. Yuan and B. A. Yankner, “Apoptosis in the nervous system,” Nature, vol. 407, no. 6805, pp. 802–809, 2000.
[134]
S. Porta, S. A. Serra, M. Huch et al., “RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration,” Human Molecular Genetics, vol. 16, no. 9, pp. 1039–1050, 2007.
[135]
S. V. Faraone, J. Biederman, T. Spencer et al., “Atomoxetine and stroop task performance in adult attention-deficit/ hyperactivity disorder,” Journal of Child and Adolescent Psychopharmacology, vol. 15, no. 4, pp. 664–670, 2005.
