Alzheimer’s Plaques May Grow in a Day, Precede Arrival of Inflammatory Cells

A widely held belief about Alzheimer’s disease is that its characteristic plaques accumulate over decades, preceding and possibly causing dementia and other clinical symptoms. But now a team of HMS researchers led by Bradley Hyman, the John B. Penney Jr. professor of neurology at Massachusetts General Hospital, reports in the Feb. 7 Nature that plaque formation can occur literally overnight.

Courtesy Melanie Meyer-Luehmann

Breaking down plaque build-up. With the aid of a novel microphoton imaging technique, amyloid plaques (blue) can be seen along neurites (green) and blood vessels (red). The arrow in the right image indicates a plaque that is newly formed.

This surprising finding emerged when postdoctoral researcher and first author Melanie Meyer-Luehmann and her colleagues observed plaque formation and the accumulation of brain inflammatory cells, or microglia, in real time. “A longtime goal within the field has been to uncover the kinetics of plaque formation and microglial activation. We’ve known for a while that plaques and microglia occur together in Alzheimer’s, but we’ve never known whether plaques cause microglial activation or whether microglial activation causes plaques,” said Meyer-Luehmann.

Previously, it was possible only to look at plaque formation through the production of sequential snapshots from thin slices of brain. But through a novel microphoton imaging technique, Hyman and his team were able to image thick sections of tissue in vivo, essentially allowing them to capture a movie of plaque formation.

The researchers initially imaged plaque-free areas in several strains of transgenic mice so they could detect the onset of a new plaque and monitor its growth. To their amazement, new plaques developed in as quickly as 24 hours and stabilized soon after.

The researchers then went back to examine the point at which the microglial response occurred and found that while the plaques were definitely the first to appear, it was not long before microglia were recruited to the site.

“It is still unknown if the microglia are good or bad, but we think they may be involved in restricting plaque growth,” said Meyer-Luehmann. Whatever their precise role may be, it is clear from the studies that their coexistence with plaques resulted in progressive degeneration in neuronal function.

“We now know the actors, and we know when they come on stage,” Hyman said. “So now we would like to track the changes from initial plaque formation up to the onset of alterations in neuronal function, and then explore ways where we can either reverse the progression of these changes or, better still, inhibit them.”

—Yvonna Reekie

Nanoparticles Refined to Deliver Prostate Cancer Drug

The laboratories of Omid Farokhzad, HMS assistant professor of anesthesia at Brigham and Women’s Hospital, and Robert Langer, a scientist at the Massachusetts Institute of Technology, have engineered a novel self-assembling targeted nanoparticle to maximize the efficiency of drug delivery to prostate cancer cells.

The challenge of this nanotechnology is to create a “maximally stealth” and “maximally targeted” delivery vehicle that can be consistently reproduced. Although the first targeted nanocarrier was developed nearly 30 years ago, these investigators are at the forefront in reproducibly creating the delicate balance among cell targeting, immune evasion, and drug release necessary for efficient drug delivery.

“Until now, there has been no good way to ensure that a targeted nanoparticle is consistently successful,” said Langer. Designing a drug-encapsulated nanoparticle with targeting ability has been challenging because each parameter requires optimal conditions that are difficult to reproduce using traditional methodologies, which require a chemical reaction for each step of the carrier design.

The study, published online Feb. 13 in Proceedings of the National Academy of Sciences, reports a nanoparticle self-assembly method that needs no chemistry once the biopolymers are made. Two of the components have Food and Drug Administration approval for use in other drugs: poly(D,L-lactide-co-glycolide), a biodegradable matrix used for encapsulation and sustained release of drugs, and polyethylene glycol, which enables immune system evasion. The third component is an RNA aptamer, which recognizes prostate cancer cells. It is stable in organic solvents during polymer synthesis and nanoparticle formation, making it uniquely suitable for self-assembly. By precipitating this triblock copolymer of PLGA, PEG, and RNA in water, the polymer self-assembles to form a nanoparticle for drug delivery and uptake in a cell-specific manner.

Working in culture and in a mouse model of prostate cancer, the researchers tested nanoparticles encapsulating docetaxel, a standard chemotherapeutic drug for prostate cancer. They determined the optimal aptamer density on the nanoparticle surface required for maximal uptake by prostate cancer cells. Maximal tumor targeting resulted from nanoparticles with a very low aptamer density. Increasing the aptamers caused more nanoparticle clearance by the liver and less accumulation in tumors.

“More isn’t always better when it comes to attaching targeting molecules or other functionalities to the surface of nanoparticles. A narrow window exists when the properties of a targeted particle are optimally engineered to work well,” said Farokhzad.

“This exciting finding adds validation to the role that nanotechnology can play in treating cancer and has application to any disease that can be targeted with nanoparticles,” said first author Frank Gu, a researcher in the Harvard–MIT Division of Health Sciences and Technology.

—Kafi Meadows

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