Alzheimer’s disease is growing in Canada at an unprecedented rate. At the moment, over half a million people suffer from this debilitating condition but that number is expected to nearly double over the next generation. The effects of this illness are tragic, such as memory loss as well as changes in behaviour, judgement, and normal daily function. For this reason, understanding this disease and finding meaningful treatments are considered a priority.
As Alzheimer’s progresses, a protein, known as amyloid-β, begins to clump together, forming what is officially called a plaque. As this happens, the neurological landscape changes as neurons begin to die off. Despite decades of research, the mechanism behind this loss remains, for the most part, a mystery.
Over the years, researchers have taken a closer look at amyloid- β and have revealed some potential warning signs. The different cell types, including neurons as well as microglia and astrocytes, appear to act differently when near a plaque. They also appear to be hyperactive, suggesting the microenvironment may be toxic. Yet, whether this contributes to the loss of neurons has yet to be shown.
Now the proof may be at hand thanks to a group at the University of British Columbia led by Dr. Brian MacVicar. His team ventured into the area around amyloid-β in search of mechanisms responsible for cell death. Their results, published in the journal Nature Communications, reveal one particular molecule may act as a lynchpin. Perhaps more importantly, this molecule, known as a glutamate transporter, or GLT-1, may be a target for treatment using already approved medications.
The team worked with a special type of mouse, known as APPPS1, which stands for amyloid precursor protein and mutant human presenilin-1. This mouse is unique as it makes the human forms of the components needed to form amyloid- β. As the animal ages, a similar progression to Alzheimer’s occurs, allowing researchers to track the molecular dynamics of disease.
The method for testing was rather straightforward. The mice were injected with a molecule called the intensity-based glutamate-sensing fluorescent reporter, more commonly called iGluSnFR. As the name implies, when the molecule encounters an amino acid, known as glutamate, it glows. The mice were then observed using a specialized microscope, which was designed to track changes in glutamate levels in real time.
The choice of glutamate as a marker was not a random choice. For well over a decade, researchers have known glutamate movement in the brain is an important indicator of cellular health. Glutamate regularly moves out of cells as it is used at the synapse during neuronal communication in the brain. The key to these dynamics is the protein that moves the molecule back into cells. This is GLT-1.
When brain cells are healthy, GLT-1 is in ample supply and neuronal communication using glutamate is controlled because cells take back the glutamate to prevent overexcitation. However, when GLT-1 disappears, glutamate is prolonged leading to uncontrolled activity similar to the positive feedback noise from an amplifier. This is a bad sign of the cell as not long after, death inevitably follows. For the team, the loss of GLT-1 in cells near the amyloid- β would confirm cells in that region are destined to die.
As expected, when the tests were run, cells around those amyloid-β deposits had less GLT-1 activity. This meant the cells in the region were suffering from a toxic environment and neurons eventually would face an untimely death. For the researchers, this helped to prove amyloid- β was indeed toxic and causing cell death.
While this evidence alone was noteworthy, for the team, it only represented the first step. The next involved trying to restore GLT-1 levels in the hopes of counteracting the effects of amyloid- β. To do this, they relied on a decade-old approach to protect the brain using antibiotics.
Although most people view antibiotics solely as bacterial killers, these chemicals also have the ability to change the dynamics of our own bodily systems. One particular drug, ceftriaxone, can single-handedly increase the levels of GLT-1 in the nervous system. For MacVicar’s team, this offered a perfect opportunity to see if they could reverse the effects of amyloid- β.
When the mice were given the antibiotic, the results were remarkable. The drug did exactly as expected and began to raise the GLT-1 levels. As this happened, the toxic effects of the area decreased. Glutamate went back to its usual dynamics and the cells regained – at least for a short period of time – some respite against the toxic environment.
For the authors, the results provide a real link between the formation of amyloid- β and cell death in the surrounding region. As expected, the lynchpin in this study is GLT-1, suggesting this protein may be considered a priority in understanding disease progression. Perhaps more importantly, the identification of GLT-1 offers hope for treatment in the future.
While ceftriaxone is not currently being used for Alzheimer’s treatment, the potential for its use appears to be strong. This study may invigorate researchers to find ways to use this antibiotic as part of combination therapy. While this is not a cure, new management strategies may be developed to help those hundreds of thousands of Canadians suffering to manage their symptoms as they await a cure.
Read the original research article:
Hefendehl JK, LeDue J, Ko RW, Mahler J, Murphy TH, MacVicar BA. Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat Commun. 2016 Nov 11;7:13441. doi: 10.1038/ncomms13441.