New targets for the therapeutics

Tsuneya Ikezu, MD, PhD, had made seminal contributions to Alzheimer’s disease (AD) research. Previously, this body of research was divided into studies of either therapeutic intervention of anti-inflammatory cytokines and chemokines using animal models of AD or molecular and cellular mechanisms of tau pathology in animal models. His laboratory pioneered adeno-associated virus-mediated gene transfer to the central nervous system. Using this technology, Dr. Ikezu characterized the therapeutic effect of several anti-inflammatory molecules, such as interleukin-4, interleukin-10 and CD200, on the hippocampal function, which is the critical brain region for the neurogenesis and memory formation. He was one of the first to demonstrate that neuroinflammation and hippocampal neurogenesis are potential therapeutic targets in AD. He further extended this research to demonstrate the therapeutic potential of the neuronal anti-inflammatory cytokine CD200, neurogenic fibroblast growth factor-2 (Kiyota T. et al. PNAS) and suppression of inflammatory microRNA (miR-155, Woodbury M. et al J Neurosci) on the hippocampal neurogenesis and cognitive enhancement.



Tau propagation mechanisms

Dr. Ikezu has been a pioneer in defining the roles of microglia and extracellular vesicles in the spread of pathogenic tau protein in the brain (Asai H. et al. Nat Neurosci 2015). His group elegantly demonstrated how microglia phagocytose tau-containing neurons secrete extracellular vesicles containing tau protein to accelerate tau pathology using the AAV-mediated gene transfer system. In 2016, the publication of this discovery was recognized by the Alzheimer’s Association as the most impactful paper in the previous two years.

Dr. Ikezu also made significant contributions to the classification of the activation phenotype of microglia, a cell type of enormous interest. These microglial activation phenotypes were originally adapted from the M0, M1 and M2 classification of macrophages. However, his and his colleagues’ more recent works on the characterization of the microglial gene expression phenotype in disease conditions, which were published in PLoS One (Freilich R. et al. 2013) and Immunity (Krasemann S. et al. Immunity 2017), show that microglia are largely in homeostatic or disease-associated states. The studies on which these articles were based  identified miR-155, APOE and TREM2 as key molecules for shaping the neurodegenerative microglia, which are also genetically associated with AD. To evaluate the TREM2 signaling in vitro, his laboratory also developed a cell-based TREM2/TYROBP signaling reporter tool (Varum M, et al. J Biol Chem 2017).  These works are re-framing the biology of microglia and their disease implications.



Therapeutic target of Alzheimer's disease

In addition to the above discoveries, Dr. Ikezu cloned a neuron-specific tau kinase, tau-tubulin kinase 1 (TTBK1) from the human brain tissue cDNA library (Sato S. et al. J Neurosci) and characterized the role of TTBK1 in tau aggregation in the context of AD pathogenesis. While intracellular accumulation of phosphorylated tau is the diagnostic marker of AD, to date there has not been successful drug development targeting tau phosphorylation. Moreover, other tau kinases, such as cyclin-dependent kinase 5 and glycogen synthase kinase 3-beta are ubiquitously expressed yet have failed in drug development, making. TTBK1 known as a neuron-specific tau kinase, is an attractive target for the future drug development. His laboratory created the TTBK1 BAC mouse and characterized its relevance in AD progression by crossing it with tau and APP mouse models, advancing the understanding of the role of TTBK1 in AD pathogenesis.



Microglial augmented neuritogenic factor

Maternal immune activation (MIA) disrupts the central innate immune system during a critical neurodevelopmental period. Microglia are primary innate immune cells in the brain although their direct influence on the MIA phenotype is largely unknown. We have shown that MIA alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons in the prefrontal cortex of mice. MIA increases plastic dendritic spines of the intrinsically bursting neurons and their interaction with hyper-ramified microglia. Treating MIA offspring by colony stimulating factor 1 receptor inhibitors induces depletion and repopulation of microglia, and corrects protein expression of the newly identified MIA-associated neuritogenic molecules in microglia, which coalesces with correction of MIA-associated synaptic, neurophysiological, and behavioral abnormalities. Our study demonstrates that maternal immune insults perturb microglial phenotypes and influence neuronal functions throughout adulthood, and reveals a potent effect of colony stimulating factor 1 receptor inhibitors on the correction of MIA-associated microglial, synaptic, and neurobehavioral dysfunctions.

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