Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive functional decline, dementia and neuronal loss affecting approximately 40 percent of persons over the age of 85 years. The demographics make evident that as the median age of the world's population increases, the prevalence and socioeconomic burden of AD will increase substantially. Pathological hallmarks of the disease include amyloid beta (A3) plaques and neurofibrillary tangles, which play a key role in the pathogenic mechanism of Alzheimer's disease, evolving in a temporal and spatial manner. We are interested in understanding the early mechanisms that cause or perpetuate this temporal and spatial progression of AD pathogenesis. Inflammatory processes have been proposed as being integral for initiating and/or propagating AD-associated pathology within the brain, as the elaboration of inflammatory cytokine expression and other markers of inflammation is more pronounced in individuals with known AD pathology. Recently, a 3xTg-AD mouse model of AD that develops both amyloid and tau pathology has been created, which to date is the most disease-relevant model system depicting what occurs in human Alzheimer's disease. We have observed significant up-regulation of the pro-inflammatory cytokine TNF-a in this model prior to the onset of overt amyloid pathology. As TNF-a has been shown to be enhanced in persons with mild cognitive impairment and Alzheimer's disease, the 3xTg-AD mouse provides a novel paradigm in which to investigate the role of this cytokine during early disease stages. We hypothesize that TNF-a mediated inflammation perpetuates disease in an AD model where genetic predisposition to amyloid and tau pathologies exist and that dampening this inflammatory response will diminish the pathological amyloid and tau outcome. Additionally, we hypothesize that the focal induction of an inflammatory event prior to the onset of inflammation will exacerbate pathological outcomes in a regional and temporal manner. We will administer recombinant adeno-associated virus (rAAV) vectors expressing either TNF-a to create a sustained focal inflammatory response or a TNF receptor antagonist to inhibit the endogenous inflammatory response prior to existing pathology. This work will provide major insight into the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially elucidate new therapeutic targets.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
Schools of Dentistry
United States
Zip Code
Rappold, Phillip M; Cui, Mei; Grima, Jonathan C et al. (2014) Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun 5:5244
Montgomery, Sara L; Narrow, Wade C; Mastrangelo, Michael A et al. (2013) Chronic neuron- and age-selective down-regulation of TNF receptor expression in triple-transgenic Alzheimer disease mice leads to significant modulation of amyloid- and Tau-related pathologies. Am J Pathol 182:2285-97
Montgomery, Sara L; Bowers, William J (2012) Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 7:42-59
Montgomery, Sara L; Mastrangelo, Michael A; Habib, Diala et al. (2011) Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-? suppressive therapeutic strategies in the brain. Am J Pathol 179:2053-70
Desai, Maya K; Guercio, Brendan J; Narrow, Wade C et al. (2011) An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction. Glia 59:627-40
Hunter, Jesse M; Bowers, William J; Maarouf, Chera L et al. (2011) Biochemical and morphological characterization of the A?PP/PS/tau triple transgenic mouse model and its relevance to sporadic Alzheimer's disease. J Alzheimers Dis 27:361-76
Bowers, William J; Breakefield, Xandra O; Sena-Esteves, Miguel (2011) Genetic therapy for the nervous system. Hum Mol Genet 20:R28-41
Park, Keigan M; Yule, David I; Bowers, William J (2010) Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons. Cell Signal 22:519-26
Park, Keigan M; Bowers, William J (2010) Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 22:977-83
Ryan, Deborah A; Narrow, Wade C; Federoff, Howard J et al. (2010) An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studies. J Neurosci Methods 190:171-9

Showing the most recent 10 out of 18 publications