New Antibody Drug Clears Brain of Amyloid Plaques and Delays Onset of Alzheimer’s Disease Symptoms in Small Clinical Trial

An experimental drug called aducanumab seem to be able to remove the toxic proteins that build up and cause the onset of Alzheimer’s disease in the brain, according to findings from a small clinical trial. Because of the small size of this trial, I must stress that these results, though potentially exciting, should also elicit some caution.

The results of this small clinical trial were reported in the journal Nature on August, 31, 2016. In this trial, aducanumab dissolved amyloid-β proteins in patients suffering from early-stage Alzheimer’s disease. This was a Phase I clinical trial, and therefore, was designed mainly to test the safety of aducanumab in human patients. Thus, the final word on whether aducanumab works to mitigate the memory losses and cognitive decline associated with Alzheimer’s disease must be subjected to clinical trials specifically designed to test such things. Two larger phase III trials are presently in progress, and are planned to be completed approximately in 2020 (note: this is an estimate).

The latest study enrolled 165 subjects who were split into different groups; subjects in one group received aducanumab and subjects in the other group were administered a placebo. In the group that received aducanumab infusions, 103 patients were given the drug once a month for up to 54 weeks. These patients experienced a reduction in the amount of tangled amyloid-β in their brains. These clinical recapitulated the results of pre-clinical experiments in laboratory mice that were actually reported in the same paper. Aducanumab seems to clear amyloid-β plaques from the brains of laboratory mice and human patients.

“This drug had a more profound effect in reversing amyloid-plaque burden than we have seen to date,” says psychiatrist Eric Reiman, who serves as executive director of the Banner Alzheimer’s Institute in Phoenix, Arizona. Reiman and his colleagues are in the process of testing other approaches for Alzheimer’s prevention and treatment. “That is a very striking and encouraging finding and a major advance.” Reiman wrote a commentary accompanying the article.

“This is the best news we’ve had in my 25 years of doing Alzheimer’s research, and it brings hope to patients and families affected by the disease,” says neurologist Stephen Salloway of Butler Hospital in Providence, Rhode Island, who is a member of the clinical team that ran the trial.

Patients in those groups that received aducanumab were divided into different subgroups that were given one of four different doses. Those patients who received the highest doses also had the highest reductions in plaques, and a group of 91 patients who had been treated for 54 weeks saw slower cognitive declines than did those who received placebo infusions.

Neuroscientists have had a long-standing and often spirited debate over the significance of the accumulation of amyloid-β in the pathology of Alzheimer’s disease. The memory loss and other symptoms of Alzheimer’s disease almost certainly result from the die-off of neurons in the brain, but do the amyloid-β plaques form as a consequence of this massive neuronal die-off or are they the cause of it? This clinical trial seems to provide good evidence for the “amyloid hypothesis,” since the elimination of amyloid-β protein seems to ameliorate the symptoms of Alzheimer’s disease.

Reiman however, cautions, wisely I think, that this trial is too small to definitively demonstrate that aducanumab actually works. Several other drugs for Alzheimer’s disease have shown promising results in the early-stage of clinical trials only to end in failure, and even in the deaths of patients.

Aducanumab led to abnormalities on brain-imaging scans in less than one-third of the patients. Researchers must closely monitor these anomalies in Alzheimer’s trials, because some participants in previous Alzheimer’s antibody trials have died as a result of brain inflammation. Fortunately, all of the reported imaging abnormalities eventually disappeared in about 4 to 12 weeks, and none of the patients who showed such abnormalities were hospitalized. Curiously, some of the patients who showed imaging anomalies continued to take the drug despite these side effects. Patients who received higher doses of the drug, or who had genetic risk factors for Alzheimer’s, were more likely to develop the brain anomalies.

Biogen, the company that makes aducanumab, has adjusted the drug’s dosage and the monitoring schedule for patients who have an increased genetic risk for Alzheimer’s in its phase 3 trials. According to Reiman, drug makers, like Biogen, must determine if a particular dosage that hits a “sweet spot” that is strong enough to work without causing potentially lethal brain inflammation.

Aducanumab is a bright spot in the field of Alzheimer’s therapeutics after years of failed antibodies and other types of drug trials. The antibody drug solanezumab failed to slow cognitive decline in two large 2013 clinical trials.  However solanezumab may have a second life and is being tested in multiple other trials, one of which includes individuals with mild Alzheimer’s disease. Results from this trial might be reported as early as the end of 2016.

Other therapeutic strategies undergoing clinical trials include strategies that target enzymes called β-secretase 1 that processes amyloid proteins, antibodies that attack the so-called the microtubule-binding tau protein, which is found in high concentrations in the neurofibrillary tangles found in the brains of many Alzheimer’s disease patients.

“The fact that we now have an antibody that gets into the brain sufficiently enough to engage its target and remove plaques is an important development, and we look forward to seeing results from this and other phase 3 trials,” Reiman says.

Genetically Modified As a Potential Treatment of Alzheimer’s Disease

A neurobiology team from UC Irvine (full disclosure, my alma mater) has used genetically engineered neural stem cells to treat mice with a form of Alzheimer’s disease (AD). Such implanted neural stem cells ameliorated some of the symptoms and pathological consequences of this disease in affected mice.

Patients with AD show accumulation of the protein amyloid-beta in their brains. These amyloid-beta clusters form clear plaques in the brain that are also quite toxic to nearby neurons.

Amyloid beta plaques can be cleared with the protein in them is degraded. Fortunately, the enzyme neprilysin can degrade these plaques, but the brains of AD patients show low levels of this enzyme. Neprilysin levels decrease with age and this is probably one of the reasons AD tends to be a disease of the aged.

The UC Irvine group, under the direction of Mathew Blurton-Jones, tried to deliver neprilysin to the brains of afflicted mice and used neural stem cells to do it. The goal of this work was to determine if increased degradation of the amyloid plaques abated the pathological effects of AD.

In this work, two different AD model systems were used. Thy1-APP and 3xTg-AD mice both exhibit many of the pathological effects of AD, and both were used in this study. Neural stem cells were transfected in express 25 times more neprilysin that normal. Then these genetically modified neural stem cells were transplanted into two areas of the brain known to be affected by AD: the hippocampus and the subiculum, which lies just below the hippocampus. Other AD mice were transplanted with neural stem cells that had not been transformed with neprilysin.

Post-mortem examination of both groups of mice even up to three months after transfection of the neural stem cells showed that those mice that received injections of neprilysin-expressing neural stem cells had significant reductions in amyloid-beta plaques within their brains compared to control mice. The neprilysin-expressing cells even seemed to promote the growth of neurons and the establishment of connections between them.

A truly remarkable finding of this work was that numbers of amyloid-beta plaques were also reduced in area of the brain that were some distance from the areas where the stem cells were injected. This suggests that the injected stem cells migrates across the brain, reducing plaque formation as they went.

Future experiments will seek to see if the reduction in amyloid-beta plaques also leads to improvements in cognition. Also, before this protocol can make its transition from animal models of human trials, the UC Irvine group will need to determine if the neprilysin also degrades soluble forms of amyloid-beta.

Every AD mouse model varies as to the types of pathologies observed in the brains of the affected mice. For this reason, this group tested their treatment strategy in two distinct AD mouse models, and in both cases, the neprilysin-expressing neural stem cells reduced the incidence of amyloid beta plaques. This strengthens the conclusion and neprilysin-expressing neural stem cells can indeed degrade amyloid-beta plaques.

More work needs to be done before this work can be used to support a human trial, but this is certainly an encouraging start to something great.

Using Human Stem Cells to Predict the Efficacy of Alzheimer’s Drugs

Scientists who work in the pharmaceutical industry have seen this time and time again: A candidate drug that works brilliantly in laboratory animals fails to work in human trials. So what’s up with this?

Now a research consortium from the University of Bonn and the biomedical company Life & Brain GmbH has shown that animal models of Alzheimer’s disease fail to recapitulate the results observed with cultured human nerve cells made from stem cells. Thus, they conclude that candidate Alzheimer’s disease drugs should be tested in human nerve cells rather than laboratory animals.

In the brains of patients with Alzheimer’s disease beta-amyloid protein deposits form that are deleterious to nerve cells. Scientists who work for drug companies are trying to find compounds that prevent the formation of these deposits. In laboratory mice that have a form of Alzheimer’s disease, over-the-counter drugs called NSAIDs (non-steroidal anti-inflammatory drugs), which include such population agents as aspirin, Tylenol, Advil, Nuprin and so on prevent the formation of beta-amyloid deposits. However in clinical trials, the NSAIDs royally flopped (see Jaturapatporn DIsaac MGMcCleery JTabet N. Cochrane Database Syst Rev. 2012 Feb 15;2:CD006378).

Professor Oliver Brüstle, the director of the Institute for Reconstructive Neurobiology at the University of Bonn and Chief Executive Officer of Life and Brain GmbH, said, “The reasons for these negative results have remained unclear for a long time.”

Jerome Mertens, a former member of Professor Brüstle’s research, and the lead author on this work, said, “Remarkably, these compounds were never tested directly on the actual target cells – the human neuron.”

The reason for this disparity is not difficult to understand because purified human neurons were very difficult to acquire. However, advances in stem cell biology have largely solved this problem, since patient-specific induced pluripotent stem cells can be grow in large numbers and differentiated into neurons in large numbers.

Using this technology, Brüstle and his collaborators from the University of Leuven in Belgium have made nerve cells from human patients. These cells were then used to test the ability of NSAIDs to prevent the formation of beta-amyloid deposits.

According to Philipp Koch, who led this study, “To predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells.”

Nerve cells made from human induced pluripotent stem cells were completely resistant to NSAIDs. These drugs showed no ability to alter the biochemical mechanisms in these cells that eventually lead to the production of beta-amyloid.

Why then did they work in laboratory animals? Koch and his colleagues think that biochemical differences between laboratory mice and human cells allow the drugs to work in one but not in the other. In Koch’s words, “The results are simply not transferable.”

In the future, scientists hope to screen potential Alzheimer’s disease drugs with human cells made from the patient’s own cells.

“The development of a single drug takes an average of ten years,” said Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer’s medications could be greatly streamlined.”

Why Do Some People Get Alzheimer’s Disease but Others Do Not?

Everyone has a brain that has the tools to develop Alzheimer’s disease. Why therefore do some people develop Alzheimer’s disease (AD) while others do not? An estimated five million Americans have AD – a number projected to triple by 2050– the vast majority of people do not and will not develop the devastating neurological condition. What is the difference between those whole develop AD and those who do not?

Subhojit Roy, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, asked this exact question. In a paper published in the journal Neuron, Roy and colleagues offer an explanation for this question. As it turns out, in most people there is a critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.

“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” says principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”

Neurologists measure the severity of AD by the loss of functioning neurons. In terms of pathology, there are two tell-tale signs of AD: a) clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and, b) threads or “tangles” of ‘tau” protein found inside neurons. Most neuroscientists believe AD is caused by the accumulation of aggregates of beta-amyloid protein, which triggers a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.

Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.

“Both of these proteins are highly expressed in the brain,” says Roy, “and if they were allowed to combine continuously, we would all have AD.”

It sounds inexorable, but it doesn’t always happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy and Utpal Das, a postdoctoral fellow in Roy’s lab who was the first author of this paper, and other colleagues, discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, which ensures that these two proteins do not have much contact with each other.

“Nature seems to have come up with an interesting trick to separate co-conspirators,” says Roy.

What then brings APP and BACE together? Roy and his team found that those conditions that promote greater production of beta-amyloid protein also increase the convergence of APP and BACE. Specifically, an increase in neuronal electrical activity, which is known to increase the production of beta-amyloid, also increased the convergence of APP and BACE. Post-mortem examinations of AD patients have shown that the cellular locations of APP and BACE overlap, which lends credence to the pathophysiological significance of this phenomenon in human disease.

Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details). (B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right). (C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can
Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or
picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details).
(B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right).
(C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can

Das says that their findings are fundamentally important because they elucidate some of the earliest molecular events triggering AD and show how a healthy brain naturally avoids them. In clinical terms, they point to a possible new avenue for ultimately treating or even preventing the disease.

“An exciting aspect is that we can perhaps screen for molecules that can physically keep APP and BACE-1 apart,” says Das. “It’s a somewhat unconventional approach.”

StemCells, Inc. Human Neural Stem Cells Restore Memory in Models of Alzheimer’s Disease

StemCells, Inc., a Newark, California-based company has announced preclinical data that demonstrates that its proprietary human neural stem cell line restored memory and enhanced synaptic function in two animal models that are relevant to Alzheimer’s disease (AD). They presented these data at the Alzheimer’s Association International Conference 2012 in Vancouver, Canada.

In this study, neuroscientists from University of California, Irvine transplanted a neural stem cell line called HuCNS-SC, a proprietary stem cell line made by StemCells and is a purified human neural stem cell line, into a specific region of the brain, the hippocampus in laboratory animals. These injections improved the memories of two different types of laboratory animal that act as AD-significant models. The hippocampus is a portion of the brain that is critically important to the control of memory, and unfortunately, it is severely affected by AD. Specifically, hippocampal synaptic density is reduced in AD and these reductions in synaptic connections are highly correlated with memory loss. After injections of HuCNS-SCs, the animals showed increased synaptic density and improved memory after the cells had been transplanted. Importantly, these results did not require reduction in beta amyloid or tau that accumulate in the brains of patients with AD and account for the pathological hallmarks of the disease.

This research study resulted from collaboration between Frank LaFerla, Ph.D., who is the Director of the University of California, Irvine (UCI) Institute for Memory Impairments and Neurological Disorders (UCI MIND), and Chancellor’s Professor, Neurobiology and Behavior in the School of Biological Sciences at UCI, and Matthew Blurton-Jones, Ph.D., Assistant Professor, Neurobiology and Behavior at UCI.

“This is the first time human neural stem cells have been shown to have a significant effect on memory,” said Dr. LaFerla. “While AD is a diffuse disorder, the data suggest that transplanting these cells into the hippocampus might well benefit patients with Alzheimer’s. We believe the outcomes in these two animal models provide strong rationale to study this approach in the clinic and we wish to thank the California Institute of Regenerative Medicine for the support it has given this promising research.”

Stephen Huhn, M.D., FACS, FAAP, Vice President and Head of the CNS Program at StemCells Inc, added, “While reducing beta amyloid and tau burden is a major focus in AD research, our data is intriguing because we obtained improved memory without a reduction in either of these pathologies. AD is a complex and challenging disorder. The field would benefit from the pursuit of a diverse range of treatment approaches and our neural stem cells now appear to offer a unique and viable contribution in the battle against this devastating disease.”