Tackling Neuroinflammation for Early Intervention and Better Treatment


Image Credit: Charles River Laboratories

For several decades, Alzheimer's researchers have grappled with the “chicken or the egg” question regarding the proteins commonly associated with the condition.

It is accepted that over-production or under-clearance of amyloid beta (a protein associated with nerve repair and development) forms hard plaques in the brains of Alzheimer's disease (AD) patients, and that the tau protein found in brain cells is toxic. Maybe, making strings like tangled spaghetti.

The problem is whether the abnormal formation of amyloid plaques or dysfunctional tau induces neurodegeneration in the brains of AD patients, or whether these are the results of an exceptionally complex disease process has not been confirmed by researchers.

Dr. Rudolph Tanzi, professor of neurology at Harvard and director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH), believes that amyloid is the main driver of AD. In the 1980s, his team (along with others) identified a beta-amyloid-forming gene on chromosome 21, where rare mutations can cause early-onset familial AD. The gene codes for amyloid beta-protein precursor (APP) can increase levels of amyloid beta peptides in the brain. Longer and more adhesive forms of this peptide can accumulate, leading to amyloid plaques, a characteristic of AD.

Tanzi believed in the amyloid hypothesis, but in time he realized that therapeutic targeting of these toxic proteins in the brain of AD patients would be insufficient to stop the disease. To prevent the disease, intervention must be done much earlier, ideally. formally before symptoms appear.

Tau proteins in red and yellow.

Amyloid plaques on neurons. Image Credit: Charles River Laboratories

Neuroinflammation in AD

While tau tangles and amyloid plaques cause damage in the early stages of the disease, most of the damage is arguably caused by specialized immune cells (malfunctioning microglia) in the central nervous system that trigger near-constant neuroinflammation.

Normally, microglia displace neurological debris (including amyloid remnants). However, in AD they become overactive, destroying healthy neurons and accelerating the course of the disease. Many scientists believe that chronic immune response is the third major pathological feature of AD.

In 2008, Tanzi's laboratory linked CD33 to neuroinflammation: CD33 is a surface cell receptor found on microglia and other immune cells that is more abundant in AD patients. Increased levels of CD33 are associated with disease severity. Five years later, Tanzi found that highly expressed CD33 could damage neurons by signaling microglia to initiate neuroinflammation.


Tau proteins in red and yellow. Image Credit: Charles River Laboratories

TREM2, another gene expressed by microglia, also plays a complex role in neuroinflammation. Normally it encodes for proteins that regulate microglia response to infection and injury, including clearing excessive tau and amyloid from the brain. However, in 2012 a scientist at the University of London found that the variations actually reduce the protein's function, potentially increasing the risk of AD by three times.

Tanzi's laboratory has published animal data demonstrating how the crosstalk of CD33 and TREM2 may play a role in neuroinflammation, where CD33 turns it on and TREM2 turns it off. Tanzi said that if CD33 is silenced but TREM2 is maintained, the toxic inflammation that triggers AD could potentially be reduced. Approximately 20% of disease-modifying drugs in phase III trials for AD have immunomodulating actions targeting microglia, the majority of which target TREM2.

Multiple targets of neuroinflammation

Research leader Dan Rocca, PhD, of Charles River Laboratories, says microglia undoubtedly have a complex role within Alzheimer's disease, and their behavior may be difficult to determine as the disease progresses. “Depending on what stage you are in, microglia can either aggravate the disease, or protect you from it and reduce some symptoms,” Rocca says. “They can potentially put out a lot of cytokines, which cause inflammation and death of neurons, but they can also engulf amyloid beta and thus reduce those plaques.”

While TREM2 and CD33 are obvious targets for drug developers, other avenues of research exist. Rocca says some companies are targeting inflammasomes, danger-sensing proteins that become activated when a cell is infected or damaged. There is evidence that both beta amyloid and tau in the brain can induce persistent activation of the NLRP3 inflammasome, leading to chronic neuroinflammation.

“There are companies that have developed small molecules that have been chemically modified to enter the brain. “They work by targeting the inflammasome to potentially prevent the adverse effects of microglia.” Rocca says.

Pharmaceutical companies are currently exploring preclinical models to demonstrate microglial activation, says Dr. Suzanne Back, PhD, senior manager of CNS pharmacology at Charles River's Kuopio, Finland site. Dr. Back says several mouse models exist that can be used to measure neuroinflammation in AD. “But this is difficult because in most models, neuroinflammation is primarily a secondary response to amyloid overproduction and plaque formation and does not capture all of the inflammatory changes seen in human Alzheimer's.”

The future of AD therapeutics

Tanzi says one potential way to control Alzheimer's treatment is a combination of drugs, including a therapeutic antibody to clear plaques and a small-molecule drug such as a gamma secretase modulator to reduce amyloid levels. When combined with other medications, these can control the spread of tangles and reduce neuroinflammation. “But, for it to work, it would be best to give the antibodies before people show symptoms,” Tanzi says.

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