On a sunny Spring afternoon at USC, I opened my dissertation defense with statistics and graphs illustrating the growing concern over the mounting number of people that would one day develop Alzheimer’s, coupled with unimaginable numbers that reflected the global economic burden of Alzheimer's and dementia. I suppose as any hopeful grad student, I thought a possible cure was in the near future. This was almost seven years ago - and today, I'm afraid we have not yet developed adequate therapeutics for this disease.
It was only several weeks ago that the pharmaceutical giant Eli Lilly announced the failure of their heralded breakthrough drug, solanezumab, targeted at breaking down the brain’s beta-amyloid plaques, a known hallmark of Alzheimer’s. Over the past decade, at least 244 compounds have been tested in Alzheimer’s clinical trials, with only one being approved by Food and Drug Administration (FDA). This represents a 99.6 percent failure rate. The vast majority of these trials were for therapies targeting the protein beta-amyloid. Maybe we’re barking up the wrong tree?
Protective Plaques
We tend to demonize things that are linked to a problem or disorder. But science isn’t cut and dry, and neither is it black and white. Take stress. Everyone balks at the horrors stress causes. In truth, unregulated responses to stressors are linked to a variety of maladies, but at the end of the day it is our response to stress, not stress itself that can be damaging. Stress, even inflammation, are biologically protective mechanisms. Perhaps plaque formation in the brain is as well. In researching the effects of sleep deprivation on neurodegenerative diseases, I came across an array of new studies linking brain infection to amyloid plaque formation. These findings suggest that beta amyloid possesses antimicrobial and antiviral powers, enough to categorize it as part of our own immune system’s efforts in battling invaders. What’s more, researchers recently presented intriguing findings that some elderly brains, despite being riddled with plaques and tangles, showed normal cognitive and memory function. Future drugs targeting this important protein need not wipe it out from our brains, especially as we’re still uncovering its functions.
Novel Therapeutics
One of the ways in which our brain removes plaques and general waste is through sleep. During sleep, the glymphatic system - a system akin to dams and rivers - flushes out the extracellular junk and clears the path for a new day of thinking, moving, breathing and everything else that requires consciousness. A novel way to prevent or even reverse the damage that leads to dementia and Alzheimer’s is to boost waste clearance (beyond getting those 8hrs each night). Researchers recently noted that aquaporin-4, a key component of the glymphatic system, appears disorganized in Alzheimer’s brains, pointing to a possible new area for therapeutics. Similarly, other investigators are using flashing lights to mobilize the immune system to clear these plaques. Flashing light at specific frequency and duration can trigger gamma waves, which then recruit a class of janitorial cells called microglia that help with the clean-up process (in mice). These approaches enhance the brain’s own waste clearance systems, rather than introduce a pharmaceutical that targets specific end-products, providing a fresh - and hopefully more successful - approach to dealing with neurodegenerative diseases.
From Autism to Alzheimer’s
There’s still hope in pharmaceuticals. Active research on elements so fundamental to our biology that they're implicated in health and illness, from neurodevelopment to neurodegeneration, are being targeted for their wide implications. One such process is the elemental calcium shuttling between and inside cells that often acts as a key to unlocking a variety of cellular functions. One special receptor, the sigma-1 receptor can regulate this intracellular calcium signaling, along with a host of other functions such as neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis. When its gene is mutated, devastation in the body occurs, in the form of ALS (remember the ice bucket challenge?). It’s also linked to a number of diseases including Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, stroke/ischemia, pain/neuropathic pain, and even Autism Spectrum Disorder. To top it off, the recently determined structure reveals it is a relatively ‘promiscuous’ one, meaning a variety of compounds can bind to it, no problem. It’s no wonder this is curious receptor is becoming increasingly researched as a therapeutic target. In fact, there are even clinical trials underway for potential therapies.
Perhaps a shotgun approach, rather than focusing on a single element, will allow next-generation drugs to make some real progress.
Today, finding adequate therapies for dementia and neurodegenerative diseases is even more pressing than when I was in grad school. The global cost of dementia alone has recently been estimated to be $818 billion. As the number of people living with Alzheimer's disease is expected to almost triple by 2050, the race is on to find a treatment that can prevent or slow the condition. The good news is, we may have the best weapon to prevent or reverse the damage in our own brain.