Department of International Collaborative Research
Principal Investigator：Douglas G Walker Ph.D.
Special Contract Professor
The research projects of this laboratory are focused on investigating how chronic neuroinflammation affects the pathological processes of Alzheimer’s disease (AD), and Parkinson’s disease (PD) and related Lewy body diseases (LBD. There are still many unanswered questions about the interactions of inflammation with degenerating neurons and how this affects their production, responses to and removal of the insoluble proteins of AD or PD/LBD, namely aggregated amyloid beta peptide, aggregated/phosphorylated tau and aggregated/phosphorylated α-synuclein. Different cellsare involved inneuroinflammation with the primary one being the microglia, the brain resident tissue macrophages.With the identification of gene changes associated with microglia enhancing the risk of AD, neuroinflammation has become a focus for developing treatment strategies. Microglia can produce large amounts of neurotoxic molecules if activated, but the question is “Are they actually doing this in the AD brain”? Microglia can also be highly protective if exposed to different chemicals. A related researchtheme is how and why do the brains natural defenses against inflammation fail? There are different systems that control the fine balance of pro- and anti-inflammation to maintain brain homeostasis, but they become defective with disease and aging.
a) the scope of inflammation in human brain tissue. This project has used the microglial marker P2RY12, a receptor for ADP/ATP, to identify homeostatic (non-activated) microglia that are doing a maintenance function and identify their association with activated proinflammatory microglia. As P2RY12 is rapidly downregulated when microglia become activated, the association of this and other microglia markers will be able to define the areas of inflammation in the human brain in relation to plaque and tangle pathology (see panel A). With this information, it will be possible to develop more refined anti-inflammatory treatments. Related to this has been our findings that a variant form of the protein CD105 recognized by specific antibodies is a marker for a specific subset of activated microglia.
b) The neuronal anti-inflammatory ligand CD200. CD200 is a protein on the surface of neurons with the sole function of deactivating microglia by binding to their CD200 receptor. This interaction turns off inflammation thus protecting neurons from damage. Loss of this system results in enhanced tissue damage, and we showed that CD200 becomes deficient with AD and aging, but not in PD/LBDs. The factors that regulate the expression of CD200 in human neurons are not understood, and basic studies will identify how to therapeutically enhance this protein expression and function. The interaction of CD200 with its receptor is mediated by short amino acid sequence interactions. Enhancing this system therapeutically may be possible with short peptide.
c) Understanding defective lysosomal function/autophagy in AD/PD. A central question for neurodegenerative disease is – why are insoluble aggregated proteins allowed to accumulate in the brain? Cells have machinery called lysosomes for handling these unwanted materials. This question is also important for neuroinflammation – “why do microglia not efficiently remove amyloid plaques?” We are approaching this by examining the properties of the autophagy and lysosome master regulator Transcription Factor EB (TFEB) in human AD brains. Activating this factor increases the removal of Ab and α-synuclein, but it is unknown whether there is a deficit of TFEB in AD brains. Understanding this feature will help in devising therapeutic strategies.
d) Three-dimensional human cell culture models for neuroinflammation. Many of the drugs that have failed to show effects in treating human AD and PD patients were very effective in rodent animal models of these diseases. It is generally agreed that validated human cell models of these diseases are also needed to test agents at some stage. We are developing and validating a novel 3D cell model system for neuroinflammation studies using differentiated cholinergic neuronal-like cells and microglia-like cells for basic and translational application. The goal is to develop a model similar to the human brain (panel B).
Mohammad Khusni, M.D., PhD, Assistant Professor
Anarmaa Mendsaikhan M.D., PhD, Assistant Professor