This research was supported by BrightFocus
Cynthia Lemere, PhD, a member of the BrightFocus Scientific Review Committee,
BrightFocus SRC member Cindy Lemere, PhD, of Harvard, helped develop a way to image inflammatory cells that contribute to Alzheimer’s. Here, she talks to a reporter after an SfN press conference.
Society for Neuroscience meeting in Washington, DC, this week. Two close colleagues of BrightFocus took part in press conferences to explain new directions in Alzheimer’s research.
Cynthia Lemere, PhD, a member of the BrightFocus Scientific Review Committee, was part of a panel on detecting and preventing neuroinflammation as a factor contributing to Alzheimer’s. She is a researcher and associate professor of neurology at Harvard’s Brigham and Women’s Hospital.
As background, the human brain consists primarily of neurons, which transmit signals, and nonneuronal cells, called “glia,” that are there to nourish and protect neurons. Already, the blood-brain barrier defends the brain against entry of pathogens and toxic substances, but beyond that, a subcategory of glia, called “microglia,” are the first line of active immune defense against unwanted intruders. Like an occupying force, their job is to constantly sweep the neuronal terrain for signs of danger, including plaques, damaged neurons, and infectious agents. The microglia remove these threats mostly remove by ingesting them (a process known as phagocytosis).
Even in healthy people, microglia levels naturally increase with aging. Microglia also increase in the presence of early plaques and neuronal damage associated with preclinical Alzheimer’s. This in turn seems to trigger downstream changes, like inflammation, that hasten the disease.
Currently there is no FDA-approved technology for imaging neuroinflammatory factors. In people known to be at risk for Alzheimer’s disease, such imaging might be useful as a “biomarker” or early warning of the disease, and it could possibly help determine when treatment should begin.
Lemere discussed the results of a study funded by GE Healthcare that uses its PET scan technology with a new tracing agent to track the spread and worsening of these inflammatory factors. She is senior author on the SfN abstract by Bob Liu, PhD, et al, showing that in mice engineered with Alzheimer’s disease, the tracer was successful in showing more microglial activity in the cortex and hippocampal regions involved with memory.
Whereas the definitive diagnosis of Alzheimer’s disease traditionally occurs postmortem, after pathologists have had a chance to examine a person’s brain, “we now have a new tool,” Lemere remarked, and “with these new PET tracers, it’s possible to get more insights into Alzheimer’s disease in the living.”
GE Healthcare is expected to seek FDA approval for the new technology.
Surprising News About Tau Turnover--An SfN ‘Hot Topic’
Another member of the BrightFocus Scientific Review Committee, David Holtzman, MD, of Washington University in St. Louis, had his study differentiated from thousands at SfN as an SfN “hot topic.”
Holtzman is senior author on the abstract by Kaoru Yamada, PhD, (first author) of the University of Tokyo, and other colleagues worldwide. It describes their investigation into tau protein clearance in the brain. Their results were presented at an SfN scientific session (SfN Program No. 578.02).
Tau, these researchers note, is a normally soluble protein that becomes insoluble and accumulates in its diseased state. In the healthy brain, there’s a balance between tau production and clearance to maintain normal levels. It’s been hypothesized that impaired tau clearance may be one of the mechanisms behind the accumulation of misfolded tau, contributing to Alzheimer’s disease. However, tau “turnover” in the living brain has not been well studied.
After investigating tau clearance in living mice, these investigators found that even normal tau protein has a relatively long half-life of 10-11 days (as compared with 1-2 hours for Aβ peptide) and does not disappear as quickly from the brain as expected. For most abnormal forms of tau, the rate of clearance is longer, but varies. Their results have led them to speculate that, for different forms of tau, different clearance mechanisms are involved. It also supports the hypothesis that inefficient clearance of particular forms of tau might lead to tau tangles. These researchers speculate that improving clearance of the slowest-clearing, more insoluble forms of tau could become a therapeutic strategy against Alzheimer’s.
Exosomes: A Mechanism for Spreading ‘Bad’ Tau?
At another press conference, Boston University Professor Tsuneya Ikezu, MD, PhD, described the BrightFocus-funded discoveries made in his lab by Hirohide Asai, MD, PhD, a 2013-15 BrightFocus grantee, and others, to determine how tau pathology spreads in Alzheimer’s disease. Asai is second author on the abstract by Ikezu et al.
Using special microscopy techniques, these researchers discovered tau in tiny cellular vesicles, called exosomes, in an Alzheimer’s mouse model. They also found that microglia cells helped spread the tau-containing exosomes to other nerve cells, and that this process can be stopped by depleting the amount of microglia or by inhibiting the creation of exosomes – both of which might be potential treatment approaches.
The aim of Asai’s BrightFocus research proposal was to determine how tau spreads and whether that's a neuron-to-neuron or neuron-to-glia phenomenon. The work supports the latter hypothesis and strengthens impressions of role that microglial “surveillance,” triggering inflammatory factors, might play in Alzheimer’s progression.
As background, it’s important to know that tau protein is present in the healthy brain, and helps to stabilize tube-shaped structures (known as “microtubules”) within neurons that are used to transport other molecules in and out. Like many proteins, tau “folds” into a characteristic shape that assists this function. The problem comes when tau undergoes biochemical changes and phosphorylizes, causing it to misfold and harden (ie, become less soluble). In this form, it is toxic to neurons. Ultimately it aggregates into “tangles”—or debris fields of dead and disintegrating neurons—and possibly spreads to other neurons within the brain.
For years, researchers have lined up into different camps, one hypothesizing that beta-amyloid (AΒ) plaques, which accumulate outside of neurons, are the main trigger behind the progression of Alzheimer’s, and another proposing that intracellular tau is the instigator. At this SfN meeting, there was less speculation about which is the culprit—beta amyloid or tau—and more about which of these bad players activates a hypothetical immune response that triggers Alzheimer’s progression. Generally, it’s agreed that whereas AΒ overproduction and accumulation is a gradual, decades-long process, tau phosphorylation is a sped-up event that leads more directly to Alzheimer’s symptoms.
Referring to this debate, Ikezu called it a “chicken and egg” question. Nonetheless, he mentioned a possible hypothesis that in his mind, can be garnered from these results, that possibly “a-beta stimulates the phosphorylation of tau.”
Further support—or even the answer--may come from research into other common neurodegenerative diseases associated with misshapen tau, which together are known as “tauopathies.” These include Parkinson’s disease, Huntington’s disease, and frontotemperal dementia, second only to Alzheimer’s disease as a common form of early-onset dementia in people aged 55-65 years.
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