By Calvin J.
I was completely blown away in a storm of tears and emotion after watching the critically acclaimed film, “Still Alice”. For those who haven’t seen and/or heard of it (don’t worry, I was on that same boat just a couple days ago), the story follows linguist Dr. Alice Howland (played by Oscar winner, Julianne Moore) as she discovers and eventually deteriorates from early-onset Alzheimer’s. As the title suggests, the film deals with not only her own struggle to reclaim her identity as the disease progresses, but also her family’s attempt to endure and reconcile this confused, frail and vulnerable Alice, with the sharp-witted and independent woman she once was.
The story was particularly emotional for me not only because of Julianne Moore’s powerhouse performance (she really did deserve that Oscar win), but also because my grandmother was diagnosed with Alzheimer’s disease several years ago. I see in Alice’s story the same heart-wrenching pain I felt watching my sweet and charming grandmother transform into someone I can now barely recognize. But behind the tears the film was also a clear reminder for me the important research thousands of scientists perform everyday to pull us closer and closer to a better understanding of this cruel, unforgiving disease and the eventual cure for it.
Still Searching for the Cause
Characterized by a decline in short-term memory as well as a number of other symptoms (problems sleeping, mood swings, disorientation etc). Over 5 million individuals in America alone live with Alzheimer’s disease. But despite it being identified in 1906 by Dr. Alois Alzheimer over a century ago, its complex pathogenesis and exact cause is still baffling to researchers today. One of the major models that have dominated and driven Alzheimer’s research is the AMYLOID HYPOTHESIS. In simple terms, the hypothesis postulates that the major cause of Alzheimer’s and its associated gradual mental deterioration is driven by the accumulation of protein fragments called, amyloid-β. Amyloid-β is produced and released outside of neurons (brain cells) when the amyloid precursor protein (APP) is cleaved or cut by specific enzymes. The amyloid-β product then accumulate overtime outside of neurons, aggregate inside the brain and leads to the formation of amyloid plaques, a hallmark of the disease. Alongside the plaques, we also often find the formation of neurofibrillary tangles inside the neurons themselves. These tangles are formed by the accumulation of Tau proteins (Tau normally function as components of microtubules, a major skeletal network in healthy cells). Its believed that the formation of these plaques and tangles damage neurons, impede their communication and signalling, gradually leading to cell death and a reduction in brain tissue. But how these two phenomenons are linked, how they arise and which one is the “major driver” of Alzheimer’s disease remain heavily debated within the field. However, what I find even more interesting than the amyloid-β vs Tau debate, has been some of the NEW potential causes of Alzheimers proposed within the last couple years.
What is this exciting NEW hypothesis? VIRUSES!!! In an editorial published just earlier this year in the Journal of Alzheimer’s Disease, a number of scientists are urging researchers to further explore potential links between viral infection and the development of Alzheimers. Soscia et al., (2010) have shown that these amyloid plaques formed during the progression of the disease actually has anti-microbial properties. This lead the research team to postulate that perhaps the production of excessive amyloid-β may be our body’s imperfect attempt at responding to chronic infections. Similarly, Hickman et al., (2008) found that chronic inflammatory signalling of microglial cells (our brain’s clean up crew and key players in immune defence) can lead to a dysfunction in the clearance of amyloid-β, leading to accumulation and plaque formation. Could it be possible that the progression of Alzheimer’s be caused by infections and chronic inflammation in the brain?
Well, its been previously shown that having a specific variant of the APOE gene (APOE ε4) increased an individual’s chance of developing Alzheimer’s. However, scientists have since observed that person with the same gene variant who ALSO became infected with the herpes simplex virus – type 1 (HSV-1; the same virus that causes cold sores and genital herpes) showed an even higher chance of developing Alzheimer’s (~12 times more likely). In mouse models, they found that mice carrying the APOE ε4 variant had higher viral loads when infected with HSV-1 (more viral DNA was produced) and also exhibited accumulation of amyloid plaques. But what we see in mice models might not necessarily be whats happening actual human brains, and we can’t go around cutting up people’s brains looking for HSV-1 for obvious ethical reasons.
Still Searching for the Cure
So what does this mean, well obvious a lot more research still needs to be done but how we understand the development of a disease really shapes how we can begin to treat it. If Alzheimer’s really does have a link to viruses, one way of preventing Alzheimer’s may soon involve vaccinations against these specific pathogens. Similarly, doctors may be able to treat or prevent progression of the disease using anti-virals or even anti-inflammatory drugs.
More traditional approaches have been to target the production and or clearance of amyloid-β in the brain. There has been a lot of research done in the development of Aducanumab, an antibody that targets aggregated amyloid-β to reduce neurotoxicity and encourage clearance. Results from the phase 1 trial yielded strong positive results, with increasing dosage leading to increased reduction in amyloid-β in the brain. Phase 3 clinical trials remain ongoing.
Using a different approach, an Australian research group has been looking into non-invasive ultrasound technology to promote clearance of amyloid plaques in the brain. Using focused therapeutic ultrasound they were able to stimulate the brain’s microglial cells to remove accumulated amyloid-β. When tested on mouse models the team found that 75% of mice responded positively to treatment and were able to dramatically clear amyloid plaques. The mice also showed improvement in basic memory tasks.
So despite the film being only 2 years old, there has been many great leaps and many small victories in Alzheimer’s research. Obviously a lot more work has to be done in this uphill battle, but only as we begin to better understand how a disease works are we able to imagine and develop new methods to tackle it! So that one day, it’ll be Alzheimer’s itself that will be forgotten.
PS. For those who haven’t seen Still Alice, I honestly do highly recommend it! Give it a watch and let me know what you think down below!
The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics
The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide.
Alzheimer’s disease: the amyloid hypothesis on trial
Controversial New Push to Tie Microbes to Alzheimer’s Disease
Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease http://www.nature.com/nature/journal/v537/n7618/full/nature19323.html
Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model