Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer’s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of the β-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein by β-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβ peptide. Increased amounts of APP in the DS brain result in increased amounts of Aβ and extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS. 1. Introduction According to the CDC, 1 in 700 infants born have Down syndrome (DS), approximately 400,000 people in the US and 6 million people world-wide. DS is caused by an extra copy of chromosome 21 that arises during gametogenesis. In 95% of cases, this occurs as the result of chromosomal nondisjunction [1]. This is usually due to improper segregation of chromosomes into daughter cells during meiosis I (Figure 1), although nondisjunction in meiosis II also occurs. This results in gametes that have two copies of chromosome 21 (HSA 21), and upon fusion with another gamete, results in trisomy 21. Although HSA 21 is the smallest human autosome, the chromosome encodes more than 400 known genes [2], a number that may increase with further study. Less frequently, DS occurs due to somatic mosaicism or translocations [1]. DS presents with an easily recognizable phenotype, including a characteristic set of facial features, delayed development, and varying levels of intellectual disability, shortened stature, muscle hypotonia, joint laxity, AD-like neuropathology, and a heterogeneous range of other traits. Figure 1: Chromosomal nondisjunction. (a) Most often Down syndrome (DS) occurs as an error in meiosis I (usually in the oocyte). Chromosomal nondisjunction, or improper segregation of chromosome 21 (the smallest autosome; orange), results in one precursor cell having 2 copies (b), upper half) while the other has zero (b), lower half). (c) Meiosis II then proceeds, with the outcome being two gametes that possess an extra copy of chromosome 21 which, after fusion with another gamete, bears 3 copies of
References
[1]
S. L. Sherman, E. G. Allen, L. H. Bean, and S. B. Freeman, “Epidemiology of Down syndrome,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 13, no. 3, pp. 221–227, 2007.
[2]
K. Gardiner and A. C. S. Costa, “The proteins of human chromosome 21,” American Journal of Medical Genetics, Part C, vol. 142, no. 3, pp. 196–205, 2006.
[3]
E. G. Allen, S. B. Freeman, C. Druschel et al., “Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects,” Human Genetics, vol. 125, no. 1, pp. 41–52, 2009.
[4]
D. M. Mann, “Neuropathology of Alzheimer's disease in down syndrome,” in Down Syndrome and Alzheimer's Disease, V. P. Prasher, Ed., pp. 15–36, Radcliffe-Oxford, London, UK, 2006.
[5]
A. Abbott, “Dementia: a problem for our age,” Nature, vol. 475, supplement 7355, pp. S2–S4, 2011.
[6]
J. Lejeune, M. Gautier, and R. Turpin, “étude des chromasomes somatiques de neuf enfants mongoliens,” Comptes rendus hebdomadaires des séances de l'Académie des sciences, vol. 248, no. 11, pp. 1721–1722, 1959.
[7]
G. McKhann, D. Drachman, and M. Folstein, “Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease,” Neurology, vol. 34, no. 7, pp. 939–944, 1984.
[8]
C. M. Van Duijn, L. Hendriks, M. Cruts, J. A. Hardy, A. Hofman, and C. Van Broeckhoven, “Amyloid precursor protein gene mutation in early-onset Alzheimer's disease,” The Lancet, vol. 337, no. 8747, p. 978, 1991.
[9]
J. A. Hardy and G. A. Higgins, “Alzheimer's disease: the amyloid cascade hypothesis,” Science, vol. 256, no. 5054, pp. 184–185, 1992.
[10]
D. J. Selkoe, “Alzheimer's disease: genes, proteins, and therapy,” Physiological Reviews, vol. 81, no. 2, pp. 741–766, 2001.
[11]
C. Haass, A. Y. Hung, D. J. Selkoe, and D. B. Teplow, “Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β-protein precursor,” Journal of Biological Chemistry, vol. 269, no. 26, pp. 17741–17748, 1994.
[12]
C. Haass, C. A. Lemere, A. Capell et al., “The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway,” Nature Medicine, vol. 1, no. 12, pp. 1291–1296, 1995.
[13]
H. Braak and E. Braak, “Neuropathological stageing of Alzheimer-related changes,” Acta Neuropathologica, vol. 82, no. 4, pp. 239–259, 1991.
[14]
H. Lassmann, C. Bancher, H. Breitschopf et al., “Cell death in Alzheimer's disease evaluated by DNA fragmentation in situ,” Acta Neuropathologica, vol. 89, no. 1, pp. 35–41, 1995.
[15]
G. Smale, N. R. Nichols, D. R. Brady, C. E. Finch, and W. E. Horton, “Evidence for apoptotic cell death in Alzheimer's disease,” Experimental Neurology, vol. 133, no. 2, pp. 225–230, 1995.
[16]
M. E. Velasco, M. A. Smith, S. L. Siedlak, A. Nunomura, and G. Perry, “Striation is the characteristic neuritic abnormality in Alzheimer disease,” Brain Research, vol. 813, no. 2, pp. 329–333, 1998.
[17]
S. W. Scheff, D. A. Price, F. A. Schmitt, and E. J. Mufson, “Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment,” Neurobiology of Aging, vol. 27, no. 10, pp. 1372–1384, 2006.
[18]
E. Masliah, M. Mallory, L. Hansen, R. DeTeresa, M. Alford, and R. Terry, “Synaptic and neuritic alterations during the progression of Alzheimer's disease,” Neuroscience Letters, vol. 174, no. 1, pp. 67–72, 1994.
[19]
J. Hardy and D. J. Selkoe, “The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics,” Science, vol. 297, no. 5580, pp. 353–356, 2002.
[20]
J. Kang, H. G. Lemaire, and A. Unterbeck, “The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor,” Nature, vol. 325, no. 6106, pp. 733–736, 1987.
[21]
I. Hussain, D. Powell, D. R. Howlett et al., “Identification of a novel aspartic protease (Asp 2) as β-secretase,” Molecular and Cellular Neurosciences, vol. 14, no. 6, pp. 419–427, 1999.
[22]
G. Thinakaran and E. H. Koo, “Amyloid precursor protein trafficking, processing, and function,” Journal of Biological Chemistry, vol. 283, no. 44, pp. 29615–29619, 2008.
[23]
J. T. Huse and R. W. Doms, “Closing in on the amyloid cascade: recent insights into the cell biology of Alzheimer's disease,” Molecular Neurobiology, vol. 22, no. 1–3, pp. 81–98, 2001.
[24]
D. J. Selkoe, T. Yamazaki, M. Citron et al., “The role of APP processing and trafficking pathways in the formation of amyloid β-protein,” Annals of the New York Academy of Sciences, vol. 777, pp. 57–64, 1996.
[25]
N. Suzuki, T. T. Cheung, X. D. Cai et al., “An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants,” Science, vol. 264, no. 5163, pp. 1336–1340, 1994.
[26]
K. Maruyama, T. Tomita, K. Shinozaki et al., “Familiar Alzheimer's disease-linked mutations at Val717 of amyloid precursor protein are specific for the increased secretion of Aβ42(43),” Biochemical and Biophysical Research Communications, vol. 227, no. 3, pp. 730–735, 1996.
[27]
C. G. Glabe, “Structural classification of toxic amyloid oligomers,” Journal of Biological Chemistry, vol. 283, no. 44, pp. 29639–29643, 2008.
[28]
D. J. Selkoe, “Normal and abnormal biology of the β-amyloid precursor protein,” Annual Review of Neuroscience, vol. 17, pp. 489–517, 1994.
[29]
B. J. Cummings, T. Satou, E. Head et al., “Diffuse plaques contain C-terminal Aβ42 and not Aβ40: evidence from cats and dogs,” Neurobiology of Aging, vol. 17, no. 4, pp. 653–659, 1996.
[30]
C. A. Lemere, F. Lopera, K. S. Kosik et al., “The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology,” Nature Medicine, vol. 2, no. 10, pp. 1146–1150, 1996.
[31]
R. Vassar, B. D. Bennett, S. Babu-Khan et al., “β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE,” Science, vol. 286, no. 5440, pp. 735–741, 1999.
[32]
S. Sinha, J. P. Anderson, R. Barbour et al., “Purification and cloning of amyloid precursor protein β-secretase from human brain,” Nature, vol. 402, no. 6761, pp. 537–540, 1999.
[33]
R. Yan, M. J. Blenkowski, M. E. Shuck et al., “Membrane-anchored aspartyl protease with Alzheimer's disease β- secretase activity,” Nature, vol. 402, no. 6761, pp. 533–537, 1999.
[34]
X. Lin, G. Koelsch, S. Wu, D. Downs, A. Dashti, and J. Tang, “Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 4, pp. 1456–1460, 2000.
[35]
A. Solans, X. Estivill, and S. De La Luna, “A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein β-secretase,” Cytogenetics and Cell Genetics, vol. 89, no. 3-4, pp. 177–184, 2000.
[36]
K. Ishii, K. Ii, T. Hasegawa, S. Shoji, A. Doi, and H. Mori, “Increased Aβ 42(43)-plaque deposition in early-onset familial Alzheimer's disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS-1 gene,” Neuroscience Letters, vol. 228, no. 1, pp. 17–20, 1997.
[37]
J. H. Stockley and C. O'Neill, “The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain,” Biochemical Society Transactions, vol. 35, no. 3, pp. 574–576, 2007.
[38]
I. Hussain, G. Christie, K. Schneider, S. Moore, and C. Dingwall, “Prodomain processing of Asp1 (BACE2) is autocatalytic,” Journal of Biological Chemistry, vol. 276, no. 26, pp. 23322–23328, 2001.
[39]
K. C. Chou, “Insights from modeling the tertiary structure of human BACE2,” Journal of Proteome Research, vol. 3, no. 5, pp. 1069–1072, 2004.
[40]
H. Fukumoto, D. L. Rosene, M. B. Moss, S. Raju, B. T. Hyman, and M. C. Irizarry, “β-secretase activity increases with aging in human, monkey, and mouse brain,” American Journal of Pathology, vol. 164, no. 2, pp. 719–725, 2004.
[41]
J. S. Miners, Z. Van Helmond, P. G. Kehoe, and S. Love, “Changes with age in the activities of β-secretase and the aβ-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme,” Brain Pathology, vol. 20, no. 4, pp. 794–802, 2010.
[42]
R. R. Ahmed, C. J. Holler, R. L. Webb, F. Li, T. L. Beckett, and M. P. Murphy, “BACE1 and BACE2 enzymatic activities in Alzheimer's disease,” Journal of Neurochemistry, vol. 112, no. 4, pp. 1045–1053, 2010.
[43]
H. Fukumoto, B. S. Cheung, B. T. Hyman, and M. C. Irizarry, “β-secretase protein and activity are increased in the neocortex in Alzheimer disease,” Archives of Neurology, vol. 59, no. 9, pp. 1381–1389, 2002.
[44]
L. B. Yang, K. Lindholm, R. Yan et al., “Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease,” Nature Medicine, vol. 9, no. 1, pp. 3–4, 2003.
[45]
M. Mullan, H. Houlden, M. Windelspecht et al., “A locus for familial early-onset alzheimer's disease on the long arm of chromosome 14, proximal to the α1-antichymotrypsin gene,” Nature Genetics, vol. 2, no. 4, pp. 340–342, 1992.
[46]
S. L. Roberds, J. Anderson, G. Basi et al., “BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics,” Human Molecular Genetics, vol. 10, no. 12, pp. 1317–1324, 2001.
[47]
M. Willem, A. N. Garratt, B. Novak et al., “Control of peripheral nerve myelination by the β-secretase BACE1,” Science, vol. 314, no. 5799, pp. 664–666, 2006.
[48]
X. H. Chen, R. Siman, A. Iwata, D. F. Meaney, J. Q. Trojanowski, and D. H. Smith, “Long-term accumulation of amyloid-β, β-secretase, presenilin-1, and caspase-3 in damaged axons following brain trauma,” American Journal of Pathology, vol. 165, no. 2, pp. 357–371, 2004.
[49]
I. Blasko, R. Beer, M. Bigl et al., “Experimental traumatic brain injury in rats stimulates the expression, production and activity of Alzheimer's disease β-secretase (BACE-1),” Journal of Neural Transmission, vol. 111, no. 4, pp. 523–536, 2004.
[50]
C. J. Holler, R. L. Webb, A. L. Laux et al., “BACE2 expression increases in human neurodegenerative disease,” American Journal of Pathology, vol. 180, no. 1, pp. 337–350, 2012.
[51]
M. S. Cheon, M. Dierssen, S. H. Kim, and G. Lubec, “Protein expression of BACE1, BACE2 and APP in Down syndrome brains,” Amino Acids, vol. 35, no. 2, pp. 339–343, 2008.
[52]
J. S. Miners, S. Morris, S. Love, and P. G. Kehoe, “Accumulation of insoluble amyloid-β in Down's syndrome is associated with increased BACE-1 and neprilysin activities,” Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 101–108, 2011.
[53]
V. Hook, L. Funkelstein, J. Wegrzyn, S. Bark, M. Kindy, and G. Hook, “Cysteine Cathepsins in the secretory vesicle produce active peptides: cathepsin L generates peptide neurotransmitters and cathepsin B produces beta-amyloid of Alzheimer's disease,” Biochimica et Biophysica Acta, vol. 1824, no. 1, pp. 89–104, 2012.
[54]
M. Farzan, C. E. Schnitzler, N. Vasilieva, D. Leung, and H. Choe, “BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 17, pp. 9712–9717, 2000.
[55]
L. Barbiero, L. Benussi, R. Ghidoni et al., “BACE-2 is overexpressed in Down's syndrome,” Experimental Neurology, vol. 182, no. 2, pp. 335–345, 2003.
[56]
M. S. Cheon, M. Dierssen, S. H. Kim, and G. Lubec, “Protein expression of BACE1, BACE2 and APP in Down syndrome brains,” Amino Acids, vol. 35, no. 2, pp. 339–343, 2008.
[57]
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.
[58]
X. Sun, G. He, and W. Song, “BACE2, as a novel APP θ-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome,” FASEB Journal, vol. 20, no. 9, pp. 1369–1376, 2006.
[59]
R. Fluhrer, A. Capell, G. Westmeyer et al., “A non-amyloidogenic function of BACE-2 in the secretory pathway,” Journal of Neurochemistry, vol. 81, no. 5, pp. 1011–1020, 2002.
[60]
G. Azkona, A. Amador-Arjona, C. Obradors-Tarragó et al., “Characterization of a mouse model overexpressing beta-site APP-cleaving enzyme 2 reveals a new role for BACE2,” Genes, Brain and Behavior, vol. 9, no. 2, pp. 160–172, 2010.
[61]
G. Azkona, D. Levannon, Y. Groner, and M. Dierssen, “In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model,” Amino Acids, vol. 39, no. 5, pp. 1571–1580, 2010.
[62]
D. Watson, E. Casta？o, T. A. Kokjohn et al., “Physicochemical characteristics of soluble oligomeric Aβ and their pathologic role in Alzheimer's disease,” Neurological Research, vol. 27, no. 8, pp. 869–881, 2005.
[63]
C. Mori, E. T. Spooner, K. E. Wisniewski et al., “Intraneuronal Aβ42 accumulation in Down syndrome brain,” Amyloid, vol. 9, no. 2, pp. 88–102, 2002.
[64]
J. Lu, G. Esposito, C. Scuderi et al., “S100B and APP promote a gliocentric shift and impaired neurogenesis in down syndrome neural progenitors,” PLoS One, vol. 6, no. 7, Article ID e22126, 2011.
[65]
B. H. Han, M. L. Zhou, F. Abousaleh et al., “Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-β peptide, partial restoration via γ-secretase inhibition,” Journal of Neuroscience, vol. 28, no. 50, pp. 13542–13550, 2008.
[66]
K. C. Chou and W. J. Howe, “Prediction of the tertiary structure of the β-secretase zymogen,” Biochemical and Biophysical Research Communications, vol. 292, no. 3, pp. 702–708, 2002.
[67]
M. Vilardell, A. Rasche, A. Thormann et al., “Meta-analysis of heterogeneous Down Syndrome data reveals consistent genome-wide dosage effects related to neurological processes,” BMC Genomics, vol. 12, article 229, 2011.
[68]
J. O. Korbel, T. Tirosh-Wagner, A. E. Urban et al., “The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 29, pp. 12031–12036, 2009.
[69]
S. J. Krinsky-McHale, D. A. Devenny, H. Gu et al., “Successful aging in a 70-year-old man with down syndrome: a case study,” Intellectual and Developmental Disabilities, vol. 46, no. 3, pp. 215–228, 2008.
[70]
R. E. Nieuwenhuis-Mark, “Diagnosing Alzheimer's dementia in Down syndrome: problems and possible solutions,” Research in Developmental Disabilities, vol. 30, no. 5, pp. 827–838, 2009.
[71]
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.
[72]
J. V. Haxby and M. B. Schapiro, “Longitudinal study of neuropsychological function in older adults with Down syndrome,” Progress in Clinical and Biological Research, vol. 379, pp. 35–50, 1992.
[73]
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.
[74]
J. O. Edgin, G. M. Mason, M. J. Allman et al., “Development and validation of the Arizona Cognitive Test Battery for Down syndrome,” Journal of Neurodevelopmental Disorders, vol. 2, no. 3, pp. 149–164, 2010.
[75]
S. Salomone, F. Caraci, G. M. Leggio, J. Fedotova, and F. Drago, “New pharmacological strategies for treatment of Alzheimer's disease: focus on disease-modifying drugs,” British Journal of Clinical Pharmacology. In press.
[76]
J. L. Price, D. W. McKeel, V. D. Buckles et al., “Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease,” Neurobiology of Aging, vol. 30, no. 7, pp. 1026–1036, 2009.
[77]
M. L. Oster-Granite, M. A. Parisi, L. Abbeduto et al., “Down syndrome: national conference on patient registries, research databases, and biobanks,” Molecular Genetics and Metabolism, vol. 104, no. 1-2, pp. 13–22, 2011.
