New Understandings of Cell Death Show Promise for Preventing Alzheimer’s

New research on peptides important to understanding Alzheimer’s disease and their effects on cell toxicity could lead to treatments for preventing or delaying neurodegenerative diseases

Alzheimer’s disease is a progressive neurodegenerative disorder that leads to dementia via advanced neuronal dysfunction and death. A person with Alzheimer’s disease suffers loss of control over thought, memory and language abilities. Additionally, the disease takes an emotional, social and economic toll on family members of individuals living with the disease. Alzheimer’s disease is also a burden for health care system in the U.S., with as many as 5 million Americans living with the disease in 2013, according to the U.S. Centers for Disease Control and Prevention, and that number is expected to continue rising.

Currently, the predominant theory behind Alzheimer’s disease is the “amyloid hypothesis,” which states that abnormally increased levels of amyloid beta (Aβ) peptides outside of brain cells produce a variety of low molecular weight Aβ aggregates that are toxic to the nervous system. These Aβ aggregates interact directly with target cells and lead to cell death.

During the Biophysical Society’s 61st Annual Meeting, being held Feb. 11-15, 2017, in New Orleans, Louisiana, Antonio De Maio, a professor of surgery and neuroscience at the University of California, San Diego (UCSD), will present his work hunting for the specific mechanisms behind Aβ-induced toxicity to cells, or cytoxicity.

Cells exposed to stressful conditions respond by expressing heat shock proteins (hsps), whose job is to preserve cell viability. Hsp70, in particular, is a molecular chaperone that plays a major role in protein folding and the solubilization of misfolded, aggregated polypeptide proteins inside cells.

The researchers were interested in Hsp70 because, according to De Maio, it has also been found outside of cells, potentially coexisting with Aβ peptides.
His team observed that HsP70 did, in fact, reduce oligomerization of Aβ peptides.

Significantly, the researchers further inferred that the reduced oligomerization of Aβ, where individual monomer molecules join to form a longer oligomer, might result in lower cellular toxicity, perhaps by blocking the assembly of Aβ ion channels. And in fact this is what they found, demonstrating a substantial reduction — approximately 70 percent — of Aβ peptide’s toxicity upon co-exposure to Hsp70.

“Based upon these observations, we predicted that inducing the extracellular release of Hsp70 might have a beneficial effect on Alzheimer’s disease,” said De Maio. “But it should be taken into consideration that we don’t know any potential long-term side effects of extracellular Hsp70 for human health.”

While extremely promising at this stage, “more investigations of the interface between Hsp70 and Aβ peptides are necessary for any further developments,” De Maio said.

Weston Brain Institute Funds Clinical Trials of New Alzheimer’s Treatment

Electrocranial stimulation offers hope for Alzheimer’s patients

Funding for clinical trials of a new treatment for Alzheimer’s disease has been announced by the Weston Brain Institute. Dr. Zahra Moussavi, Canada Research Chair in Biomedical Engineering in the Faculty of Engineering, is receiving $1,737,960 for her project on investigating the efficacy of high-frequency rTMS treatment for Alzheimer’s disease.

Alzheimer’s disease has no known cure and is called the pandemic of the century. Recent trials applying repetitive transcranial magnetic stimulation (rTMS) in Alzheimer’s patients have reported encouraging results in improving or stabilizing cognition. This proposal is the first large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in Alzheimer’s.

“The Weston Brain Institute is pleased to support this kind of critical high-risk, high-reward work,” said Alexandra Stewart, Executive Director at the Weston Brain Institute.

“If successful, Dr. Moussavi’s work with rTMS will be a significant step forward in developing effective treatments for Alzheimer’s disease,” Stewart said.

Moussavi will lead a team of local, national and international collaborators on this research that includes: Drs. Mandana Modirrousta (Psychiatry), Colleen Millikin (Clinical Health Psychology), Xikui Wang (Statistics), Behzad Mansouri (Neurology), and Craig Omelan (Psychiatry) in collaboration with colleagues from McGill (Montreal – Drs. Lesley Fellows and Lisa Koski) and Monash (Australia – Dr. Paul Fitzgerald) universities.

“All Manitobans will benefit from the research discoveries this funding will fuel,” says Dr. John (Jay) Doering, Associate Vice-President (Partnerships) at the University of Manitoba. “New treatments for Alzheimer’s disease are being sought worldwide. Dr. Moussavi’s research program will result in better quality of life for patients, families and caregivers.”

Transcranial Magnetic Stimulation (TMS) is a procedure in which a current passes through a coil placed on the scalp producing a magnetic field. The magnetic field passes through the skull to the brain, wherein a small current is induced. Application of repetitive(r) TMS at either low or high frequencies has been used for treatment of many neurological and neurodegenerative disorders but is still at the research stage in all except depression, for which rTMS is approved for treatment worldwide.

Genetic ‘Switch’ Identified As Potential Target For Alzheimer’S Disease

A team at the MRC Clinical Sciences Centre (CSC), based at Imperial College London, has found an important part of the machinery that switches on a gene known to protect against Alzheimer’s Disease.

Working in collaboration with scientists at the Hong Kong University (HKU) and the Erasmus University in Rotterdam, CSC associate professor Richard Festenstein explored the steps by which this Neuroglobin gene is gradually switched on, or up-regulated.

Neuroglobin has previously been shown to protect against Alzheimer’s disease in mice in which it makes the protective Neuroglobin. It is thought that the gene might play a protective role early in the disease in patients, but appears to be down-regulated as the disease progresses. It may therefore prove useful in developing new ways to try to prevent or treat this common cause of dementia, for which there is currently no cure.

Professor Festenstein and Dr Tan-Un from HKU, with help from Professor Sjaak Phillipsen at the Erasmus University, examined how the Neuroglobin gene ‘folds up’ in the cell using a technique called chromosome conformation capture. In results published today in the journal Nucleic Acids Research, they showed that a particular region of DNA, outside the coding region of the Neuroglobin gene itself, loops round to make contact with the start of the gene.

They tested the ability of this newly-identified DNA region to switch on the Neuroglobin gene using two approaches. First, they linked the DNA region directly to another so-called ‘reporter’ gene, and demonstrated simply that it does indeed act as an up-regulator. Second, they used the new ‘Crispr’ technique of gene editing to completely remove this section of DNA from the cell, and showed that the Neuroglobin gene was no longer switched on.

Together, the results gave the team confidence that this newly-identified DNA region is indeed a powerful switching mechanism of the Neuroglobin gene.

As Neuroglobin is thought to be protective in Alzheimer’s, it may be possible in the future to use this ‘switch’ in developing new treatments, such as gene therapy. Such therapeutic approaches require a compact ‘chunk’ of DNA to be most efficient. Importantly, the team pinpointed the position of the new regulatory region, and found that it is some distance away from the Neuroglobin gene itself. It may now be possible to remove the less relevant sections of DNA in between the Neuroglobin gene and its regulator to create an efficient therapeutic gene therapy unit. It may be that this target may prove useful not only in Alzheimer’s but also in other neurodegenerative diseases.

Vesicles That Trap Amyloid Appear to Also Contribute to Alzheimer’s Disease

Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer’s, appear to also contribute to the disease, scientists report.

Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition, scientists at the Medical College of Georgia at Augusta University report in The Journal of Neuroscience.

When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it, said Dr. Erhard Bieberich, neuroscientist in the MCG Department of Neuroscience and Regenerative Medicine and the study’s corresponding author.

“If you swarm astrocytes with amyloid, you trigger an aggressive response,” he said. Happy astrocytes, on the other hand, don’t make exosomes.

Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression, Bieberich said.

MCG scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer’s that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer’s. In fact, with disease, the brain has two to three times more of the lipid known for its skin-softening ability.

The MCG scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer’s. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing.

For reasons that are unclear, female mice did not reap similar benefits, said Bieberich, noting that Alzheimer’s tends to be more aggressive in women. His earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.

His new work is the first evidence that mice whose brain cells don’t make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer’s. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer’s therapy, Bieberich said. Current strategies to prevent plaque formation, have been unsuccessful, the researchers write.

“We show clearly that sphingomyelinase is causative here in making ceramide, making exosomes and in making plaques,” Bieberich said. He and his teams already are testing different drugs given to patients for reasons other than Alzheimer’s that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.

Inside the brain, ceramide is an important component of the cell membrane, but too much starts collecting in the exosomes, combining with the amyloid to form a disruptive and eventually deadly aggregate. In fact, MCG scientists could see the ceramide and amyloid clustered together in the brains of mice without sphingomyelinase suppression, further implicating a close association.

In a scenario that seems to go full circle, Bieberich has mounting evidence that in Alzheimer’s, there is a shorter, “bad” form of ceramide coating the antennae of astrocytes. Normally, antennae help astrocytes focus on taking care of neurons. But the shorter version that he believes contributes to disease has astrocytes giving up their caretaker role, spending their energy on themselves and starting to divide.

Bieberich and his team already are looking for other exosome triggers such as inflammation-producing immune cells called cytokines as well as physical trauma. Ceramide levels have been proposed as an early Alzheimer’s biomarker as has evidence of amyloid-positive exosomes in the blood.

Understanding How Chemical Changes in the Brain Affect Alzheimer’s Disease

A new study from Western University is helping to explain why the long-term use of common anticholinergic drugs used to treat conditions like allergies and overactive bladder lead to an increased risk of developing dementia later in life. The findings show that long-term suppression of the neurotransmitter acetylcholine – a target for anticholinergic drugs – results in dementia-like changes in the brain.

“There have been several epidemiological studies showing that people who use these drugs for a long period of time increase their risk of developing dementia,” said Marco Prado, PhD, a Scientist at the Robarts Research Institute and Professor in the departments of Physiology and Pharmacology and Anatomy & Cell Biology at Western’s Schulich School of Medicine & Dentistry. “So the question we asked is ‘why?'”

For this study, published in the journal Cerebral Cortex, the researchers used genetically modified mouse models to block acetylcholine in order to mimic the action of the drugs in the brain. Neurons that use acetylcholine are known to be affected in Alzheimer’s disease; and the researchers were able to show a causal relationship between blocking acetylcholine and Alzheimer’s-like pathology in mice.

“We hope that by understanding what is happening in the brain due to the loss of acetylcholine, we might be able to find new ways to decrease Alzheimer’s pathology,” said Prado.

Prado and his partner Dr. Vania Prado, DDS, PhD, along with PhD candidates Ben Kolisnyk and Mohammed Al-Onaizi, have shown that blocking acetylcholine-mediated signals in neurons causes a change in approximately 10 per cent of the Messenger RNAs in a region of the brain responsible for declarative memory. Messenger RNA encodes for specific amino acids which are the building blocks for proteins and several of the changes they uncovered in the brains of mutant mice are similar to those observed in Alzheimer’s disease.

“We demonstrated that in order to keep neurons healthy you need acetylcholine,” said Prado. “So if acetylcholine actions are suppressed, brain cells respond by drastically changing their messenger RNAs and when they age, they show signs of pathology that have many of the hallmarks of Alzheimer’s disease.” Importantly, by targeting one of the messenger RNA pathways they uncovered, the researchers improved pathology in the mutant mice.

The study, conducted at Western’s Robarts Research Institute, used human tissue samples to validate the mouse data and mouse models to show not only the physical changes in the brain, but also behavioral and memory changes. The researchers were able to show that long-term suppression of acetylcholine caused brain cell to die and as a consequence decrease memory in the aging mice.

“When the mutant mice were old, memory tasks they mastered at young age were almost impossible for them, whereas normal mice still performed well,” said Kolisnyk.

The researchers hope their findings will have an impact on reducing the burden of dementia by providing new ways to reverse the loss of acetylcholine.