Summary: Researchers have developed a new technique to measure levels of amyloid beta in the brain. They have also discovered new insights into why mutations of the TREM2 gene increases the risk of developing Alzheimer’s disease.
Studies hint at therapeutic strategies against devastating disease.
New Alzheimer’s disease research details a technique that speedily measures levels in the brain of a damaging protein fragment, and insight into why mutations in a specific gene increase the risk of developing the disease.
Both studies, from researchers at Washington University School of Medicine in St. Louis, are available online in The Journal of Experimental Medicine.
The new measuring technique could lead to a better understanding of how amyloid beta, a key protein associated with Alzheimer’s disease, is produced in and removed from the brain, which would help scientists design treatments to limit the protein’s accumulation. Meanwhile, the genetic insight suggests that the brain’s own immune cells are crucial for containing the damage due too having too much amyloid beta.
When you use your brain – planning a meal, remembering the route to the store – your neurons release a sticky molecule known as amyloid beta, as a byproduct of their normal functioning. In healthy people, the protein fragment is cleared before it can do any damage. In people with Alzheimer’s disease, clearance is impaired, and amyloid beta builds up into clumps known as plaques.
Many of the treatments being studied for Alzheimer’s are designed to reduce amyloid beta in the brain. John Cirrito, PhD, an associate professor of neurology, Carla Yuede, PhD, an instructor in neurology, and colleagues have developed a new technique that measures minute-by-minute changes in amyloid beta levels in the brain. Previous techniques had allowed measurements only once an hour.
“For the last 14 years we had a technique in which we would do something to the mouse – give it a drug, have it perform a certain behavior – and we’d find out what happened to its amyloid beta levels an hour later,” said Cirrito, the senior author. “Waiting that long just wasn’t good enough. Neural activity happens on a rapid time scale, and we needed to see a direct connection between the intervention and the amyloid beta levels.”
In people, amyloid beta releases electrons when exposed to a small amount of voltage. These electrons can be measured as electric current, and the amount of current is directly proportional to the amount of amyloid beta.
The researchers attached antibodies that specifically detect amyloid beta onto a tiny electrode, zapped it with a small amount of voltage and measured the resulting current.
“People have used this approach for other molecules, but the detectors were the size of a microscope slide,” Cirrito said. “We adapted it into a five-micron fiber, which is way thinner than a human hair, so it could be implanted into the brain.”
Since mouse amyloid beta, unlike the human version, does not produce a current when exposed to voltage, the researchers used mice genetically modified to produce human amyloid beta. They treated the mice with a drug that blocked the production of new amyloid beta, and monitored how quickly the existing pool of amyloid beta disappeared.
The experiment revealed something surprising: One clearance pathway rapidly cleared amyloid beta at higher levels, but a different, slower one became dominant later as the levels dropped. These results contradicted research that Cirrito himself, among others, had published that suggested that the rate of clearance and the relative importance of the different pathways did not depend on the amyloid beta concentration.
“This is important if you’re devising a therapeutic strategy against Alzheimer’s disease,” said Cirrito. “If you hit the first pathway, you might have an effect quickly, but you may not be able to lower amyloid beta levels beyond a certain point. You’d have to consider targeting multiple pathways.” Mutations increase risk
In a separate study, another Washington University team of researchers found that mutations in a specific gene increase the risk of Alzheimer’s by compromising the function of a cell that cleans up molecular debris.
People who carry a mutated form of the gene TREM2 have a fivefold increase in the risk of developing Alzheimer’s disease. The gene codes for a protein that, in the brain, is found only on a type of immune cell known as microglia.
“We found that microglia without TREM2 behaved abnormally,” said co-senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “We speculate that in Alzheimer’s patients, over time, microglia fail to contain the accumulation of amyloid beta, which causes increasing damage to their brains.”
Microglia are the cleanup crew of the brain, engulfing and destroying dying cells, microbes and molecular debris, including amyloid beta. When TREM2 detects the presence of a kind of fat called phospholipids, it sends a signal that activates microglia.
To find out why losing TREM2 function raises the risk of Alzheimer’s disease, Colonna, co-senior author David Holtzman, MD, and colleagues knocked out the TREM2 gene in mice that have a genetic propensity to develop amyloid plaques.
In the brains of mice with TREM2, the microglia surround the amyloid plaques, but in those without TREM2, the microglia are dispersed. Without microglia hemming them in, the plaques spread out and markers of neuronal damage go up, although the total amount of amyloid beta stays the same.
“If you don’t have TREM2, the plaque spreads into the brain and destroys key parts of the neurons,” Colonna said.
Identification of the role of microglia in Alzheimer’s opens up possibilities for developing treatments. TREM2 is the first step in a molecular pathway that leads from detecting phospholipids to activating the cell. Microglia also bear inhibitory receptors on their surface, which send signals through a parallel molecular pathway to prevent the cell from being activated.
“You could target not just TREM2 but any molecule in the TREM2 pathway to make microglia more active,” said Colonna. “Or you could block any step in the inhibitory pathway.”
Another possibility is to have antibodies that act as a bridge between the plaques on one side and microglia on the other. In Alzheimer’s patients whose microglia do not surround the plaques on their own, such as those with defects in TREM2 or another molecule in the pathway, antibodies could bring the cells to the plaques.
Holtzman, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, already is studying antibodies as a treatment.
“Now that we have shown how important microglia are, there are lots of things we can do to increase their function that might help,” Colonna said.
Fuding: Research into measuring beta amyloid levels in the brain was supported by National Institutes of Health (NIH) grant numbers R21 AG045691, R01 AG042513, P01 NS074969, P50 AG568132, R01 DA037838 and R15 ES021079; National Science Federation grant number 1334417; and the Brightfocus Foundation.
Research into the role of TREM2 in Alzheimer’s disease was funded by NIH grant numbers RF1 AG05148501, 5T32CA009547-30, and AG047644; the National Multiple Sclerosis Society grant RG4687A1/1; Cure Alzheimer’s Fund; the JPB Foundation; the Knight Alzheimer’s Disease Research Center, pilot grant P50 AG005681-30; and the Lilly Innovation Fellowship Award from Eli Lilly and Co.
Source: Tamara Bhandari – WUSTL Image Source: This NeuroscienceNews.com image is in the public domain. Original Research:Abstract for “Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model” by Carla M. Yuede, Hyo Lee, Jessica L. Restivo, Todd A. Davis, Jane C. Hettinger, Clare E. Wallace, Katherine L. Young, Margaret R. Hayne, Guojun Bu, Chen-zhong Li, and John R. Cirrito in Journal of Experimental Medicine. Published online May 2 2016 doi:10.1084/jem.20151428
Abstract for “TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques” by Yaming Wang, Tyler K. Ulland, Jason D. Ulrich, Wilbur Song, John A. Tzaferis, Justin T. Hole, Peng Yuan, Thomas E. Mahan, Yang Shi, Susan Gilfillan, Marina Cella, Jaime Grutzendler, Ronald B. DeMattos, John R. Cirrito, David M. Holtzman, and Marco Colonna in Journal of Experimental Medicine. Published online May 2 2016 doi:10.1084/jem.20151948
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]WUSTL. “A New Role For Amyloid Beta in Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 15 June 2016. <https://neurosciencenews.com/neurology-amyloid-beta-alzheimers-4482/>.[/cbtab][cbtab title=”APA”]WUSTL. (2016, June 15). A New Role For Amyloid Beta in Alzheimer’s. NeuroscienceNews. Retrieved June 15, 2016 from https://neurosciencenews.com/neurology-amyloid-beta-alzheimers-4482/[/cbtab][cbtab title=”Chicago”]WUSTL. “A New Role For Amyloid Beta in Alzheimer’s.” https://neurosciencenews.com/neurology-amyloid-beta-alzheimers-4482/ (accessed June 15, 2016).[/cbtab][/cbtabs]
Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model
Findings from genetic, animal model, and human studies support the observation that accumulation of the β-amyloid (Aβ) peptide in the brain plays a central role in the pathogenic cascade of Alzheimer’s disease (AD). Human studies suggest that one key factor leading to accumulation is a defect in brain Aβ clearance. We have developed a novel microimmunoelectrode (MIE) to study the kinetics of Aβ clearance using an electrochemical approach. This is the first study using MIEs in vivo to measure rapid changes in Aβ levels in the brains of living mice. Extracellular, interstitial fluid (ISF) Aβ levels were measured in the hippocampus of APP/PS1 mice. Baseline levels of Aβ40 in the ISF are relatively stable and begin to decline within minutes of blocking Aβ production with a γ-secretase inhibitor. Pretreatment with a P-glycoprotein inhibitor, which blocks blood–brain barrier transport of Aβ, resulted in significant prolongation of Aβ40 half-life, but only in the latter phase of Aβ clearance from the ISF.
“Rapid in vivo measurement of β-amyloid reveals biphasic clearance kinetics in an Alzheimer’s mouse model” by Carla M. Yuede, Hyo Lee, Jessica L. Restivo, Todd A. Davis, Jane C. Hettinger, Clare E. Wallace, Katherine L. Young, Margaret R. Hayne, Guojun Bu, Chen-zhong Li, and John R. Cirrito in Journal of Experimental Medicine. Published online May 2 2016 doi:10.1084/jem.20151428
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
“TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques” by Yaming Wang, Tyler K. Ulland, Jason D. Ulrich, Wilbur Song, John A. Tzaferis, Justin T. Hole, Peng Yuan, Thomas E. Mahan, Yang Shi, Susan Gilfillan, Marina Cella, Jaime Grutzendler, Ronald B. DeMattos, John R. Cirrito, David M. Holtzman, and Marco Colonna in Journal of Experimental Medicine. Published online May 2 2016 doi:10.1084/jem.20151948