Seminar with Michael Heneka, MD, German Center for Neurodegenerative Disease
Innate immune activation in Alzheimer’s disease
The accumulation of neurotoxic amyloid beta peptides along with neuroﬁbrillary tangle formation are key pathological hallmarks of Alzheimer’s disease. The brain has been considered as an immune-privileged organ, however, increasing evidence from translational, genetic, and pathological studies suggests that activation of distinct innate immune pathways are a third important disease hallmark which, once initiated, actively contributes to disease progression and chronicity.
Microglia play a pivotal role in this immune response and are activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors. This immune activation leads to the release of inﬂammatory mediators, but also distracts microglia cells from their physiological functions and tasks, including debris clearance and trophic factor support. NLRP3 inflammasome activation and release of ASC specks contribute to spreading of pathology and impair microglia clearance mechanisms, and together contribute to neuronal spine loss, neuronal degeneration, and ultimately to spatial memory deficits. In keeping with this immune hypothesis of neurodegeneration, inhibition of this immune pathway protects from neurodegeneration in cellular and murine models of Alzheimer’s disease. Modulation of the microglia driven innate immune response at key signaling steps might therefore be protective and alter disease progression. However, the microglia are not a stable population, but have continuous turn over, most likely resulting in more than one generation of microglia being involved in disease progression. Moreover. their turnover is increased in response to neurodegeneration. Along with the regional diversity of microglia, these phenomena need to be understood in more detail prior to targeting innate immune mechanisms for therapeutic purposes.Neurological Association, and the Lamport Award for Excellence in Clinical Science Research from Columbia University.