Alzheimer disease (AD) impairs memory and causes cognitive and psychiatric deficits. Over 35 million people throughout the world are afflicted, including 5.4 million in the USA. All AD cases are marked by the accumulation of two lesions in the brain called plaques (consisting of a protein called A?) and tangles (consisting of a protein called tau that becomes hyperphosphorylated. One of the most fundamental and unresolved questions in the field centers around elucidating the relationship between A? and tau and their role in cognitive decline. It is critical to determine if A? triggers pathology in human wild-type au, rather than the mutant used in previous models. Moreover, this proposal seeks to identify the interactions between these two critical proteins at the synapse using synaptoneurosomes, thereby enabling us to quantify A? and tau levels in the synapse and other key markers of synaptic function. Lastly, the broad goal of this application is to understand how these synaptic changes lead to cognitive deficits, and whether therapies that remove either A? or tau alone are sufficient to improve behavior. It is important to point out that research in the AD field can only progress if the tools evolve, hence there is an urgent need to develop and characterize new animal models until an effective treatment is discovered. Because the 3xTg-AD mice harbor mutant tau, addressing these issues necessitated the generation of innovative new transgenic models and viral vectors to manipulate gene expression in vivo. The first novel model we developed is a floxed human APP transgenic mouse that permits ablation of APP expression using Cre recombinase. We also created a novel human wild-type tau transgenic model that develops phosphotau pathology. After crossing these two lines, we can discover the impact A? has on the development of tau pathology during various stages (i.e., before, during, and after tau pathology is established). Results from this study will reveal the conditions under which A? induces wild-type tau pathology. Additionally, we will be uniquely positioned to determine if tau pathology continues to cause synaptic deficits even if A? is suppressed using Cre. Using viral gene delivery to the CNS, we will determine whether intracellular and extracellular A? plays a greater role in modulating tau pathology and cognitive decline. The development of the floxed human APP transgenic mice represents a significant advance for the field, as it enables abrogation of human APP gene expression using viral delivery of Cre recombinase during temporally-specified timepoints. Utilizing these novel models and innovative genetic approaches that add significantly to the research tool armatorium, we will unravel the distinctions between the cognitive loss due to A?-dependent and -independent mechanisms, the pathological time point of A?-induced tau dysfunction, and whether the presence of A? intracellularly or extracellularly facilitates tau pathology and cognitive decline. Because a better understanding of these pathways is critical not only for academic reasons but also for helping to identify novel drug targets, the translational impact of this work is substantial and significant.

Public Health Relevance

Alzheimer's disease leads to severe memory loss and problems with activities of daily living, and will continue to be a significant public health problem that extolls a heavy burden on our society, particularly as the baby- boomers advance in age. The work proposed in this application utilizes newly developed animal models (floxed APP and wildtype human tau transgenic mice) to unravel the molecular connection between two hallmark Alzheimer's disease proteins and elucidate their relationship to cognitive decline. The translational impact of the proposed work is high and not only of major significance for academic reasons but because a better understanding of the relationship offers real and concrete opportunities to develop novel drug therapies for tackling the cognitive deficits associated with Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Petanceska, Suzana
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University of California Irvine
Internal Medicine/Medicine
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United States
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Sosna, Justyna; Philipp, Stephan; Albay 3rd, Ricardo et al. (2018) Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener 13:11
Baglietto-Vargas, David; Prieto, Gilberto Aleph; Limon, Agenor et al. (2018) Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease. Aging Cell :e12791
Martini, Alessandra C; Forner, Stefania; Trujillo-Estrada, Laura et al. (2018) Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease. J Alzheimers Dis 64:S365-S378
Baglietto-Vargas, David; Shi, Jessica; Yaeger, Devin M et al. (2016) Diabetes and Alzheimer's disease crosstalk. Neurosci Biobehav Rev 64:272-87
Fisher, Abraham; Bezprozvanny, Ilya; Wu, Lili et al. (2016) AF710B, a Novel M1/?1 Agonist with Therapeutic Efficacy in Animal Models of Alzheimer’s Disease. Neurodegener Dis 16:95-110
Martinez-Coria, Hilda; Yeung, Stephen T; Ager, Rahasson R et al. (2015) Repeated cognitive stimulation alleviates memory impairments in an Alzheimer's disease mouse model. Brain Res Bull 117:10-5
Baglietto-Vargas, David; Chen, Yuncai; Suh, Dongjin et al. (2015) Short-term modern life-like stress exacerbates A?-pathology and synapse loss in 3xTg-AD mice. J Neurochem 134:915-26
Prieto, G Aleph; Snigdha, Shikha; Baglietto-Vargas, David et al. (2015) Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1? in the aged hippocampus. Proc Natl Acad Sci U S A 112:E5078-87
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
Yeung, S T; Myczek, K; Kang, A P et al. (2014) Impact of hippocampal neuronal ablation on neurogenesis and cognition in the aged brain. Neuroscience 259:214-22

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