Aspects of microglial activation in neuroinflammation associated with CNS neurodegeneration have alternately been reported to be further damaging or to be protective against disease progression. Thus, the translational potential of targeting microglia in new drug development for CNS neurodegenerative diseases remains uncertain. A major challenge in this context has been that relevant microglial phenotypes and activation states have been exceedingly difficult to recapitulate in cell line models or even in primary cultures of microglia. Conversely, microglial studies in vivo are time- and cost-intensive, and consequently have limited scalability. To address this need, we propose to develop and provide validation for a novel, brain tissue- based drug discovery model for the identification and mechanistic evaluation of new drug and drug target candidates for modulating microglial activation in CNS neurodegenerative disorders. Brain tissue models capture important aspects of intercellular interactions within the intact, local 3-dimensional structure of native neural tissues, and thereby have increased physiological relevance and can be more predictive of clinical benefit compared to cell-based models. Moreover, we have shown previously that brain slice assays can be scaled to useful throughputs for drug discovery in Huntington's disease (HD), Alzheimer's disease (AD), and stroke. The goal of the present proposal is thus to establish the experimental framework for a brain slice-based screening and mechanistic assay for microglial-neuronal interactions, and to provide initial validation that perturbation of microglial activation and/or numbers leads to clear and reproducible effects on rates and/or extents of neurodegeneration. In addition, we will extend the assay to interrogate potential effects of peripheral monocytes, whose infiltration is associated with later stages of CNS disease. We will initially focus on an HD brain slice model that we have used extensively in both screening as well as mechanistic studies, and then ask if our findings are generalizable to different models of CNS neurodegeneration driven by amyloid precursor protein and tau isoforms relevant to AD and frontotemporal dementias (FTD), respectively. If successful, the proposed studies should provide a new 3-D brain tissue-based model for capturing clinically relevant microglial-neuronal interactions scalable to screening throughputs for the discovery of new candidate drugs and drug targets for CNS neurodegeneration, and for their mechanistic evaluation and validation.
Statement of Relevance to Public Health Inflammation of brain tissues is a prominent feature of a range of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and ischemic stroke, and is thought to have both protective and accelerating effects on disease progression. Yet, to date few clear therapeutic strategies exist for modulating neuroinflammation for clinical benefit in brain neurodegenerative diseases and injury. In this context, the present proposal seeks to develop a drug discovery screening platform that can be used to identify novel drug and drug target candidates for modulating the activation of the sole resident immune cell of the brain, the microglial cell, to slow the progression of neurodegenerative disease mechanisms.
| Khoshnan, Ali; Sabbaugh, Adam; Calamini, Barbara et al. (2017) IKK? and mutant huntingtin interactions regulate the expression of IL-34: implications for microglial-mediated neurodegeneration in HD. Hum Mol Genet 26:4267-4277 |
| Zhang, Zhiquan; Ma, Qing; Shah, Bijal et al. (2017) Neuroprotective Effects of Annexin A1 Tripeptide after Deep Hypothermic Circulatory Arrest in Rats. Front Immunol 8:1050 |
