Morgan Lab

 

Lab Personnel


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 brain. We tried for many years to use the M1/M2 distinction to differentiate microglial stages of activation, similar to the designations found useful in the periphery with macrophages. In general we found this distinction un-informative and others have concurred this distinction does not explain the overall impacts of manipulations on the phenotype of the cells or the effects of treatments on Alzheimer-related pathology. Because we examine both amyloid depositing and tau depositing mice, we are able to separately examine specific manipulations of the innate immune system on each type of pathology. Overall, there tends to be opposite effects of these manipulations on the two pathologies, with activation of microglia removing amyloid but exacerbating tau pathology, and suppression of microglial activation exacerbating amyloid pathology and diminishing tau pathology. Examples of manipulations include lipopolysaccharide injections, fractalkine overexpression, dexamethasone administration, MCP-1 expression and IL-1ra (receptor antagonist) expression. One hypothesis we are testing is that innate immune system activation in response to amyloid deposition participates in increasing the tau pathology in Alzheimer’s disease. We are also testing if inflammation in the peripheral immune system can result in increased tau pathology in the brain.

 

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 rare 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-measureable analytes.  We have started collaborations with McGill University and the Mayo Clinic in Minnesota to measure markers of innate immune activation in CSF samples taken from longitudinal studies of aging adults. One important feature of these samples is that we can ascertain what the innate immune signatures are both before and after individuals begin to deposit amyloid and/or tau, and what the signatures are of individuals who do not deposit amyloid and/or tau. Several studies have found that in cognitively normal older adults, those with early stage amyloid deposition have signatures which suggest suppression of the innate immune system compared to older adults without amyloid deposition. 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 (published in Nature and referenced over 1900 times). We further demonstrated multiple means by which antibodies can impact the deposition of amyloid in mouse brain. Most importantly, we found in old mice that immunotherapy could cause the development of hemorrhages around blood vessel that had amyloid deposits, and that the immunotherapy increased the amount of vascular amyloid. 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 was caused by hemorrhages and edema (edema cannot be detected postmortem in mice in mice). 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. We are presently examining the impact of anti-amyloid immunotherapy upon the rates of tau deposition in aged amyloid precursor protein transgenic mice.

Gene Therapy

We have been working with AAV-based gene therapy for 15 years. In general, we have administered genes of multiple types into the brains of amyloid or tau depositing mice to ascertain the impact of the expressed gene on amyloid or tau deposition and mouse behavior. We have published technical methods for expanding the portion of the brain transduced using a variety of methods. However, in general, less than a quarter of the mouse brain can be effectively transduced using intracranial injections of AAV, limiting the use of this direct injection method in human 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 circulation. These AAV transduce the entire brain, and also some peripheral tissues. Such an approach might also be amenable to transducing human brain. We are experimenting with various promoters and peripheral receptor inhibitors to try to maximize the expression in brain relative to peripheral tissues using this approach. One of the advantages of gene therapy over germ line transgenesis is the ability to assign age as a variable in experimental design. Another advantage is the ability to rapidly examine the effects of existing knockout lines on development of AD-like pathology by, for example, injecting AAV tau constructs systemically. We continue to explore other uses of this systemic administration paradigm to develop better therapies for AD.

Memory Screening

In addition to our laboratory research, our team is developing a clinical research program. One issue in performing clinical trials to test drugs to treat Alzheimer’s disease is the finding that only 35-40% of persons with dementia ever receive a formal diagnosis. If you don’t know you have Alzheimer’s, you don’t think about the possibility of being in a clinical trial. A second feature is that for those who do receive a diagnosis, the severity of the disease is such that the tests of cognition are no longer sensitive to changes produced by drugs. There are an estimated 5.5 million people with Alzheimer’s, but it takes 2-3 years just to enroll a phase 3 clinical trial (using 2000 people at over 100 sites). It then takes another 1.5-2 years to conduct the study. If enrolment could be done in 1 year, this would bring meaningful drugs to patients much faster, and cost less to develop the medications. We have initiated a Community Based Memory Screening Program providing free memory screening evaluations to older adults at over 20 locations in the greater Grand Rapids area. This program uses volunteers to leverage the efforts of our staff members to perform the screenings. For each participant, contact information, health history and interest in clinical research participation is put into a database registry. This Memory Care registry can then be used to find individuals to participate in clinical trials in Grand Rapids, accelerating the enrollment into these pivotal studies.

Cognitive Training Clinical Trial

Our team is presently conducting a clinical trial to prevent the development of medically diagnosed cognitive impairment in older adults. This is the Preventing Alzheimer’s with Cognitive Training; PACT study. The study is based upon over 20 years of research demonstrating the ability of certain computer games to improve cognitive performance and memory in older adults. However, the games have not been tested in a clinical trial to see if they can prevent or delay mild cognitive impairment or dementia. Study participants will first be given a memory screening evaluation and depression assessment. If they are cognitively normal and over 65 they will be trained to perform specific computer games in our facilities over three sessions. Participants will then be asked to perform 22 more computer gaming sessions over the next 18 weeks. One year after the first visit, the participants will be asked to complete 10 additional gaming sessions. An additional 10 sessions will be completed at the 2 year time point. At the 3 year time point another memory evaluation will be performed. Those participants dropping below the normal range on the evaluation will be provided a free medical diagnosis procedure including MRI and amyloid PET scans to determine if they have developed mild cognitive impairment or dementia, and a treatment plan will be prescribed. The hypothesis is that some forms of computer games will decrease the risk of developing medically diagnosed cognitive impairment. To our knowledge this is the only Alzheimer’s clinical trial being conducted in the greater Grand Rapids area.