Frank M LaFerlaChancellor's Professor of Neurobiology and Behavior; Director Institute for Brain Aging and Dementia, Neurobiology and Behavior |
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Research Interests |
Molecular biology of Alzheimer's disease and neurodegenerative disorders; Transgenic and Genetically-modified Animal Models, Presenilins and calcium signaling; Learning and memory | |
| URL | neurobiology.bio.uci.edu/faculty/laferla/ | |
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Academic Distinctions | Chancellor's Professor (2008); Promising Work Award, MetLife Foundation Awards for Medical Research (2006); UCI Faculty Innovation Award (2005); Zenith Fellow Award, Alzheimer's Association (2005); Chancellor's Fellow (2005-2008); Distinguished Mid-career Faculty Award for Research (2005); Ruth Salta Junior Investigator Achievement Award in Alzheimer’s Disease from the American Health Assistance Foundation (2001); Intracellular Imaging Inc. Ratio Imaging Award (1999); Young Scientist Travel Grant --Calgary, Italy (1995); F. M. Firby/Cancer Research Institute Postdoctoral Fellow (1990-93). | |
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Research Abstract |
The neuropathological correlates of Alzheimer’s disease (AD) include amyloid-ß (Aβ) plaques and tau-laden neurofibrillary tangles. Although it has been possible to develop transgenic mice that develop one of these lesions, it has proven to be quite challenging to develop mice with both histopathological lesions in the same mouse, in AD-relevant brain regions such as the hippocampus and cortex. To better model AD neuropathology, my lab utilized a novel approach to create a triple transgenic model of AD (3xTg-AD). Rather than crossing independent lines, we microinjected two transgenes (ßAPP and tau) into single-cell embryos from homozygous PS1M146V knockin mice, generating mice with the same genetic background. Compared to crossbreeding, the approach we used offers several major advantages. The integration of the ßAPP and tau transgenes at the same genetic locus renders it unlikely that either transgene will independently assort in subsequent generations. Therefore, this tight linkage coupled to the ‘knockin’ of the PS1 mutation indicates that the 3xTg-AD mice breed as readily as any single transgenic line, particularly because these mice have also been bred to homozygosity. Thus, deriving a large colony is straightforward, cost-effective, and does not require extensive genotyping of the progeny. Moreover, the easy propagation of this transgenic line facilitates their crossing to other transgenic or gene-targeted mice to assess the impact of other genotypes on the neuropathological or physiological phenotype. Lastly, another advantage to this approach is that multiple transgenes are introduced into an animal without altering or mixing the background genetic constitution. Thus, an important confounding variable is avoided, which may be a crucial parameter for behavioral, electrophysiological, and vaccine-based experiments The 3xTg-AD mice develop both plaque and tangle pathology in AD-relevant brain regions. The 3xTg-AD mice develop extracellular Aß deposits prior to tangle formation, consistent with the amyloid cascade hypothesis. Despite equivalent overexpression of the human ßAPP and human tau transgenes, Aß deposition develops prior to the tangle pathology, consistent with the amyloid cascade hypothesis. In addition, these mice exhibit deficits in synaptic plasticity, including long-term potentiation (LTP) that occurs prior to extracellular Aß deposition and tau pathology, but is associated with intracellular Aß immunoreactivity. These studies support the view that synaptic dysfunction is a proximal defect in the pathobiology of AD, preceding extracellular plaque formation and neurofibrillary pathology. As these 3xTg-AD mice phenocopy critical aspects of AD neuropathology, this model will be useful in pre-clinical intervention trials, particularly because the efficacy of anti-AD compounds in mitigating the neurodegenerative effects mediated by both signature lesions can be evaluated. |
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| Publications | Billings, L. M. and Green, K. N., McGaugh, J. L., and LaFerla, F. M. (2007). Learning decreases Aß56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. Journal of Neuroscience 27, 751-761. | |
| Green, K. N., Demuro, A., Akbari, Y., Hitt, B. D., Smith, I. F., Parker, I., and LaFerla, F. M. (2008). SERCA pump activity is physiologically regulated by presenilin and regulates Aß production. Journal of Cell Biology 181, 1107-1116. | ||
| Green, K. N. and LaFerla, F. M. (2008). Linking calcium to Aß and Alzheimer’s disease. Neuron 59, 190-194. | ||
| Kitazawa, M., Trinh, D., and LaFerla, F. M. (2008). Inflammation induces tau hyperphosphorylation in a mouse model of inclusion body myositis via a mechanism involving glycogen synthase kinase-3ß. Annals of Neurology 64, 15-24. | ||
| LaFerla, F. M., Green, K. N., and Oddo, S. (2007). Intracellular amyloid-ß in Alzheimer’s disease. Nature Reviews Neuroscience 8, 499-509. | ||
| Oddo, S., Vasilevko, V., Caccamo, A., Kitazawa, M., Cribbs, D. H., and LaFerla, F. M. (2006). Reduction of soluble Aß and tau, but not soluble Aß alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. Journal of Biological Chemistry 281, 39413-23. | ||
| Green, K. N., Billings, L. M., Roozendaal, B., McGaugh, J. L., and LaFerla, F. M. (2006). Glucocorticoids increase amyloid-ß and tau pathology in a mouse model of Alzheimer’s disease. Journal of Neuroscience 26, 9047-9056. | ||
| Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., and LaFerla, F. M. (2006). M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671-682. | ||
| Billings, L., Oddo, S., Green, K. N., McGaugh, J. L., and LaFerla, F. M. (2005). Intraneuronal Aß causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45, 675-688. | ||
| Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., and LaFerla, F. M. (2004). Aß immunotherapy leads to clearance of early, but not late hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321-332. | ||
| Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T.E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., and LaFerla, F. M. (2003). Triple transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aß and synaptic dysfunction. Neuron 39, 409-421. | ||
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Sugarman, M. S., Yamasaki, T. R., Oddo, S., Echegoyen, J. C., Murphy, M. P., Leissring, M. A., & LaFerla, F. M. (2002). Inclusion body myositis-like phenotype induced by transgenic overexpression of beta-APP in skeletal muscle. Proc. Natl. Acad. Sci., U.S.A. 99, 6334-6339. |
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Professional Societies |
Society for Neuroscience
American Society for the Advancement of Science |
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| Graduate Programs |
Neurobiology and Behavior Interdepartmental Neuroscience Program |
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| Research Centers | Institute for Brain Aging and Dementia | |
| Center for the Neurobiology of Learning and Memory | ||
| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=3269 | |
| Last updated | 08/22/2008 | |