By any measure, Alzheimer’s disease is a neurodegenerative condition with a massive impact. Currently more than 7 million Americans over 65 are living with this progressive, memory-robbing illness, which brings steady decline and heartbreak for those living with the disease and the millions of family members and friends who care for them.
To get a better handle on how this outsized disease begins in the brain, Johns Hopkins pathologist Meaghan O’Malley Morris is looking small, very small — to a 2-millimeter-wide region buried deep in the brain stem known as the locus coeruleus (LC). Specifically, her team is zeroing in on the very earliest formation of abnormal Tau protein in the LC, and then tracing how those abnormal Tau proteins accumulate and spread to other regions in the brain. Tau protein is an important target, since it is known to clump and produce tangles that are implicated in Alzheimer’s disease, notes Morris, who is the Anne and C. Michael Armstrong CIM Human Aging Project (HAP) Scholar.
“Thanks to funding I have received as a HAP Scholar, our lab has been able to take a step into more advanced protein studies, known as spatial proteomics, to look at which proteins in which cell types are associated with the early formation and the spread of Tau,” says Morris, who earned her M.D./Ph.D. from Johns Hopkins and also completed her residency and fellowship training here.
To get a better picture of how the disease “gets off the ground,” Morris and her team are examining the post-mortem brain tissue of people ages 16–65, a period in the human age span before symptoms of Alzheimer’s disease would typically appear.
In addition to studying the formation and spread of abnormal Tau protein and associated inflammatory cells in the LC, the researchers are also examining the presence of Amyloid beta protein — which is known to accumulate into clumps or plaques in people with Alzheimer’s — to see how the two proteins interact.
“It’s very important for us to figure out what is going on very early in the disease, because by the time people start showing symptoms of Alzheimer’s, there is already a decent amount of Tau and Amyloid that has accumulated,” says Morris.
“It’s very important for us to figure out what is going on very early in the disease, because by the time people start showing symptoms of Alzheimer’s, there is already a decent amount of Tau and Amyloid that has accumulated.” – Meaghan O’Malley Morris
Until recently, traditional proteomic techniques have not been fine-grained enough to offer a useful window into the ultra-tiny locus coeruleus, which is barely the size of a toothpick tip. But thanks to advances in spatial proteomics, which reveals which proteins are active where, Morris and her team can now get down to a 20-micron level, basically the size of a single cell, in their investigations.
They are finding the presence of abnormal Tau protein in nearly all of the brain tissue they examine, even those of younger people under 40.
What causes Tau cells in some people to leave the LC and travel from deep in the brain stem up into regions like the cortex, where they grow into tangles and wreak havoc? How might inflammatory cells surrounding Tau in the LC contribute to Tau’s early formation and growth?
These are among the big questions that Morris and her team are working to shed light on as they tap into the latest advances in proteomics, data science and biostatistics. The answers they find could hold tantalizing clues for stopping Alzheimer’s disease early in its tracks, before it is able to take hold and cause destruction in our brains.
“The funding I have received as the Anne & C. Michael Armstrong CIM HAP Scholar has been crucial to advancing our work,” says Morris. “We are so excited about what lies ahead.”
