Mitigating chronic neuroinflammation in Alzheimer mice by novel immunomodulatory imide drugs (IMiDs) conserves neuroplasticity and cognitive function and also alleviates neurodegeneration‐behavioral impairments in TBI‐challenged mice

Abstract

AbstractBackgroundNeuroinflammation is an invariable characteristic of chronic neurodegenerative disorders, such as Alzheimer’s disease (AD), and acute ones, epitomized by traumatic brain injury (TBI). However, whether neuroinflammation development drives disease progression or is an epiphenomenon remains unknown.MethodsTo test the hypothesis that, once initiated, AD‐associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline irrespective of changes in amyloid‐β (Aβ) peptide generation, a new class of immunomodulatory imide drugs (IMiDs) was developed on the backbone of thalidomide/pomalidomide to reduce proinflammatory cytokine generation and resulting inflammation, but lacking action on SALL4 – a key protein implicated in thalidomide teratogenicity. (i) 5xFAD mice, known to develop neuroinflammation consequent to excessive Ab generation, were evaluated over a 4‐month period during which cognitive deficits develop, and (ii) wild type mice subjected to TBI and impacted with motor and cognitive impairments were evaluated to assess whether selective resolution of neuroinflammation by novel IMiDs could mitigate behavioral declines.ResultsPomalidomide (Pom) and the more potent novel analog, 3,6’‐dithioPom (3,6’‐DP), which does not impact SALL4 levels, were administered to reduce microglial cell activation ‐ as confirmed in primary cortical cultures challenged with Aβ and RAW 264.7 cells challenged with lipopolysaccharide (LPS). 3,6’‐DP, in particular, decreased microglial and astrocyte activation in hippocampus and cerebral cortex of 5xFAD mice. This was accompanied by reductions in synaptic and neuronal cell loss, and behavioral impairment in the absence of changes in Aβ plaque or peptide generation. In TBI challenged mice, 3,6’‐DP, likewise, mitigated neuroinflammation and resulted in reduced neuronal loss and behavioral impairments.ConclusionsAD‐associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation provides a means to mitigate AD‐associated cognitive/behavioral impairments, and provides a new drug candidate to alleviate other neurodegenerative disorders, such as TBI.