Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia

Molecular Neurodegeneration

Eduardo M Castaño²  María F Ceriani²  Laura Morelli²  Rubén Vidal³  Osvaldo L Podhajcer²  Cecilia Rotondaro¹  Luz A Avendaño¹  Agata C Fernández-Gamba¹  María S Marcora² 

[1] From Fundación Instituto Leloir, Av. Patricias Argentinas 435, Buenos Aires C1405BWE, Argentina;Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Av. Patricias Argentinas 435, Buenos Aires C1405BWE, Argentina;Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Dr, MSB A136, Indianapolis, IN 46202, USA

关键词: Drosophila;    Neurotoxicity;    ADan;    ABri;    Familial Danish dementia;    Familial British dementia;    Alzheimer’s disease;   

Others  :  861768
DOI  :  10.1186/1750-1326-9-5

 received in 2013-07-26, accepted in 2013-12-29,  发布年份 2014

【 摘 要 】

Background

Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI₂ gene. Processing of the mutated BRI₂ protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic.

Results

By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri₂-23 (the normal product of wild-type BRI₂ processing) and amyloid-β (Aβ) 1–42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4-Upstream Activating Sequence (UAS) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri₂-23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity.

Conclusions

Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.

【 授权许可】

   
2014 Marcora et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Vidal R, Frangione B, Rostagno A, Mead S, Révész T, Plant G, et al.: A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 1999, 24:776-781.
• [2]Vidal R, Revesz T, Rostagno A, Kim E, Holton JL, Bek T, et al.: A decamer duplication in the 3′ region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci U S A 2000, 97:4920-4925.
• [3]Mead S, James-Galton M, Revesz T, Doshi RB, Harwood G, Pan EL, et al.: Familial British dementia with amyloid angiopathy: early clinical, neuropsychological and imaging findings. Brain 2000, 123:975-991.
• [4]Strömgren E, Dalby A, Dalby MA, Ranheim B: Cataract, deafness, cerebellar ataxia, psychosis and dementia: a new syndrome. Acta Neurol Scand 1970, 46:261-262.
• [5]Holton JL, Lashley T, Ghiso J, Braendgaard H, Vidal R, Guerin CJ, et al.: Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol 2002, 61:254-267.
• [6]Holton JL, Ghiso J, Lashley T, Rostagno A, Guerin CJ, Gibb G, et al.: Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia. Am J Pathol 2001, 158:515-526.
• [7]Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 210:885-890.
• [8]Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985, 82:4245-4249.
• [9]Creemers JWM, Chu S, Thinakaran G, Sisodia SS: Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides. J Biol Chem 2002, 277:1872-1877.
• [10]Sánchez-Pulido L, Devos D, Valencia A: BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer. Trends Biochem Sci 2002, 27:329-332.
• [11]Garringer HJ, Murrell J, D’Adamio L, Ghetti B, Vidal R: Modeling familial British and Danish dementia. Brain Struct Funct 2010, 214:235-244.
• [12]El-Agnaf OM, Nagala S, Patel BP, Austen BM: Non-fibrillar oligomeric species of the amyloid ABri peptide, implicated in familial British dementia, are more potent at inducing apoptotic cell death than protofibrils or mature fibrils. J Mol Biol 2001, 310:157-168.
• [13]Gibson G, Gunasekera N, Lee M, Lelyveld V, El-Agnaf OM, Wright A, Austen BM: Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia. J Neurochem 2004, 88:281-290.
• [14]Vidal R, Barbeito AG, Miravalle L, Ghetti B: Cerebral amyloid angiopathy and parenchymal amyloid deposition in transgenic mice expressing the Danish mutant form of human BRI2. Brain Pathol 2009, 19:58-68.
• [15]Garringer HJ, Murrell J, Sammeta N, Gnezda A, Ghetti B, Vidal R: Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice. PLoS ONE 2013, 8:e56426.
• [16]Giliberto L, Matsuda S, Vidal R, D’Adamio L: Generation and initial characterization of FDD knock in mice. PLoS ONE 2009, 4:e7900.
• [17]Coomaraswamya J, Kilgera E, Wölfinga H, Schäfera C, Kaesera SA, Wegenast-Brauna BM, et al.: Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer’s disease. Proc Natl Acad Sci U S A 2010, 107:7969-7974.
• [18]Pickford F, Coomaraswamy J, Jucker M, McGowan E: Modeling familial British dementia in transgenic mice. Brain Pathol 2006, 16:80-85.
• [19]Tamayev R, Giliberto L, Li W, d’Abramo C, Arancio O, Vidal R, et al.: Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis. J Neurosci 2010, 30:14915-14924.
• [20]Fotinopoulou A, Tsachaki M, Vlavaki M, Poulopoulos A, Rostagno A, Frangione B, et al.: BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Aβ) production. J Biol Chem 2005, 280:30768-30772.
• [21]Kim J, Miller VM, Levites Y, West KJ, Zwizinski CW, Moore BD, et al.: BRI2 (ITM2b) inhibits Aβ deposition in vivo. J Neurosci 2008, 28:6030-6036.
• [22]Chandran J, Lewis P: Mad fly disease. J Neurosci 2007, 27:971-972.
• [23]Lu B, Vogel H: Drosophila models of neurodegenerative diseases. Annu Rev Pathol 2009, 4:315-342.
• [24]Lanson NA Jr, Pandey UB: FUS-related proteinopathies: lessons from animal models. Brain Res 2012, 1462:44-60.
• [25]Jaiswal M, Sandoval H, Zhang K, Bayat V, Bellen HJ: Probing mechanisms that underlie human neurodegenerative diseases in Drosophila. Annu Rev Genet 2012, 46:371-396.
• [26]Greeve I, Kretzschmar D, Tschäpe JA, Beyn A, Brellinger C, Schweizer M, et al.: Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 2004, 24:3899-3906.
• [27]Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M: A model for studying Alzheimer’s Aβ42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 2004, 26:365-375.
• [28]Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolakis M, Zhong Y: Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: a potential model for Alzheimer’s disease. Proc Natl Acad Sci U S A 2004, 101:6623-6628.
• [29]Crowther DC, Kinghorn KJ, Miranda E, Page R, Curry JA, Duthie FA, et al.: Intraneuronal Aβ, non-amyloid aggregates and neurodegenertion in a Drosophila model of Alzheimer’s disease. Neuroscience 2005, 132:123-135.
• [30]Iijima K, Chiang H, Hearn S, Hakker I, Gatt A, Shenton C, et al.: Aβ42 mutants with different aggregation profiles induce distinct pathologies in Drosophila. PLoS One 2008, 3:e1703.
• [31]Iijima AK, Hearn SA, Shenton C, Gatt A, Zhao LJ, Iijima K: Mitochondrial mislocalization underlies Aβ42-induced neuronal dysfunction in a Drosophila model of Alzheimer’s disease. PLoS One 2009, 4:e8310.
• [32]Zhao XL, Wang WA, Tan JX, Huang JK, Zhang X, Zhang BZ, et al.: Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila. J Neurosci 2010, 30:1512-1522.
• [33]Huang JK, Ma PL, Ji SY, Zhao XL, Tan JX, Sun XJ, Huang FD: Age-dependent alterations in the presynaptic active zone in a Drosophila model of Alzheimer’s. Neurobiol Dis 2013, 51:161-167.
• [34]Luheshi LM, Tartaglia GG, Brorsson AC, Pawar AP, Watson IE, Chiti F, et al.: Systematic in vivo analysis of the intrinsic determinants of amyloid β pathogenicity. PLoS Biol 2007, 5:e290.
• [35]Iijima-Ando K, Hearn SA, Granger L, Shenton C, Gatt A, Chiang HC, et al.: Overexpression of neprilysin reduces alzheimer amyloid-β42 (Aβ42)-induced neuron loss and intraneuronal Aβ42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. J Biol Chem 2008, 283:19066-19076.
• [36]Iijimaa K, Kanae Iijima-Ando K: Drosophila models of Alzheimer’s amyloidosis: the challenge of dissecting the complex mechanisms of toxicity of amyloid-β 42. J Alz Dis 2008, 15:523-540.
• [37]Cao W, Song HJ, Gangi T, Kelkar A, Antani I, Garza D, et al.: Identification of novel genes that modify phenotypes induced by Alzheimer’s β-amyloid overexpression in Drosophila. Genetics 2008, 178:1457-1471.
• [38]Tan L, Schedl P, Song HJ, Garza D, Konsolaki M: The Toll → NFkB signaling pathway mediates the neuropathological effects of the human Alzheimer’s Aβ42 polypeptide in Drosophila. PLoS One 2008, 3:e3966.
• [39]Chiang HC, Wang L, Xied Z, Yaua A, Zhonga Y: PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila. Proc Natl Acad Sci U S A 2010, 107:7060-7065.
• [40]Tare M, Modi RM, Nainaparampil JJ, Puli OR, Bedi S, Fernandez-Funez P, et al.: Activation of JNK signaling mediates amyloid-β-dependent cell death. PLoS One 2011, 6:e24361.
• [41]Rogers I, Kerr F, Martinez P, Hardy J, Lovestone S, Partridge L: Ageing increases vulnerability to Aβ42 toxicity in Drosophila. PLoS One 2012, 7:e40569.
• [42]Bischof J, Maeda RK, Hediger M, Karch F, Basler K: An optimized transgenesis system for Drosophila using germ-line-specific-C31 integrases. Proc Natl Acad Sci U S A 2007, 104:3312-3317.
• [43]Kramer JM, Staveley BE: GAL4 causes developmental defects and apoptosis when expressed in the developing eye of Drosophila melanogaster. Genet Mol Res 2003, 2:43-47.
• [44]Rezával C, Berni J, Gorostiza EA, Werbajh S, Fagilde MM, Fernández MP, et al.: A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration. PLoS One 2008, 3:e3332.
• [45]DiAngelo JR, Erion R, Crocker A, Sehgal A: The central clock neurons regulate lipid storage in Drosophila. PLoS One 2011, 6:e19921.
• [46]Buchanan RL, Benzer S: Defective glia in the drosophila brain degeneration mutant drop-dead. Neuron 1993, 10:839-850.
• [47]Lang M, Wang L, Fan Q, Xiao G, Wang X, Zhong Y, et al.: Genetic inhibition of solute-linked carrier 39 family transporter 1 ameliorates Aβ pathology in a Drosophila model of Alzheimer’s disease. PLoS Genet 2012, 8:e1002683.
• [48]Choi SI, Vidal R, Frangione B, Levy E: Axonal transport of British and Danish amyloid peptides via secretory vesicles. FASEB J 2004, 18:373-375.
• [49]Gargano JW, Martin I, Bhandari P, Grotewiel MS: Rapid iterative negative geotaxis (RING): a new method for assessing age-related locomotor decline in Drosophila. Exp Gerontol 2005, 40:386-395.