My lab utilized a novel strategy to produce a triple transgenic model of Alzheimer's disease (AD). Rather than using a crossbreeding approach, we directly inserted two transgenes (human -beta APP/Swe and -tau P301L) into the genome of homozygous PS1M146V knocking mice. This novel strategy produces several unique and significant advantages compared to other approaches: (i) Because the tau P301L and beta APPSwe transgenes were microinjected into embryos from PS1M146V mice, the triple transgenic are on the same genetic background, thereby eliminating genetic heterogeneity. (ii) Both transgenes integrated at the same genetic locus and, therefore, will not independently assort in subsequent generations; likewise the M146V mutation is knocked-in to the PS1 gene, and this allele will also not assort in future generations. Consequently, our triple transgenic mice breed as easily as """"""""single"""""""" transgenic mice, a significant advantage for colony management and for introducing additional transgenes into this line. (iii) A large colony of triple transgenic mice can be easily and efficiently generated. In contrast, crossbreeding strategies for generating multi-transgenic genotypes are labor intensive, require extensive genotyping, and result in a low proportion of mice with the desired genotype. (iv) The triple transgenic mice have been bred to homozygosity, which doubles the expression levels, and also further facilitates colony management and breeding. Our triple transgenic mice develop a progressive, age-related AD-like phenotype that includes both both Abeta and tau pathology, synaptic dysfunction, deficits in long term potentiation, and impaired memory-related performance in the Morris water maze, a hippocampal-dependent task of spatial memory. The broad goal of this proposal is to identify and correlate genetic interactions that underlie neuronal and synaptic dysfunction in our triple transgenic mice.
In aim 1, we will perform a detailed molecular and neuropathological characterization of the triple transgenic mice and determine how various gene interactions (e.g., tau alone, tau + APP, etc.) influence the development of AD neuropathology.
In aim 2, we will determine if the synaptic dysfunction is age-related, identify molecular determinants (e.g., soluble vs. insoluble Abeta, tau hyperphosphorylation) and gene interactions (tau, PS1, or APP) that underlie the synaptic dysfunction.
In aim 3, we will determine if calcium dyshomeostasis underlies the synaptic dysfunction and propose to develop a novel transgenic mouse the expresses a calcium indicator protein (inverse pericam) in neurons.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
Zip Code
Lin, Alexander J; Ponticorvo, Adrien; Durkin, Anthony J et al. (2015) Differential pathlength factor informs evoked stimulus response in a mouse model of Alzheimer's disease. Neurophotonics 2:045001
Abbondante, Serena; Baglietto-Vargas, David; Rodriguez-Ortiz, Carlos J et al. (2014) Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol 184:819-26
Baglietto-Vargas, David; Kitazawa, Masashi; Le, Elaine J et al. (2014) Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition. Neurobiol Dis 62:407-15
Baglietto-Vargas, David; Medeiros, Rodrigo; Martinez-Coria, Hilda et al. (2013) Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and also reduces tau pathology. Biol Psychiatry 74:357-66
Walker, Michael P; LaFerla, Frank M; Oddo, Salvador S et al. (2013) Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer's disease. Age (Dordr) 35:519-31
Kitazawa, Masashi; Medeiros, Rodrigo; Laferla, Frank M (2012) Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des 18:1131-47
Neely Kayala, Kara M; Dickinson, George D; Minassian, Anet et al. (2012) Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: implications for lysosomal function. Brain Res 1489:8-16
Koike, Maya A; Lin, Alexander J; Pham, Jonathan et al. (2012) APP knockout mice experience acute mortality as the result of ischemia. PLoS One 7:e42665
Cassano, Tommaso; Serviddio, Gaetano; Gaetani, Silvana et al. (2012) Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease. Neurobiol Aging 33:1121.e1-12
Alonso, Eva; Fuwa, Haruhiko; Vale, Carmen et al. (2012) Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-ýý and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications. J Am Chem Soc 134:7467-79

Showing the most recent 10 out of 36 publications