Jorge a Busciglio
Associate Professor, Neurobiology and Behavior
Fellow, Center for the Neurobiology of Learning and Memory
Member, Institute for Memory Impairments and Neurological Disorders (UCI MIND)
|Alzheimer's disease, Down's syndrome, neurodegeneration, axonal transport, oxidative stress, mitochondrial dysfunction,|
• Named 2004-2005 National Academies Education Fellow in the Life Sciences.
• Fellow, National Academies Summer Institute on Undergraduate Education in Biology. 2004. Sponsored by HHMI and The National Academy of Sciences.
• Teaching Excellence Award, Celebration of Teaching, School of Biological Sciences. 2005. Sponsored by the Division of Undergraduate Education and the Instructional Resources Center, UCI.
• Golden Apple Teaching Award. 2005. School of Biological Sciences, UCI.
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.
1. Busciglio J, Lorenzo A and Yankner BA. Methodological variables in the assessment of ß amyloid neurotoxicity. Neurobiol Aging, 1992;13:609-612.
2. 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.
3. 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.
4. Busciglio J, Lorenzo A, Yeh J and Yankner BA. ß-Amyloid induces tau phosphorylation and loss of microtubule binding. Neuron, 1995;14:879-888.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Grace E and Busciglio J. Aberrant activation of focal adhesion proteins mediates fibrillar Aß-induced neuronal dystrophy. J Neurosci, 2003, 23:493-502.
14. 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.
15. 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.
16. 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.
17. Lott IT, Head E and Busciglio J. Beta-amyloid, oxidative stress and Down syndrome. Current Alzheimer Research, Curr Alzheimer Res, 2006, 3:521-528.
18. Cotman CW and Busciglio J. Signaling mechanisms that mediate Aß-induced neuronal dysfunction. Editors: Sisodia S and Tanzi R, “Alzheimer’s disease: Advances in genetics, molecular and cell biology”. Springer, 2006, 133-150.
19. 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.
20. Deshpande A, Win K and Busciglio J. Tau isoform expression and regulation in human cortical neurons. FASEB Journal, 2008, 22:2357-2367. PMID: 18263702.
21. 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.
22. Busciglio J and Deshpande A. Alzheimer’s disease-related mechanisms of neuronal dysfunction and degeneration: Studies in human cortical neurons. Editor: Ribak C, “From Development to Degeneration to Regeneration of the Nervous System”. Oxford University Press, 2008, 10:183-201.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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, http://www.jove.com/index/Details.stp?ID=2384, doi: 10.3791/2384.
28. Garcia O, Torres M, Helguera 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.
29. 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, in press.
30. Tiano, L, and *Busciglio J. Mitochondrial dysfunction and Down’s syndrome: Is there a role for CoQ10? BioFactors, 2011, 37:386-392
31. Helguera P, Seiglie J, Rodriguez J, Hanna M, and *Busciglio J. Adaptive downregulation of mitochondrial function in Down’s syndrome. Submitted
|Grant||NIH, California Department of Health, LL Hillblom Foundation, Alzheimer's Association|
Society for Neuroscience
Society for Neurochemistry
Neurobiology and Behavior
Interdepartmental Neuroscience Program
|Link to this profile||http://www.faculty.uci.edu/profile.cfm?faculty_id=4959|