Tag Archives: drug

“Silent Modulator” Drug Reverses Alzheimer’s Disease in Mice

Glutamate is a neurotransmitter, a chemical used to transmit signals between neurons. Its dynamics in the brain are highly complex and it is sensed by a variety of receptors, including metabotropic glutamate receptor 5 (mGluR5). mGluR5 is of particular interest due to its recently-uncovered role in Alzheimer’s disease. The receptor can interact with short strings (“oligomers”) of amyloid-beta, a toxic protein implicated in the pathology of Alzheimer’s. Multiple studies show that loss or inhibition of mGluR5 can alleviate Alzheimer’s symptoms in animal models.

An important question remaining to be answered is exactly how mGluR5 contributes to Alzheimer’s. One hypothesis is that the receptor’s interactions with amyloid-beta oligomers trigger a pathogenic signaling cascade. Another possibility is that amyloid-beta is not involved, and instead the dysregulated glutamate signaling is to blame.


Glutamate is regulated by many different neuronal receptors, including mGluRs. It is an important molecular for neuronal signaling. Image Source

A recent study published in Cell Reports attempted to solve this dilemma. Researchers from Yale University used a silent allosteric modulation (SAM) drug to target mGluR5. In humans, complete inhibition of mGluR5 would be deadly, since the receptor is necessary to maintain proper glutamate signaling in the central nervous system. To avoid this problem, the SAM drug was carefully designed so that it blocked the ability of mGluR5 to interact with amyloid-beta oligomers, but still allowed it to function normally in glutamate signaling.

The researchers then administered the drug to mice that have a mutation causing them to develop Alzheimer’s disease. After four weeks of treatment, the mice underwent a battery of tests designed to test memory and cognition. Normally, the mice with Alzheimer’s disease perform very poorly on these tests. However, after treatment with the drug, the Alzheimer’s mice performed as well as the non-Alzheimer’s mice. This result is striking, because most drug candidates for Alzheimer’s disease are only able to stop the cognitive decline from getting any worse. It is rare for a treatment to actually reverse the memory deficits.


One type of memory test is called novel object recognition. When a healthy mouse sees a novel object, it will sniff it more than it would a familiar object. Mice with Alzheimer’s disease normally can’t distinguish novel from familiar objects, but the SAM drug in this study was able to return the mice’s test scores to healthy values.

The scientists took it a step further by examining what was going on inside the mice’s brains at the cellular level. They found that levels of amyloid-beta plaques and damage to glial cells were unchanged by the drug. This is surprising, because these two factors are often considered to be among the main driving forces of Alzheimer’s disease. In contrast, they observed a dramatic change in the mice’s synapses, the junctions where neurons send signals to each other. Mice with Alzheimer’s disease typically have fewer synapses than normal mice. However, those receiving the treatment showed recovery of synapses, suggesting that modulation of synapses could be how the drug reverses memory decline.

An important limitation of the mice used in these experiments is that they only develop the amyloid-beta pathology of Alzheimer’s disease. In humans, there are many other toxic proteins involved, including a particularly important one called tau. To address this problem, the researchers also administered the drug to a different mouse strain, which expressed both amyloid-beta and tau. They saw that levels of tau were alleviated in the mice receiving the treatment.

This study helps to solve an important dilemma, demonstrating that mGluR5’s contributions to Alzheimer’s disease are solely due to its interactions with amyloid-beta, and not due to abnormalities in glutamate signaling. Thus by developing human versions of the SAM drug used in this study, it might be possible to stop or even reverse memory decline in Alzheimer’s patients. However, it’s important not to get too excited just yet. We’ve seen time and time again that the vast majority of drug candidates that have encouraging results in mice end up failing to treat the disease in humans. Only time will tell whether these results could have clinical applications.


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New Alzheimer’s Drug Shows Promise in Clinical Trials

One of the main hallmarks of Alzheimer’s disease is the accumulation of toxic protein clumps called amyloid-beta plaques inside the brain (for more detail see Alzheimer’s Disease: A General Overview). For the past several decades, the predominant theory among neuroscientists has been that these plaques are the main cause of the disease, and that removing them is the key to a cure. This is known as the amyloid cascade hypothesis.

A recent study published in Nature, one of the world’s premier scientific journals, reported promising results from a phase 1b clinical trial of a new drug called aducanumab. This drug works by selectively targeting amyloid-beta aggregates and marking them for destruction by the body’s immune system, an approach known as immunotherapy. The researchers demonstrated using mice that the drug is able to penetrate the blood-brain barrier and reduce levels of amyloid-beta plaques.

Various doses of the drug were injected into patients with mild Alzheimer’s disease once per month for one year. PET scans showed that the 125 subjects who completed the trial had reduced amyloid-beta levels in their brains compared to controls who were given a placebo. This reduction was enhanced the longer the drug was administered and the higher the dose. The subjects given the drug also had higher scores on tests of cognitive function. Notably, the drug slowed but did not prevent or reverse cognitive decline in these subjects, and the effects varied substantially based on the dosage.

Dozens of previous immunotherapeutic drug candidates for Alzheimer’s disease have failed early in clinical trials, and so these positive results are very exciting. However, this drug is far from being declared a cure, and there are several important caveats to keep in mind.

Problematic side effects have plagued Alzheimer’s drug trials for decades, and unfortunately this one was no exception. Nearly 25% of the subjects withdrew from the trial due to side effects, which included headache, urinary tract infection, upper respiratory infection, and an interesting phenomenon known as amyloid-related imaging abnormalities (ARIA). ARIA are small abnormalities that appear on MRI scans and are believed to be the result of cerebral microhemorrhages (“mini-strokes”). ARIA is a common side affect of amyloid-beta immunotherapy and is considered to be a serious condition. 41% of subjects given the highest dose of aducanumab experienced ARIA, compared to zero controls. Several subjects were also diagnosed with another type of serious hemorrhaging called superficial siderosis of the central nervous system. No deaths due to side effects were reported.

Additionally, it’s important to note that all of the subjects in the study were only in the earliest stages of Alzheimer’s disease, so it’s not clear how well this drug will work with patients in later stages. The trial was also relatively short-term and only in phase 1b. It’s not uncommon for drugs to succeed in early clinical trials but fail when they reach the final phase 3 trials, which is was happened with a promising Alzheimer’s drug candidate earlier this year.

The final point I want to make is that the success of aducanumab hinges on the amyloid cascade hypothesis being correct. The theory was considered dogmatic for years, but lately it has been experiencing scrutiny, due in large part to the discovery that nearly 1 in 3 elderly people have high levels of amyloid-beta in their brains despite being cognitively normal (for a deeper look at this controversy, see Where’s our cure to Alzheimer’s disease?). Though the majority of mainstream neuroscientists still support the amyloid cascade hypothesis, it’s important to keep its criticisms in mind. The scientific community will wait with bated breath for the drug’s phase 3 trial results.


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