Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. Drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. The results also demonstrate that the therapeutic time window is an important consideration in efficacy studies of drugs that modulate glia biological responses involved in pathology progression and suggest that such paradigms should be considered in the development of new therapeutic regimens that seek to delay the onset or slow the progression of AD.
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This research was supported in part by funds from the American Health Assistance Foundation (L.J.V.E.), an Alzheimer's Association Zenith award (L.J.V.E.), a gift from the Kleberg Foundation (C.M.N.), and NIH Grants P01 AG005119 (L.J.V.E., D.S.C.), R01 AG027297 (C.M.N.), R01 NS056051 (D.M. Watterson), R01 AG031311 (D.M. Watterson), and S10 RR026489. A.D.B. is a postdoctoral fellow supported by NIH F32 AG037280.
Bachstetter, Adam D.; Norris, Christopher M.; Sompol, Pradoldej; Wilcock, Donna M.; Goulding, Danielle; Neltner, Janna H.; St. Clair, Daret; Watterson, D. Martin; and Van Eldik, Linda J., "Early Stage Drug Treatment that Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction in a Mouse Model that Exhibits Age-Dependent Progression of Alzheimer's Disease-Related Pathology" (2012). Sanders-Brown Center on Aging Faculty Publications. 79.