Energy storehouses in the brain may be source of Alzheimer’s, targets of new therapy

Alzheimer’s disease, a severely debilitating and ultimately fatal brain disorder, affects millions worldwide. To date, clinical efforts to find a cure or adequate treatment have met with dispiriting failure.

The disease is now on an ominous course of expansion, due in part to an aging population, and is poised to become a global health emergency. The enigmatic ailment—first described over 100 years ago—remains the only leading killer without effective treatment, prevention or cure.

In a new study, researchers at the ASU-Banner Neurodegenerative Disease Research Center examine the effects of the disease on the functioning of mitochondria—structures performing a variety of essential tasks, including supplying cells with energy.

The new research reveals that a highly toxic form of beta amyloid protein— known as oligomeric a-beta (OAβ)—disrupts the normal functioning of mitochondria. The result is a fateful cascade of events that appears early in the development of Alzheimer’s disease—decades before the onset of clinical symptoms.

The most promising finding in the new study is that human neuronal cells can be protected from OAβ-induced deterioration of their mitochondria when they are pre-treated with a custom-designed compound, suggesting an exciting avenue for future drug targeting.

"Mitochondria are the major source of energy in brain cells and deficiencies in energy metabolism have been shown to be one of the earliest events in Alzheimer’s disease pathobiology. This study reinforces the toxicity of oligomeric amyloid beta on neuronal mitochondria and stresses the importance for protective compounds to protect the mitochondria from oligomeric amyloid beta toxicity," said Diego Mastroeni, a lead author of the new study.

The research findings appear in "Oligomeric Amyloid Beta Preferentially Targets Neuronal and Not Glial Mitochondrial Encoded mRNAs," made available online by Alzheimer's & Dementia: The Journal of the Alzheimer's Association as an article in press corrected proof.

Mind out of step

Alzheimer's disease, a disorder characterized by severe memory loss, is the most common form of dementia. Most AD cases occur sporadically, with advancing age posing the greatest risk for the disease. Inheritance of certain disease-related genes can also enhance an individual’s susceptibility, though familial AD represents the minority of AD cases.

Two pathological hallmarks are observed in AD brains at autopsy: intracellular neurofibrillary tangles and extracellular senile plaques, which tend to occur in the neocortex, hippocampus, and other subcortical regions crucial for cognitive function. These observations have led to a dominant theory of Alzheimer’s causality, known as the amyloid hypothesis.

The theory points to accumulations of the sticky protein substance amyloid beta as the critical factor initiating the chain of events leading to development of Alzheimer’s disease. While the amyloid hypothesis continues to exert a considerable hold on the field, an increasing consensus among researchers is moving away from the idea of amyloid beta accumulation as the primary event that sets the disease in motion. The new study focuses on mitochondria, which are currently under intense investigation for their early role in AD pathology.

Cells under assault

Alzheimer’s appears to selectively target neurons for destruction and those found in the hippocampus—an area of the brain associated with memory—appear to be particularly vulnerable. 

In the new study, cells known as pyramidal neurons, extracted from the hippocampus of patients who died of Alzheimer’s, display a marked reduction in the expression of a suite mitochondrial genes, pointing to their degradation by OAβ. The reduction of mitochondrial gene expression was also seen when cells belonging to a human neuroblastoma cell line were exposed to OAβ.

The authors stress that not all types of nervous system cells are implicated in the mitochondrial dysfunction brought on by exposure to OAβ. Hippocampal astrocyte and microglia cells taken from the same AD-afflicted brains did not display reduced mitochondrial function. (Astrocytes and microglia perform supportive functions in the nervous system, including the supply of nutrients, maintenance of chemical balance and cerebral repair following injury.)

Amyloid theory and its discontents

One problem with the amyloid theory of Alzheimer’s disease is its inconsistency. Researchers have reported that some elderly patients, bearing heavy burdens of amyloid plaque in their brains, lack any measurable cognitive deficit, while other patients showing little to no amyloid buildup nevertheless display severe Alzheimer’s-like dementia.

Most damning, a raft of amyloid targeting drugs developed to treat Alzheimer’s have failed to provide any benefit to patients in clinical trials or arrest the inexorable cognitive decline brought on by the disease. It is increasingly apparent that plaques and tangles are late-comers in the devastating sequence of events culminating in Alzheimer’s dementia.

These facts have led researchers to seek other processes occurring at the earliest stages, which may kick the disease into gear. One of the most promising avenues of new research is the mitochondrial cascade hypothesis, which places these energy-delivering powerhouses of the cell at the center of the action.

The hypothesis suggests that mitochondrial function, which declines as a natural feature of aging, may be further impaired in the presence of amyloid beta, in particular, OAb, which is formed from the successive buildup of individual units of Ab. (A million or more individual Ab units may be present in the amyloid plaques that are, along with neurofibrillary tangles, central hallmarks of the disease.) The fact that severe metabolic deficit appears as a prominent feature of AD further implicates energy-delivering mitochondria as likely culprits in the early disease process. 

Energy hog

Although the human brain represents only 2 percent of the body’s weight, it accounts for a full 20 percent of the body’s total oxygen consumption. This energy requirement is largely driven by the needs of the brain’s forest of neurons, which require prodigious amounts of energy for their electrochemical signaling. The brain’s intense thirst for energy is continuous; even brief periods of oxygen or glucose deprivation result in neuronal death.

Brain cells fulfil most of their energy needs thanks to the power plants residing in the cell’s cytoplasm—the mitochondria, which supply this energy in the form of ATP. In addition to serving as subcellular organelles essential for generating the energy powering normal cell function, mitochondria also monitor cellular health, and—when necessary—initiate programmed cell death or apoptosis. 

Mitochondria however are vulnerable to various forms of decline and degradation. One of the major factors leading to their disruption is a process known as oxidative stress. This results from a disturbance in the balance between the production of reactive oxygen species, known as free radicals, and a cell’s antioxidant defenses.

When anti-oxidant mechanisms can no longer keep pace with the production of reactive oxygen species, mitochondrial gene expression becomes impaired. Oxidative damage is known to occur long before Aβ plaque formation, pointing to mitochondrial dysfunction and oxidative stress in AD as very early players in the disease process.

Lines of evidence

In the new study, researchers compared hippocampal neurons, astrocytes and microglia from AD brains. They used laser capture microdissection, a technique allowing the identification and isolation of each particular cell type, yielding a much more accurate picture of the alterations imposed on specific cell types by the disease. (Traditional methods use brain tissue homogenates containing a mixture of cell types, thereby erasing cell-specific data.)

In complimentary experiments, the group used human neuroblastoma cells exposed to OAβ. Compared with AD neurons, the neuroblastoma cells showed a similar reduction in the expression of specific mitochondrial-encoded genes—strong circumstantial support for OAβ’s injurious effects on mitochondria.

The overlapping effects on gene expression clearly seen in both the AD and OAβ-treated neuroblastoma cells point to OAβ’s selective assault on the nervous system’s energy supply, opening the door for targeted therapy.

In subsequent experiments, human cells were pre-treated in the lab with an analog of CoQ₁₀, (a structural compound capable of boosting ATP production and limiting oxidative stress), prior to exposure to OAβ. The compound, which was designed by study co-author and Biodesign researcher Sidney Hecht, acted to protect cells from the degradation normally caused to mitochondrial function from OAβ, offering renewed hope for effective treatment.

The study further establishes mitochondrial deficit caused by exposure to OAβ as a highly promising avenue for further research in the ongoing battle against this devastating illness.

News credit: richard harth
News source: www.biodesign.asu.edu

Researchers connect two important signalling pathways in cancer and ageing for the first time

The structure of proteins that protect telomeres (shelterin proteins, from "protective shield") are promising targets to combat cancer, but to date, there has been no effective form for attacking them. In the absence of drugs that destroy telomeres, cancer retains one of its most terrible properties, which is the ability of its cells to divide perpetually. Two years ago, a research group led by Maria A. Blasco at the Spanish National Cancer Research Centre (CNIO) hit upon several compounds that caused injury to these protective chromosome structures and now, in a study published in Nature Communications, they show that these drugs achieve this effect by acting on PI3K, a key protein in cancer and ageing. This is the first time that a functional link has been described between this pathway and the telomeres.

 

For years the Telomeres and Telomerase Group has been investigating pathways to attack telomeres as a form of blocking cancer cell division and causing their death. In a study published in 2015, they described a new strategy to achieve this objective after telomerase inhibitors had failed; telomerase is an enzyme that is necessary for lengthening telomeres, but its inhibition does not have immediate effects on the destruction of telomeres.

"The idea was to look for drugs that were able to reduce levels of TRF1, one of the essential shelterin proteins for the integrity of telomeres," said Blasco. "We found several that, when administered, caused damage in these structures, and this led to the cancer cells not being able to divide, but we did not know what their precise target was."

Removal of telomere protection

In this study, Blasco, together with Paula Martínez and Marinela Méndez-Pertuz (first authors in the paper), proposed the hypothesis that the reduction of TRF1 was due to the action of PI3K, since the compounds developed at CNIO belong to a previously identified series, namely PI3K inhibitors. This molecule forms part of a key pathway in ageing (the first to be identified), described by Cynthia Kenyon thanks to her studies with C. elegans. Likewise, PI3K is one of the most mutated proteins in cancer.

Upon administration of these chemical compounds, the investigators observed that TRF1 levels were reduced and, in addition, the action of PI3K was inhibited, but they did not know if there was a connection or what it could be. This is where another component of the PI3K pathway called AKT comes into play. Under normal conditions, one of the functions of PI3K is to modify AKT, activating it by phosphorylation. However, this reaction does not occur in the presence of PI3K inhibitors.

"We then studied whether AKT modified TRF1 in any way and we saw, through different experiments, that this was indeed the case," said Blasco. "AKT also modified TRF1 by phosphorylation." By blocking PI3K, these phosphorylation reactions were blocked and TRF1 lost stability, its half-life was shortened, and it bound less to the telomere, which was left unprotected.

This finding could have implications in the management of tumours that present PI3K mutations and that are being treated with PI3K inhibitors. In Avatar or PDX mice, Blasco and collaborators determined that the response to treatment with PI3K inhibitors is related to the reduction in the levels of TRF1. In light of these results, it seems that the antitumour activity of PI3K inhibitors depends on their action on TRF1. Therefore, there is reason to believe that those patients who develop resistance to these drugs could benefit from treatment with other TRF1 inhibitors. This is the next step.

News source: www.medicalxpress.com

Targeting mitochondria in pulmonary hypertension

Pulmonary Arterial Hypertension (PAH) is a debilitating disease of the lung blood vessels that causes heart failure and early death, affecting hundreds of thousands of patients worldwide. Available therapies fail to prolong life, despite costs that may exceed $200,000/patient per year. A team of investigators at the University of Alberta (Edmonton, Canada), and the Imperial College of Medicine (London, UK), reported promising results of an early-phase clinical trial with a novel drug in PAH patients, already under treatment with approved drugs.

 

In this week's issue of Science Translational Medicine, the investigators showed that the generic drug, Dichloroacetate (DCA), can decrease the blood pressure in the lungs of PAH patients and improve their ability to walk, without significant side effects at the doses tested.

DCA works by activating mitochondria, the energy-producing units of the cell, which also regulate the cell's fate (i.e., whether the cell can grow or die by self-destruction), a process called apoptosis. Mitochondrial function is suppressed in PAH. This allows the cells lining the lumen of lung vessels to grow and avoid apoptosis. The resulting overgrowth of cells narrows the lumen of vessel, making the heart work harder to push blood through for oxygenation. This overgrowth of cells resembles the growth of cancer cells, where mitochondrial function is also suppressed and DCA has shown promise as a potential cancer treatment.

The investigators also studied lungs from PAH patients removed at transplant surgery. They were able to keep them alive for a few hours by connecting them to a respirator and perfusing them with nutrients, with or without DCA. They showed that the molecular target of DCA (a mitochondrial enzyme called Pyruvate Dehydrogenase Kinase or PDK) was higher in the lungs of PAH patients compared to lungs that do not have the disease, and that DCA effectively inhibits the enzyme, increasing mitochondrial function. In addition to measuring the pressures on the patient lungs in the clinical trial, the investigators used positron emission tomography and computed tomography (PET-CT) and showed that the patients' lung metabolism improved, due to increased mitochondrial lungs, much like in the explanted lungs. "This is the first time that a drug targeting mitochondria is shown to be effective in patients with PAH" said Dr. Evangelos Michelakis, the study's co-lead.

While no patient worsened, some patients (and some lungs) simply did not respond to DCA. The investigators showed that in these patients, the presence of two gene variants (single nucleotide polymorphisms) encoding two mitochondrial proteins were causing a mitochondrial suppression that was unrelated to PDK and thus not responsive to DCA. "This is a great example of precision medicine, where the patients' genes can be used to predict the effectiveness of a drug in a particular patient," said Dr. Martin Wilkins, the study's co-lead. "This work will be important for the design of future trials with DCA (or other mitochondrial activators). We would spare patients carrying these two gene variants from recruitment to a study from which they may not benefit, allowing them to enroll in other studies. By focusing on patients that have a greater chance of improvement, we can increase the efficiency and decrease the cost of trials," said Wilkins.

 

"Another important aspect of the study is that DCA is a generic drug, and thus the study was not sponsored by a pharmaceutical company, but from public funds and donations. This means that if future studies confirm our results and show a clear and definitive benefit of DCA in PAH, we may have an affordable, cheap treatment available to all," said Michelakis.

News source: www.medicalxpress.com

Why fathers don't pass on mitochondria to offspring

Offering insights into a long-standing and mysterious bias in biology, a new study reveals how and why mitochondria are only passed on through a mother's egg -- and not the father's sperm. What's more, experiments from the study show that when paternal mitochondria persist for longer than they should during development, the embryo is at greater risk of lethality.