Morgan Lab
Lab Personnel
- David G. Morgan, PhD, Principal Investigator
- Dylan Finneran, PhD
- Brianna Jackman
- Taylor Desjarlais
Overview
Innate Immunity
Our research team has been studying the role of glial cells in regulating the development of amyloid and tau pathology for the last 30 years. We have performed multiple studies applying agents to manipulate the microglial cells in the brains of both amyloid mice and tauopathy mice. Somewhat unexpectedly, we have generally found that activating microglia in amyloid mice is beneficial, but the same manipulation in tauopathy mice can exacerbate the pathology. Conversely, some treatments that suppress microglial activation exacerbate amyloid pathology and diminishe tau pathology. Examples of manipulations include lipopolysaccharide injections, nitro-NSAIDs, HDAC6 inhibitors administration, fractalkine overexpression, and MCP-1 overexpression. One hypothesis we are testing is that innate immune system activation in response to amyloid deposition participates in enhancing the tau pathology in Alzheimer’s disease using our amyloid-enhanced tauopathy model. We have recently found that using agents that mimic infections and produce inflammation in the peripheral immune system can result in increased tau pathology in the brain. In addition, we presently have a grant from the Alzheimer’s Association to study a novel small molecule experimental drug for its effects on tau pathology and behavior.
Biomarkers
Upon relocating to MSU in 2017, our laboratory purchased an instrument called the Simoa (single molecule array), which has 100 fold greater sensitivity in detecting proteins than traditional ELISAs. Many of the markers of innate immune activation are too low to be detected in human cerebrospinal fluid (CSF) under control conditions, making assessment of the state of microglial and astrocyte activation difficult. Using the Simoa we can now detect many of these previously un-measurable analytes. In 2000 the Michigan Alzheimer’s Disease Research Center added a new Biomarker Core located entirely at MSU in Grand Rapids, in part because of the Simoa Instrument. The Co-Leads for this core are Drs. Kanaan and Morgan in Translational Neuroscience. Through collaborations with McGill University, we have found that cognitively normal older adults with early-stage amyloid deposition have biomarker signatures which suggest suppression or impairment of the innate immune system, but ultimately as tau pathology emerges there is a dramatic increase in these innate immune biomarkers. We plan to determine if this reflects a change in innate immunity caused by amyloid deposits, or if individuals who have a suppressed innate immunity are more prone to developing amyloid deposits.
Immunotherapy
The research domain that our research team is most recognized for are our studies with immunotherapy. We were the first to demonstrate that vaccinating amyloid depositing mice against the amyloid peptide could not only lead to clearance of the amyloid, but also protect them from developing memory deficits. We further demonstrated multiple means by which antibodies can remove existing amyloid deposits from mouse brain, still the only treatment known to do this. Most importantly, we found in old mice that immunotherapy could cause the development of hemorrhages around blood vessel that had amyloid deposits. This was followed several years later by observations that humans treated with immunotherapy developed an adverse event on MRI called Amyloid Related Imaging Abnormalities (ARIA), which is caused by hemorrhages and edema. Two decades later amyloid immunotherapy was the first treatment approved by the FDA that slows progression of the disease. We have further examined the effects of immunotherapy against tau in mouse models and found its effects are not as dramatic as those against amyloid, perhaps because most of tau is inside cells, whereas amyloid is outside.
Gene Therapy
We have been working with adeno-associated virus (AAV)-based gene therapy for 20 years. In general, we have injected multiple genes into the brains of amyloid or tau depositing mice to ascertain the impact of the gene protein on the pathology and behavior phenotype. We have published technical methods for expanding the portion of the brain transduced by AAV using a variety of methods. However, at most, a quarter of the mouse brain can be effectively transduced using intracranial injections of AAV, limiting the use of this direct injection method in humans with Alzheimer’s disease (AD). Recently, some specially mutated capsids for AAV have been developed which are capable of penetrating the brain from the blood. These AAV transduce the entire brain in a relatively uniform fashion. Such an approach might be translatable to human brain. Recently, we have found that a protein called reelin, that appears to delay a genetic form of Alzheimer’s disease (from a presenilin-1 mutation) can protect our amyloid enhanced tauopathy mouse model from developing memory impairments. A new NIH grant to study this further is currently pending (fall 2025).