Besides age, many other factors are thought to influence the onset and progression of Alzheimer's disease (AD), including genetics, diet, stress, education level, physical activity, and other neurological disease. Here we seek to evaluate the effects of such co-morbidities on AD. This application proposes to utilize a systematic approach toward elucidating the effects of co-morbid conditions on AD neuropathology and cognitive phenotype in the 3xTg-AD mouse model. We propose to study three common co-morbid conditions that are clinically relevant, amenable to study in a lab setting, and for which we already have substantial preliminary data.
AIM 1. Stress as a co-morbidity that influences AD pathology. Stress is a risk factor for AD We recently reported that stress-level glucocorticoids increase APP, BACE, and A? levels as well as augmenting tau. Here we propose to evaluate the effects of physiologically-relevant stress paradigms on AD pathology and cognition in 3xTg-AD mice.
AIM 2. Determine the impact of global ischemic stress on A? and tau pathology. Here we will investigate the link between ischemic stress and the development of AD pathologies. Our preliminary data show that global ischemic insults have diverse temporal effects on both A? and tau pathology. We propose to fully elucidate these effects and explore the underlying molecular mechanisms that occur during and after ischemia which impact pathology. We seek to identify novel therapeutic targets, as we have found that ischemia leads to the rapid clearance of somatodendritic tau via lysosomal degradation. By exploring the triggers and taubinding partners involved, we can uncover signaling pathways that lead to the clearance of somatodendritic tau. Ultimately, our preliminary data show, in agreement with clinical data and other studies, that ischemia leads to an increase in AD related pathologies. The implications of this study are significant as ischemia is a prevalent feature among the elderly population and it is critical to determine its effects on the AD phenotype.
Aim 3 : Synergistic interactions among A?, tau and a-synuclein. Up to 50% of AD cases exhibit a- synuclein immunoreactive Lewy Bodies in addition to plaques and tangles (Raghavan et al., 1993;Hamilton, 2000). This common co-morbidity promotes an aggressive disease course and accelerates cognitive decline (Hansen et al., 1990;Langlais et al., 1993). Our preliminary data indicate that introducing a mutant a- synuclein transgene, as a way to induce LB formation in the brains of an AD mouse model, exacerbates the neuropathological and cognitive phenotype. We are now poised to determine whether A?-directed therapies, such as A? immunotherapy, will be effective in rescuing the cognitive decline in mice that also harbor Lewy body pathology.
This aim i s significant as it represents one of the first attempts to determine if currently pursued strategies against AD will be effective in patients with other forms of A? dementia (i.e., Lewy body variant).PUBLIC HELATH

Public Health Relevance

Alzheimer's disease (AD) is the common age-related neurodegenerative disorder, and at present there is no cure. Unfortunately, the aged population is not only susceptible to AD but they also frequently succumb to other ailments that can influence its progression and severity. These other disorders can be considered co-morbidities, and surprisingly, there has not been a systematic investigation into the effects of co-morbidities on the progression of AD in animal models. This proposal seeks to determine the impact that co-morbidities such as ischemia and stress play on the development of AD in the 3xTg-AD mouse model.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Refolo, Lorenzo
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
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
Coskun, Pinar; Wyrembak, Joanne; Schriner, Samual E et al. (2012) A mitochondrial etiology of Alzheimer and Parkinson disease. Biochim Biophys Acta 1820:553-64
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

Showing the most recent 10 out of 36 publications