Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood.

We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?

Beneficial effects of glatiramer acetate in Huntington's disease mouse models: Evidence for BDNF-elevating and immunomodulatory mechanisms.

Huntington's disease (HD) is a fatal, neurodegenerative movement disorder that has no cure and few treatment options. In these preclinical studies, we tested the effects of chronic treatment of glatiramer acetate (GA; Copaxone®), an FDA-approved drug used as first-line therapy for MS, in two different HD mouse models, and explored potential mechanisms of action of drug efficacy. Groups of CAG140 knock-in and N171-82Q transgenic mice were treated with GA for up to 1year of age (CAG140 knock-in mice) or 20weeks (N171-82Q mice). Various behavioral assays were measured over the course of drug treatment whereby GA treatment delayed the onset and reduced the severity of HD behavioral symptoms in both mouse models. The beneficial actions of GA were associated with elevated levels of promoter I- and IV-driven brain-derived neurotrophic factor (Bdnf) expression and reduced levels of cytokines, in particular, interleukins IL4 and IL12, in the brains of HD mice. In addition, the GA-induced effects on BDNF, IL4 and IL12 levels were detected in plasma from drug-treated mice and rats, suggesting utility as a peripheral biomarker of treatment effectiveness. These preclinical studies support the use of GA as a relevant clinical therapy for HD patients.