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Chemistry and Biochemistry Labs
D. Hansen Lab

Research

Microglia and Alzheimer’s disease: Where immunology meets neuroscience

Human genetic studies have identified many genes that influence the risk of late-onset Alzheimer’s disease (AD). The majority of these AD risk genes are expressed in microglia, the brain’s resident immune cells. Therefore, microglial dysfunction is a fundamental component of AD pathogenesis. When important microglial functions such as amyloid-β clearance become compromised in the aged brain, AD pathologies accumulate and spread, leading to neural injury and degeneration.

For most microglia-expressed AD risk genes, we do not yet understand the molecular mechanisms by which they impact microglial function. Likewise, the cellular activities by which microglial cells restrain AD pathogenesis in the brain are not well defined. To reveal the molecular and cellular mechanisms of AD, our research uses three general approaches:

1) We define the biochemical properties, molecular interactions, and cellular functions of proteins encoded by AD risk genes. For example, the PILRA gene encodes an inhibitory microglial receptor that opposes tyrosine kinase signaling. A single amino acid change in PILRA protein associated with reduced AD risk also reduces the interaction of PILRA with its ligands. Therefore, inhibiting PILRA is a potential therapeutic approach to prevent/delay AD. Our current research to further understand how PILRA impacts microglial function and AD pathogenesis is funded by the BrightFocus Foundation. We are very grateful and honored to receive this support from BrightFocus.

2) We perform genetic or pharmacological manipulations in cellular or animal disease models to observe how AD risk genes and their encoded proteins impact AD pathologies. For example, deletion of Trem2, a gene critical for the microglial response to neural damage, increases neural injury and degeneration in the PS2APP and TauPS2APP models of amyloid plaque and tau pathologies. TREM2 activity enables microglial cells to compact amyloid fibrils into dense plaques that are more intensely labeled by amyloid stains but are much less damaging to surrounding neurons. Several pharmaceutical companies are developing TREM2 agonists in attempts to enhance microglial neuroprotection and prevent/delay AD.

3) We use bioinformatic "-omics" approaches to compare microglial polarization states among mouse models and human tissues and clarify how microglial polarization relates to disease biology. For example, microglial transcriptomes in human AD brains display an exaggerated aging signature and fail to display the Trem2-dependent protective signature observed in mouse AD models. Currently, we are adapting our previously developed methods of brain tissue dissociation and cell type purification to profile the proteomic changes stimulated by AD pathology in microglia and other CNS cell types using mass spectrometry.

Our research reveals how AD-associated genes are utilized by microglia or other cell types to alter the course of AD pathogenesis. Our ultimate aim is to identify novel therapeutic approaches, similar to TREM2 agonism or PILRA inhibition, that may prevent or slow the progression of this debilitating and tragic illness.