Giulio Taglialatela, Ph.D.
Associate Professor of Neuroscience and Cell Biology, University of Texas Medical Branch, recipient of a 2008 Investigator-Initiated Research Grant
In his own words, investigator Dr. Giulio Taglialatela, describes his research and what receiving Association funding has meant to his career.
My interest in understanding the molecular and cellular events underlying the demise of nerve cells in the healthy or debilitated brain as it ages has been lifelong. Formally, it began during my graduate training at the Institute of Pharmacology of the University of Rome ‘La Sapienza' in Italy. I still remember the words from my mentor that set the stage for my scientific career. On one of those long-ago Roman days, I was excitedly reporting about an experiment we had conducted in which the lifespans of extremely old laboratory animals were extended. My mentor quickly dampened my enthusiasm with a grave look and a sage warning: ‘Why add years to later life, rather than add life to later years?'
Impact of Association funding
"This project could only be funded by an organization that would take a calculated risk to support a novel idea. And that is why we turned our attention and hope to the research grants program of the Alzheimer's Association."
This simple notion elegantly describes the challenge faced by hundreds of scientists through several decades of research for a cure for Alzheimer's disease. Indeed, the most devastating aspect of Alzheimer's is the individual's gradual loss of cognitive function, slowly chipping away at the faces, places and memories familiar to them. No one knows if halting or even reversing this cognitive decline may extend the individual's life, but certainly it would be a formidable step toward assuring quality life in one's later years. With this goal in mind, my research focuses on identifying mechanisms of nerve cell malfunction in the early stages of Alzheimer's that are responsible for the initial changes in mental function. The hope is that once detrimental processes are identified, they could be corrected with medications.
Role of beta-amyloid aggregates
Perhaps the best characterized physical feature of brains afflicted with Alzheimer's disease is the conspicuous presence of amyloid plaques formed by aggregates (fibrils) of individual units of the protein beta-amyloid. Although recognized for many years as a hallmark of Alzheimer's, it was found that the number of amyloid plaques on autopsy in individuals with Alzheimer's did not correlate with the disease severity. Instead, the levels of much smaller aggregates of beta-amyloid (oligomers) that precede the development of large fibrils and plaque formation were directly associated with disease severity. This indicated that beta-amyloid oligomers rather than later-formed fibrils may be the main offender in Alzheimer's disease. Significantly, other studies found that beta-amyloid oligomers injected directly into the brains of healthy laboratory rodents produced severe memory deficits without inducing the death of brain cells, thus suggesting that beta-amyloid oligomers may trigger cognitive impairment through disturbing neuron function. As such, their effect on memory may be reversible if the cellular mechanisms involved are better understood.
Calcineurin inhibition: A novel treatment?
While these seminal observations sparked a wealth of research aimed at characterizing beta-amyloid oligomers, we discovered that the levels of calcineurin, an enzyme that impedes memory formation, were elevated in the brains of mice genetically altered to produce human beta-amyloid. Elevated levels of calcineurin, the appearance of beta-amyloid oligomers, and memory deficits were present simultaneously in these mice, but months before the appearance of amyloid plaques. Most important, when we treated these cognitively impaired mice with a drug that inhibits calcineurin, their memory was restored. Could that indicate that calcineurin initiated the memory deficits associated with beta-amyloid oligomers in these genetically altered mice? And if so, could drugs that inhibit calcineurin stop or reverse this process?
Our initial results using artificial beta-amyloid oligomers published in 2008 in the journal Aging Cell were highly encouraging and suggested that calcineurin inhibition should be further explored as a way to alleviate cognitive impairment in the early stages of Alzheimer's. However, proof that the presence of beta-amyloid oligomers in the brain caused calcineurin-induced memory changes was needed to push this particular field forward. This project could only be funded by an organization that would take a calculated risk to support a novel idea. And that is why we turned our attention and hope to the research grants program of the Alzheimer's Association.
To our excitement, although not entirely surprisingly considering the long-standing track record of the Alzheimer's Association for supporting the development of innovative research, our grant application was funded in July 2008. Experimental work begun shortly thereafter, only to be abruptly stopped on September 13th, 2008, when Hurricane Ike hit Galveston Island and our campus with unprecedented devastating force. However, sometimes disasters change things in unexpected ways.
In August 2008 an influential paper was published in the journal Science by the group led by Dr. Dennis Selkoe at Harvard Medical School. This work illustrated that beta-amyloid oligomers extracted directly from autopsied brain tissue disturbed electrical activity in neurons and disrupted memory when injected into the brains of laboratory animals. While these authors did not specifically address the mechanism involved, their results fit our hypothesis and previous rodent data like a glove. Indeed, calcineurin has been known for many years to be intimately involved in regulating neuron electrical activity (the cellular basis of memory) and memory itself. Dr. Selkoe's work further suggested to us that we could take a leap forward and directly test beta-amyloid oligomers in donated human brains (rather than mice).
As a result of this new exciting evidence, and supported through the difficult months following the storm by the long-sighted generosity of the Alzheimer's Association, we secured a steady supply of Alzheimer's brain samples from two reputable national brain banks and began isolating the infamous beta-amyloid oligomers, an effort which is still under way. We also performed a wealth of biochemical analyses on these human brains that revealed signs of calcineurin over-activation similar to what we observed in the brains of genetically altered mice that express human beta-amyloid. This suggested that our hypothesis regarding what happens when beta-amyloid oligomers are present to cause toxic effects on neurons may be on target and that the elevated levels of calcineurin we found may in fact play a role in the disease.
We truly hope that achieving the goals of this project will thrust forward the novel concept of inhibition of calcineurin as a strategy to slow or halt the disruption of cognitive function in people with early to mid-stage Alzheimer's disease.
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