Jorge Busciglio

Picture of Jorge Busciglio
Professor, Neurobiology and Behavior
School of Biological Sciences
Fellow, Center for the Neurobiology of Learning and Memory
Member, Institute for Memory Impairments and Neurological Disorders (UCI MIND)
Ph.D., Neuroscience
Phone: (949) 824-4820
University of California, Irvine
3216 BioSci III
Mail Code: 4545
Irvine, CA 92697
Research Interests
Alzheimer's disease, Down's syndrome, neurodegeneration, axonal transport, oxidative stress, mitochondrial dysfunction,
Academic Distinctions
2004-05 National Academies Howard Hughes Fellow in Education in the Life Sciences
2004 Member, Institute for Brain Aging and Dementia (IBAD, currently iMIND), UCI
2004 Fellow, Center for the Neurobiology of Learning and Memory, UCI
2005 Teaching Excellence Award, Celebration of Teaching, School of Biological Sciences, UCI
2005 Golden Apple Teaching Award, School of Biological Sciences, UCI
2012 Fellowship Award from the Ministry of Education of Spain for Visiting Professors
2017 Keynote speaker, 2nd National Congress on Intellectual Disability. Acapulco, Mexico.
Children’s Hospital, Harvard University Postdoctoral 1990-1993 Neurodegenerative diseases-AD and DS
Research Abstract
The focus of our research is to understand the molecular bases of neuronal dysfunction and death in Down’s syndrome (DS) and Alzheimer’s disease (AD).
AD is the most common form of dementia in the human aged population, affecting more than four million people in the United States. It is characterized by significant neuronal loss and the abnormal accumulation of aggregated amyloid beta (Aß) and tau in the form of senile plaques and neurofibrillary tangles respectively. The presence of abundant senile plaques in various brain regions is a pathological criterion to confirm AD diagnosis. Yet, the role of Aß and tau in the disease process remains poorly understood.
DS or trisomy 21 is the most common genetic condition associated with mental retardation. It occurs in about 1 in 850 live births (approximately 350,000 DS subjects in the USA). As a result of improved medical care, the childhood survival and life expectancy of individuals affected by DS has greatly improved in recent years. Not only are greater numbers than ever surviving into adulthood, but also some are beginning to reach what would be considered old age for the population at large. Unfortunately, this dramatic public health accomplishment has been accompanied by a very high prevalence of chronic disorders in DS individuals including a very high prevalence of AD. These developments have presented unique new challenges for patients, families and health care providers.

To study the mechanisms of neuronal death and dysfunction in AD and DS, we utilize a combined experimental approach which includes the use of human fetal primary cultures from brain and other tissues, fibroblast and limphoblastoid cells from DS and AD patients, post-mortem brain tissue, and transgenic models. We are one of a few research groups utilizing human cortical neurons as an experimental paradigm for neurodegenerative diseases, and to our knowledge, the only lab using DS cortical neurons to investigate DS and AD pathology. It is relevant to look for disease mechanisms in human cells because significant structural and functional differences exist between human and rodent neurons.

Our research focuses on three areas:

A. Molecular mechanisms underlying DS pathology.
We are interested in exploring the impact of DS on mitochondrial function as a mechanistic framework to understand the tremendous vulnerability of DS subjects to develop selective neuronal degeneration and AD as they become adults. Using a combination of novel molecular and imaging techniques and genomics to assess gene function and mitochondrial activity in DS fetal and adult cells we have found that chronic mitochondrial dysfunction, energy deficits and oxidative stress in DS cells contribute to several clinical phenotypes associated with DS including mental retardation, hypotonia, type 2 diabetes, and AD.

B. Cell and molecular pathways involved in amyloid ß (Aß) neurotoxicity.
We continue working on a comprehensive analysis of the molecular mechanisms of oligomeric targeting. The results demonstrate that synaptic activity regulates the formation and accumulation of soluble Aß oligomers at synaptic sites in both rat organotypic slices and human primary neurons, and the first to establish the existence of heterogenous oligomeric structures associated with synapses in AD brains using a variety of conformation-specific antibodies. We determined that oligomer synaptic targeting involves release of ion metals (particularly zinc) during neurotransmission, and the engagement of the NR2B subunit of the NMDA receptor. These results are especially significant in light of recent experiments describing Aß-induced intermittent neuronal hyperexcitability and nonconvulsive seizure activity in the cortex and hippocampus of mouse models of AD. Since there is also a high incidence of seizures in AD patients, the emerging view is that excitatory overactivity during the course of the disease may exacerbate Aß generation and secretion, and based on our data, oligomeric formation and accumulation at synapses, eventually leading to impaired synaptic plasticity and synaptic loss. We are currently focusing on the identification of the specific oligomeric forms accumulating at synapses in the AD brain, and on the role of zinc and the zinc transporter ZnT3 in neuronal dysfunction.

C. The role of axonal transport deficits in AD.
Neurons are highly polarized cells, which depend on transport mechanisms for proper function. There is an emerging consensus that deficits in axonal transport play major roles in several neurodegenerative diseases including Huntington’s disease, ALS and AD. We continue our research on the mechanisms of axonal transport failure. We have characterized the role of transport deficits in the development of AD pathology using the triple transgenic model (3XTg-AD). The results show a significant impairment in the trafficking of mitochondria and synaptic vesicles in 3x-TgAD neurons, leading to reduced synaptic density and peripheral energy deficits. In addition, we finalized a detailed analysis of tau isoform expression and localization in human cortical neurons (HCN) developed in culture. We found in HCN a similar profile of tau isoforms as in the adult human brain. Interestingly, there was a significant difference in the intracellular distribution of 3R and 4R tau isoforms, suggesting specific functional roles 3R and 4R tau. Different toxic stimuli resulted in dramatic changes in tau phosphorylation and aggregation state, indicating that HCN represent an excellent model to study the development of tau pathology and transport deficits associated with tauopathies.
We also analyzed the mechanisms of axonal transport inhibition by Aß oligomers. Real time analysis of membrane-bound organelle mobility in isolated extruded axoplasms perfused with Aß indicates that bidirectional axonal transport is inhibited through endogenous casein kinase 2 activation, suggesting that pharmacological regulation of CK2 activity represents a promising target for therapeutic intervention in AD.
Awards and Honors
1992 Member, Society for Neuroscience
1998 Member, American Society for Neurochemistry
2002 Member, Program Committee, 33rd Annual Meeting, American Society for Neurochemistry
2003 Member, Program Committee, 34th Annual Meeting, American Society for Neurochemistry
2005-08 Editorial Board Member, American Journal of Alzheimer’s Disease and Other Dementias
2005 Member, Scientific Committee. 1st Chilean Conference on Neurodegenerative Disease. Nov 19-22,
Universidad Catolica, Santiago, Chile
2009-15 Member, NIH, CSR, Clinical Neuroscience and Neurodegeneration (CNN) Study Section
2013 Co-organizer, Cognition in Down Syndrome Workshop, April 13-15, Washington DC.
2014 Founding Member, Trisomy 21 Research Society (T21RS)
2014-15 Chair, Program Committee, 1st Meeting of the T21RS, Paris, June 2015.
2015- Member, Executive Committee, Scientific Advisory Board, T21RS
2021- Chair, Organizing Committee, 1st Virtual Conference of the T21RS
2021-2022 Chair, Organizing Committee, 4th International Conference, T21RS
1. Ferreira A, Busciglio J and Caceres A. An immunocytochemical analysis of the ontogeny of the microtubule-associated proteins MAP2 and tau in the nervous system of the rat. Dev Brain Res, 1987;34:9-31.
2. Busciglio J, Ferreira A, Steward O and Caceres A. An immunocytochemical and biochemical study of the microtubule- associated protein tau during post lesion afferent reorganization in the hippocampus of adult rats. Brain Res, 1987;419:244-252.
3. Caceres A, Busciglio J, Ferreira A and Steward O. An immunocytochemical and biochemical study of the microtubule- associated protein MAP2 during post lesion dendritic remodeling in the central nervous system of adult rats. Mol Brain Res, 1988;3:233-246.
4. Ferreira A, Busciglio J and Caceres A. Microtubule formation and neurite growth in cerebellar macroneurons which develop in vitro: evidence for the involvement of the microtubule-associated proteins MAP1a, HMW-MAP2 and tau. Dev Brain Res, 1989;59:215-228.
5. Ferreira A, Busciglio J, Landa C and Caceres A. Ganglioside enhanced neurite growth: evidence for a selective induction of high molecular weight MAP-2. J Neurosci, 1990;10(1):293-302.
6. Gravotta D, Ferreira A, Busciglio J, Caceres A, Landa C and Maccioni H. Co-expression of lactosil and gangliotetraosil gangliosides in rat cerebellar radial glial cells in culture. J Neurosci Res, 1990;25:214-222.
7. Arregui C, Busciglio J, Caceres A and Barra HS. Tyrosinated and detyrosinated microtubules in axonal processes of cerebellar macroneurons grown in culture. J Neurosci Res, 1991;28:171-181.
8. Kowall NW, Beal MF, Busciglio J, Duffy LK and Yankner BA. An in vivo model for the neurodegenerative effects of ß amyloid and protection by substance P. Proc Natl Acad Sci, USA, 1991;88:7247-7251.
9. Busciglio J, Lorenzo A and Yankner BA. Methodological variables in the assessment of ß amyloid neurotoxicity. Neurobiol Aging, 1992;13:609-612.
10. Busciglio J, Gabuzda D, Matsudaira P and Yankner BA. Generation of ß amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci, USA, 1993;90:2092-2096.
11. Busciglio J, Yeh J and Yankner BA. Beta amyloid neurotoxicity in human cortical culture is not mediated by excitotoxins. J Neurochem, 1993;61:1565-1568.
12. Gabuzda# D, Busciglio# J and Yankner BA. Inhibition of ß amyloid production by activation of protein kinase C. J Neurochem, 1993;61:2326-2329. #First co-authors.
13. Gabuzda D, Busciglio J, Chen LB and Yankner BA. Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem, 1994;269:13623-13628.
14. Busciglio J, Lorenzo A, Yeh J and Yankner BA. ß-Amyloid induces tau phosphorylation and loss of microtubule binding. Neuron, 1995;14:879-888.
15. Martin B, Schrader-Fischer G, Busciglio J, Duke M, Paganetti P and Yankner BA. Intracellular accumulation of ß amyloid in cells expressing the Swedish mutant amyloid precursor protein. J Biol Chem, 1995, 270:26727-26730.
16. Busciglio J and Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro. Nature 1995, 378:776-779.
17. Bin S, De Girolami U, He J, Shu W, Lorenzo A, Busciglio J and Gabuzda D. Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest, 1996, 98:1979-1990.
18. He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio J, Yang X, Hofmann W, Newman W, Mackay Ch, Sodroski J and Gabuzda D. CCR3 is a co-receptor for HIV-1 infection of microglia. Nature 1997, 385:645-649.
19. He J, DeCastro C, Vandenbark G, Busciglio J and Gabuzda D. Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene. Proc Natl Acad Sci, USA, 1997, 94:3954-3959.
20. Hartmann H, Busciglio J, Baumann K, Staufenbiel M and Yankner BA. Developmental regulation of presenilin-1 processing in the brain suggests a role in neuronal differentiation. J Biol Chem, 1997, 272:14505-14507.
21. Busciglio J, Hartmann H, Lorenzo A, Wong C, Baumann K, Staufenbiel M and Yankner BA. Neuronal localization of presenilin-1 and association with amyloid plaques and neurofibrillary tangles in Alzheimer's disease. J Neurosci, 1997, 17:5101-5107.
22. Bin S, Raina J, Lorenzo A, Busciglio J and Gabuzda D. Neuronal apoptosis induced by HIV-1 Tat protein and TNF-?: potentiation of neurotoxicity mediated by oxidative stress and implications for HIV-1 dementia. J Neurovirol, 1998, 4:281-290.
23. *Busciglio J, Andersen J, Schipper H, Gilad G, McCarty R, Marzatico F and Toussaint O. Stress, aging and neurodegenerative disorders: molecular mechanisms. Ann New York Acad Sci, 1998, 851: 429-444.
24. Kerkovich D, Sapp D, Weidenheim K, Brosnan C, Pfeiffer SE, Yeh HH and *Busciglio J. Fetal human cortical neurons grown in culture: morphological differentiation, biochemical correlates and development of electrical activity. Int J Dev Neurosci, 1999, 17:347-356.
25. Pigino G, Pelsman A, Mori H and *Busciglio J. Presenilin 1 mutations reduce cytoskeletal association, deregulate neurite growth and potentiate neuronal dystrophy and tau phosphorylation. J Neurosci, 2001, 21: 834-842.
26. *Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H and Yankner.BA. Altered metabolism of the amyloid ß precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron, 2002, 33:677-688.
27. Grace E, Rabiner C A, and *Busciglio J. Characterization of neuronal dystrophy and synaptic loss induced by fibrillar amyloid ß: Implications for Alzheimer's disease. Neuroscience, 2002, 11:265-273.
28. Morfini G, Pigino, G, Beffert U, Busciglio J and Brady ST. Fast axonal transport misregulation and Alzheimer’s disease. NeuroMol Med, 2002, 2:89-100.
29. Grace E and *Busciglio J. Aberrant activation of focal adhesion proteins mediates fibrillar Aß-induced neuronal dystrophy. J Neurosci, 2003, 23:493-502.
30. Wolvetang E, Wilson J, Sanij E, Busciglio J, Hatzistavrou T, Seth A, Hertzog P and Kola I. Ets2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Human Mol Genet, 2003, 12:247-255.
31. Pelsman A, Hoyo-Vadillo C, Gudasheva T, Seredenin S, Ostrovskaya R and *Busciglio J. GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons. Int J Dev Neurosci, 2003, 21:117-124.
32. Pigino G, Morfini G, Pelsman A, Mattson, MM, Brady ST and *Busciglio J. Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci, 2003, 23:4499-4508.
33. Wolvetang E , Bradfield O, Hatzistavrou T, Crack P, Busciglio J, Kola I, and Hertzog P. Overexpression of the chromosome 21 transcription factor Ets2 induces neuronal apoptosis. Neurobiol Dis, 2003, 14:349-356.
34. Heredia L, Lin R, Vigo F, Kedikian G, Busciglio J and Lorenzo A. Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid beta precursor protein. Neurobiol Dis, 2004, 16:617-629.
35. Helguera P, Pelsman A, Pigino G, Wolvetang E, Head E and *Busciglio J. Ets-2 promotes the activation of a mitochondrial death pathway in Down’s syndrome neurons, J Neurosci, 2005, 25:2295-2303.
36. Deshpande A, Mena E, Glabe CH and *Busciglio J. Divergent cytotoxic mechanisms induced by fibrillar and oligomeric amyloid ß in human cortical neurons. J Neurosci, 2006, 26:6011-6018.
37. Heredia, L, Helguera P, de Olmos S, Kedikian G, Sola Vigo F, de Olmos J, Busciglio J, Caceres A and Lorenzo A. Phosphorylation of ADF/Cofilin by LIM-kinase mediates Amyloid ß-induced degeneration: A potential mechanism of neuronal dystrophy in Alzheimer’s disease. J Neurosci, 2006, 26:6533-6542.
38. Lott IT, Head E and Busciglio J. Beta-amyloid, oxidative stress and Down syndrome. Current Alzheimer Research, Curr Alzheimer Res, 2006, 3:521-528.
39. *Busciglio J, Pelsman A, Helguera P, Ashur-Fabian O, Pinhasov A, Brenneman DE and Gozes I. NAP and ADNF-9 protect normal and Down's syndrome cortical neurons from oxidative damage and apoptosis. Curr Pharm Des, 2007, 13:1091-1098.
40. Deshpande A, Win K and *Busciglio J. Tau isoform expression and regulation in human cortical neurons. FASEB Journal, 2008, 22:2357-2367.
41. Resende R, Moreira P, Proença T, Deshpande A, Busciglio J, Pereira C and Oliveira C. Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Rad Biol & Med, 2008, 44:2051-2057.
42. Deshpande A, Kawai H, Metherate R, Glabe Ch G, and *Busciglio J. A Role for Synaptic Zinc in Activity-Dependent Aß Oligomer Formation and Accumulation at Excitatory Synapses. J Neurosci, 2009, 29:4004-4015.
43. Pigino G, Atagi Y, LaDu M, Deshpande A, Busciglio J, Morfini G and Brady S. Novel pathogenic mechanism for intraneuronal amyloid beta: disruption of fast axonal transport. Proc Natl Acad Sci, USA, 2009, 106:5907-5912.
44. Rahman AS, Parvinjah S, Hanna MA, Helguera PR, *Busciglio J. Cryopreservation of cortical tissue blocks for the generation of highly enriched neuronal cultures. JoVE, 2010, 45,, doi: 10.3791/2384.
45. Garcia O, Torres M, Helguera P, Coskun P and *Busciglio J. A role for thrombospondin-1 deficits in astrocyte-mediated spine and synaptic pathology in Down’s syndrome. PLoS ONE, 2010, 5(12): e14200. doi:10.1371/journal.pone.0014200.
46. Tiano, L, and *Busciglio J. Mitochondrial dysfunction and Down’s syndrome: Is there a role for CoQ10? BioFactors, 2011, 37:386–392.
47. Coskun P, and *Busciglio J. Oxidative stress and mitochondrial dysfunction in Down’s syndrome: Relevance to aging and dementia. Current Gerontology and Geriatrics Research, 2012, doi:10.1155/2012/383170 – PMC3350950
48. Yeo M, Berglund K, Hanna M, Guo J, Kittur J, Torres M, Abramowitz J, Busciglio J, Gao Y, Birnbaumer L and Liedtke W. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2/Slc12a5 promoter. PNAS, USA, 2013, 110:4315-4320.
49. Helguera P, Seiglie J, Rodriguez J, Hanna M, Helguera G and *Busciglio J. Adaptive downregulation of mitochondrial function in Down syndrome. Cell Metabolism, 2013, 17, 132-140.
50. Vogler E, and *Busciglio J. Disruption of zinc neuromodulation by Aß oligomers: Therapeutic implications. Curr Pharm Des, 2013, DOI: 10.2174/13816128113199990510
51. Busciglio J, Capone G, O’Bryan J, and Gardiner K. Down Syndrome: Genes, Model Systems, and Progress towards Pharmacotherapies and Clinical Trials for Cognitive Deficits. Cytogenet Genome Res, 2013, 141:260–271.
52. Sosa LJ, Guo R, Postma NL, Estrada-Bernal A, Hanna M, Busciglio J and Pfenninger KH. Dosage of Amyloid Precursor Protein Affects Axonal Contact Guidance in Down Syndrome. FASEB J, 2014, 28:195-205
53. Iulita M, Do Carmo S, Ower A, Fortress A, Flores Aguilar L, Hanna M, Wisniewski T, Granholm AC, Buhusi M, Busciglio J and Cuello AC. Nerve Growth Factor Metabolic Dysfunction in Down’s Syndrome Brains. BRAIN, 2014, 137:860-872.
54. Peiris H, Duffield M, Fadista J, Jessup C, Kashmir V, Genders A, McGee S, Martin A, Saiedi M, Morton N, Carter R, Cousin M, Kokotos A, Oskolkov N, Volkov P, Hough T, Fisher E, Tybulewicz V, Busciglio J, Coskun P, Becker A, Belichenko P, Mobley W, Ryan T, Chan J, Laybutt DR, Coates P, Yang S, Ling Ch, Groop L, Pritchard M, and Keating D. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to ß-Cell Mitochondrial Dysfunction in Type 2 Diabetes. PLoS Genetics, 2016,
55. Delabar J, Allinquant B, Bianchi D, Blumenthal T, Dekker A, Edgin J, O’Bryan J, Dierssen M, Potier M-C, Wiseman F, Guedj F, Créau N, Reeves R , Gardiner K, and Busciglio J. Changing paradigms in Down syndrome. Mol Syndromol, 2016,
56. Coskun PE, Nemati Z, Thomas J, Bohannan RC, Schriner SE, Argueta J, Doran E, Wallace DC, Lott IT and Busciglio J. Journal of Alzheimer’s Disease 2016. Differential growth characteristics in lymphoblastoid cell lines from adult individuals with Down syndrome and Alzheimer Disease. J Alzheimers Dis. 2017;55(2):737-748.
57. Torres MD, Garcia O, Tang C and Busciglio J. Dendritic spine pathology and thrombospondin 1 deficits in Down syndrome. Free Radic Biol Med. 2018 Jan;114:10-14.
58. Vogler E, Flynn D, Busciglio F, Bohannan R, Tran A, Mahavongtrakul M, Busciglio J. Electroencephalogram electrode implantation in mice. Front. Neurosci., 2017, |
59. Reeves RH, Delabar J, Potier M-C, Bhattacharyya A, Head E, Lemere C, Dekker AD, De Deyn P, Caviedes P, Dierssen M, Busciglio J. Paving the Way for Therapy in Down Syndrome. Mol Syndromol, 2018,
60. Zamponi E, Zamponi N, Coskun P, Quassollo G, Lorenzo A, Cannas S, Pigino G, Chialvo D, Gardiner K, Busciglio J*, Helguera P*. Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells. Aging Cell, 2018,
61. Hwang S, Williams JF, Kneissig M, Lioudyno M, Rivera I, Helguera P, Busciglio J, Storchova S, King MC and Torres E. Suppressing aneuploidy-associated phenotypes improves the fitness of trisomy 21 cells. Cell Reports, 2019,
62. Evolution of neuroinflammation across the lifespan of individuals with Down syndrome. Flores-Aguilar, L, Iulita F, Kovecses O, Torres M, Levi S, Zhang Y, Askenazi M, Wisniewski T, Busciglio J and Cuello C. BRAIN, Volume 143, Issue 12, December 2020, Pages 3653–3671,
63. Dierssen M, Herault Y, Helguera P, Martínez de Lagran M, Vazquez A, Christian B, Carmona-Iragui M, Wiseman F, Mobley W, Fisher EMC, Brault V, Esbensen A, Jacola LM, Potier MC, Hamlett E.D, Abbeduto
L, del Hoyo Soriano L, Busciglio J, et al. Building the Future Therapies for Down Syndrome. Mol Syndromol, 2021. doi: 10.1159/000514437.
64. •Yeo M, Chen Y, Jiang Ch, Chen G, Wang K, Chandra Sh, Bortsov A, Lioudyno M, Zeng Q, Wang P, Wang Z, Busciglio J, Ji R, Liedtke W. Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission. Nat Comm 2021. 12(1):6208. doi: 10.1038/s41467-021-26270-3
NIH, California Department of Health, LL Hillblom Foundation, Alzheimer's Association
Professional Societies
Society for Neuroscience
Society for Neurochemistry
Other Experience
Graduate Programs
Interdepartmental Neuroscience Program
Neurobiology and Behavior
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