This continuation begins with three key observations: a) Although limited glia-associated Abeta remains for more than a year, most of the injected or infused beta-peptide (Abeta) is rapidly scavenged by microglia/macrophages, a process key for Abeta removal. Abeta deposits are not stable and may be degraded or contribute to soluble Abeta aggregates that are potentially neurotoxic. b) Persistent plaque-like deposits in rats chronically infused with Abeta can be induced by an initial co- injection (i.e. transient presentation) of the potent anti- inflammatory cytokine, TGFbeta1. c) Abeta deposition by itself may not be sufficient to induce the major neurodegeneration found in AD because human and animal models can have large amyloid burdens with no dementia and limited synapse or neuron loss. We hypothesized that inflammatory factors regulate deposition and neurodegeneration and that TGFbeta1's antiinflammatory effect leads to deactivation of microglial phagocytosis of Abeta. We have now shown that TGFbetas1 and 3 also increase microglial associated Abeta (chemotaxis) and extracellular deposits in vivo as well as in an organotypic hippocampal slice culture (OHSC), a useful system for investigating the impact of cytokines on Abeta trafficking, deposition or degradation. We present new data supporting the hypothesis that TGFbetas and other microglial activation immunomodulators regulate Abeta deposition/degradation in vivo using our infusion paradigm. TGFbeta1 and very different antiinflammatory agents including steroids, curcumin and NS-398 (a specific COX II inhibitor) all increased Abeta deposition, but reduced neurotoxicity. In fact, in our Abeta infusion paradigm, increasing Abeta deposition is negatively correlated with Abeta toxicity across a number of very different manipulations consistent with the hypothesis that soluble Abeta or small aggregates available to neurons are more neurotoxic than massed aggregates walled off by glial scar formation. In contrast to TGFbetas1 and 3 brief exposure to TGFbeta2 causes increased region-specific neuronal Abeta immunoreactivity including in the CA1 and entorhinal cortex. Because TGFbeta2 is elevated in AD brains, this observation raises the hypothesis that TGFbeta2 increases trafficking of Abeta to neurons and results in neurotoxicity (Aim 1) and compromised neuronal function with reduced hippocampal LTP and spatial memory (Aim 2). The hypothesis that elevated TGFbeta2 expression is a correlate of neurotoxicity is also tested in Aim 3 which characterizes overall cytokine profiles in humans and animal models with and without major Abeta accumulation and neurotoxicity.
In Aim 4 we test the hypothesis that acute TGFbeta2 induces persistent antiinflammatory cytokine profiles and characterize the impact of chronically elevated antiinflammatory cytokines on Abeta deposit degradation and neurotoxicity in vitro.
Aim 5 pursues these goals in vivo. This project is designed to better understand the role of NSAIDs and antiinflammatory cytokines, especially TGFbeta2 in regulating Abeta deposition, trafficking, degradation and neurotoxicity. It should be of direct relevance to the prevention and treatment of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Snyder, D Stephen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Attar, Aida; Ripoli, Cristian; Riccardi, Elisa et al. (2012) Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers. Brain 135:3735-48
Frautschy, Sally A; Cole, Greg M (2011) What was lost in translation in the DHA trial is whom you should intend to treat. Alzheimers Res Ther 3:2
Frautschy, Sally A (2010) Thinking outside the box about COX-1 in Alzheimer's disease. Neurobiol Dis 38:492-4
Cole, Greg M; Frautschy, Sally A (2010) Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. CNS Neurol Disord Drug Targets 9:140-8
Frautschy, Sally A; Cole, Greg M (2010) Why pleiotropic interventions are needed for Alzheimer's disease. Mol Neurobiol 41:392-409
Ma, Qiu-Lan; Galasko, Douglas R; Ringman, John M et al. (2009) Reduction of SorLA/LR11, a sorting protein limiting beta-amyloid production, in Alzheimer disease cerebrospinal fluid. Arch Neurol 66:448-57
Hu, Shuxin; Begum, Aynun N; Jones, Mychica R et al. (2009) GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals. Neurobiol Dis 33:193-206
Hu, Shuxin; Ying, Zhe; Gomez-Pinilla, Fernando et al. (2009) Exercise can increase small heat shock proteins (sHSP) and pre- and post-synaptic proteins in the hippocampus. Brain Res 1249:191-201
Cole, Greg M; Teter, Bruce; Frautschy, Sally A (2007) Neuroprotective effects of curcumin. Adv Exp Med Biol 595:197-212
Ma, Qiu-Lan; Harris-White, Marni E; Ubeda, Oliver J et al. (2007) Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models. J Neurochem 103:1594-607

Showing the most recent 10 out of 33 publications