P240
Symposia: S4-02: Role of Immune Response/Microglia in Alzheimer’s Disease Risk
Background: Generation of neurotoxic amyloid-ß peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction actively contributes to disease progression and chronicity. Microglia is being activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors which elicit an innate immune response. The latter is characterized by the release of in €ıflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and enzyme systems. Exogenous as well as endogenous factors may promote and facilitate neuroinflammation in the AD brain. Thus, degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may drive inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. Methods: Analysis of neuroinflammatio and in particular of micro and astroglial cell function in vitro and in vivo. Determination of inflammatory markes from cell culture, murine mouse brain and brain tissue or cerebrospinal fluid of MCI and AD patients. Results: In inflammation may not just occur secondary to degeneration, but actively drive amyloid beta aggregation and APP processing. Inhibition of the microglia driven innate immune response at key signalling steps may provide protection. Conclusions: Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the pro- into an antiinflammatory phenotype will be reviewed and discussed. S4-02-02
HARNESSING INNATE IMMUNITY TO TREAT ALZHEIMER’S DISEASE
Terrence Town, David Gate, Kevin R. Doty, Marie-Victoire Guillot-Sestier, Tara M. Weitz, 1University of Southern California, Los Angeles, California, United States. Contact e-mail:
[email protected] Background: Alzheimer’s disease (AD) is defined at autopsy by histopathological presence of amyloid plaques, neurofibrillary tangles, and largescale loss of cortical and hippocampal neurons. While once thought to simply beepiphenomenon, the neuroinflammation hypothesis of AD is rapidly gaining wide acceptance. This hypothesis has been bolstered by recent genome-wide association studies that have uncovered microglial TREM2, CR1, and CD33 as key AD risk loci. However, broad-based inhibition of inflammation by non-steroidal anti-inflammatory drugs has not produced a positive signal for AD primary prevention. One possible explanation for this is that "re-balancing" neuroinflammation, rather than pan-inhibiting it, may ultimately prove to be the most beneficial strategy against AD. Methods: To test this concept, we have utilized genetic and pharmacologic approaches to block key anti-inflammatory molecules in the PSAPP transgenic mouse model of cerebral amyloidosis and in a next-generation TgF344-AD rat model of AD. Results: In the former approach, deletion of the cardinal anti-inflammatory interleukin-10 gene activates microglia to clear cerebral Ab/b-amyloid. Additionally, release of innate immune toll-like receptor (TLR) pathway suppression via deletion of the naturally-occurring TLR dominant-negative, interleukin-1 receptor-associated kinase-M (IRAK-M), produces a similar beneficial effect. As an example of the latter strategy, nanoparticle-based blockade of the key anti-inflammatory transforming growth factor-b-Smad 2/3 pathway on peripheral mononuclear phagocytes in TgF344-AD rats causes brain entry of these cells, where they home to b-amyloid plaques and clear them. Conclusions: Taken together, these convergent results have led to the conclusion that neuroinflammation need not necessarily be deleterious in the context of AD pathology. Furthermore, data from these pre-clinical rodent models provide a mechanistic framework for therapeutic strategies aimed at promoting "good" neuroinflammation to militate against AD. S4-02-03
COMPLEMENT IN ALZHEIMER’S DISEASE: LESSONS FROM C3-DEFICIENT MICE
Cynthia A. Lemere1, Qiaoqiao Shi2, Barbara Caldarone3, Saba Chowdhury4, Rong Ma4, Soyon Hong5, Beth Stevens5, 1Brigham and
Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States; 2Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States; 3Harvard NeuroDiscovery Center, Boston, Massachusetts, United States; 4Brigham and Women’s Hospital, Boston, Massachusetts, United States; 5Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States. Contact e-mail:
[email protected] Background: The complement system is an innate immune response to remove pathogens and cellular debris, and has also been reported recently to be involved in neurogenesis and microglia-mediated synaptic pruning during brain development. Complement C3, central to multiple complement pathways, is elevated in Alzheimer’s disease (AD) and appears to contribute to Abeta clearance by microglia. Recently, we demonstrated age-dependent synapse and neuron loss in CA3 of hippocampus in aged C56BL/6 WT mice but not in aged C3-deficient mice. C3 KO mice were less anxious and had better memory than their WT counterparts. Thus, we asked whether C3 plays a role in AD in APP/ PS1dE9 Tg mice. Methods: Male C3-deficient (C3KO), C57BL/6 WT, APP/PS1dE9 and APP/PS1;C3KO mice (w20/group) were aged to P30, 4 mo and 16 mo of age. Behavioral testing was performed just prior to sacrifice in the oldest mice. Pathological and biochemical analyses were performed on mouse brain tissues. Results: C3KO mice had similar locomotion as WT mice but showed enhanced cognition in several tests. APP/PS1 Tg mice demonstrated increased locomotor activity in the Open Field and deficits in the Water T Maze and Contextual Fear Conditioning (trend) compared to WT mice. C3-deficiency in APP/PS1 Tg mice normalized locomotor activity and spatial memory to that of WT mice. C3 KO and APP/PS1;C3KO mice showed an anxiolytic phenotype in the Elevated Plus Maze. Abeta burden was similar between APP/PS1 and APP/PS1;C3KO mice at 4 mo but elevated in the cortex and hippocampus of 16 mo-old APP/PS1;C3KO mice. No differences in neurons or glia were observed at P30 or 4 mo of age but there were more CA3 neurons in 16 mo-old APP/PS1;C3KO mice. C3-deficiency reduced microglial priming and astrocyte clustering at plaques in 16 mo-old APP/ PS1 mice without altering glial number. At 16 mo, mature BDNF and its receptor, TrkB, were elevated in C3KOs and reduced in APP/PS1 mice compared to WT mice, and normalized to WT levels in C3-deficient APP/PS1 mice. Conclusions: Lifelong C3-deficiency in mice protects against age-related cognitive decline, even in the context of enhanced Abeta plaque deposition, possibly by modulating microglial function and protecting synapses.
S4-02-04
MOLECULAR SIGNTAURES OF MICROGLIA IN AGING AND NEURODEGENERATION
Joseph El Khoury1, Suzanne Hickman2, 1Harvard Medical School, Boston, Massachusetts, United States; 2Massachusetts General Hospital, Charlestown, Massachusetts, United States. Contact e-mail: jelkhoury@ mgh.harvard.edu Background: Microglia are the principal neuroimmune sentinels of the brain. They continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective activation states that determine their responses to danger. In Alzheimer’s disease, microglia have been described to assume both activation states depending on the level of progression of the disease. Methods: To begin to understand the global gene expression profile of microglia in Alzheimer’s disease, we used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice and in mice with Alzheimer’s-like pathology. We validated our findings by dual fluorescent in-situ hybridization, unbiased proteomic analysis and quantitative PCR. Results: In this presentation we will discuss our findings and highlight the distinct transcriptomic signatures of microglia in these three conditions. Conclusions: Microglia express unique
