In a recent study published in the Journal of Alzheimer’s Disease, Biology Prof. George Bloom’s lab reveals how certain proteins in the brain play a key role in Alzheimer’s dementia.
Alzheimer’s disease, the most common type of progressive dementia, is the sixth leading cause of death in the United States according to the Alzheimer’s Association. Approximately 5.5 million Americans currently have Alzheimer’s, of which 5.3 million are age 65 and older while the other 200,000 are under 65 and have an early-onset version of the disease. This estimation doesn’t account for those with untreated Alzheimer’s.
Marked by memory loss, social withdrawal and disorientation with time and place, Alzheimer’s related deaths have increased by 89 percent since 2000. This is likely due to a lack of effective Alzheimer’s treatments as a result of insufficient research funding in the field, according to Sue Friedman, president and CEO of the Central and Western Virginia Chapter of the Alzheimer’s Association.
In the hope of developing improved treatment methods, Bloom’s lab, focused on Alzheimer’s research, has identified specific proteins — extracellular tau oligomers — that are able to convert originally functional neurons into those stricken by disease.
Tau is a microtubule protein found abundantly in neurons and comes in different forms — monomeric, oligomeric and filamentous. These proteins are principal constituents of neurofibrillary tangles, abnormal structures that accumulate in the brains of Alzheimer’s patients, Bloom said.
Many other labs have previously identified the effects of tau in tissue culture and proposed that aggregations of tau in the dendrites — tree-like branched extensions of nerve cells that receive and transmit information from neuron to neuron — can poison the gapped connection between neurons where cellular signals pass through, called synapses, ultimately inducing neuronal functional loss and death.
“Several labs, before we even got started doing this kind of research, showed that if you took cells, growing in liquid medium, that make their own tau, and you add soluble tau or short tau filaments into the medium, then that tau outside the cell in the medium could get taken up by cells — which then convert the ‘good tau’ inside those cells into misfolded, toxic, ‘bad tau,’” Bloom said.
Unlike previous studies, however, Bloom’s lab conducted experiments using neurons. The researchers cultured these brain cells in a medium — a solution containing nutrients to sustain cellular growth — and added monomeric, oligomeric or filamentous tau.
“What we found was, in general, that the tau oligomers in the medium were able to cause the tau inside the neurons to aggregate,” Bloom said. “The monomeric tau in the medium didn’t cause that at all, and the oligomers were much more effective than filaments at causing the intracellular tau to aggregate.”
Based on these empirical data — gathered mainly by Eric Swanson, the lead scientist and a recent University Ph.D. graduate — researchers revealed that the small aggregates of tau outside the neurons, called extracellular tau oligomers, cause intracellular tau to accumulate in axons — long and thin parts of neurons where cellular impulses are conducted — and invade dendrites, prompting brain cell failure.
Another point of discovery within the study examines tau’s role in microtubules, threadlike structures that act as highways for intracellular transport of various cellular components – known as “cargo” — including RNA, vesicles and mitochondria.
According to Bloom, as extracellular tau oligomers cause tau inside axons build up, the movement of cargoes along microtubules accelerates.
“The neuron is a very delicate little cell and the cargoes that are being moved along microtubules have to be delivered all along the length of the axon to replenish worn out parts of the axon,” Bloom said. “And by sort of hyper-activating this axonal transport, we think that maybe cargo delivery is biased towards the end of the axon instead of all along the length of axon. Over the course of time, or perhaps even very quickly, that would lead to deterioration of the axon and, by extension, the neuronic cell.”
Ultimately, Bloom hopes that these findings can lead to development of target therapies — treatments directed at reducing the amount of tau in the brain — for Alzheimer’s disease and possibly other forms of dementia as well.
Currently, there are four U.S. Food and Drug Administration (FDA) approved medications for Alzheimer’s disease — Aricept, Exelon, Razadyne and Namenda. Present treatments do not offer a “cure” for the progressive dementia, University geriatrician Dr. Laurie Archbald-Pannone said. Rather, such drugs may temporarily reduce symptoms, such as memory loss and mental disorientation, according to Friedman.
“The drugs are all band-aids in the sense that when they work — and they don’t always work — they simply relieve the symptoms,” Bloom said. “And usually, that relief is pretty modest and temporary. These drugs relieve symptoms by taking synapses, which are connections between neurons as part of the brain circuitry, that are in the process of failing and let them work a little bit better for a little longer than they might otherwise.”
Archbald-Pannone and Friedman both convey the necessity of better treatment alternatives not only for the benefit of Alzheimer’s patients but also for their family members and caregivers.
“We’re spending more than a quarter of a trillion dollars in 2017 — government money — to try to support the people with Alzheimer’s disease because we don’t have proper treatment,” Friedman said. “So all we can do is maintain, support the people who have the disease and, most importantly, those who are trying to take care of them — whether they are in a long-term care facility and working a job to take care of Alzheimer’s patients, or, more likely, they are at home trying to take care of grandma, grandpa, aunt, uncle, husband or wife.”
Friedman said the impact that target therapies, potentially advanced by Alzheimer’s research studies like those of Bloom’s lab, could have on the future of Alzheimer’s treatment.
“It would be groundbreaking, because right now there is nothing that can stop or even delay the progression of the disease — certainly no cure, no prevention,” Friedman said. “Anything of the target treatment nature would be truly, truly groundbreaking.”
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