BrightFocus-Funded Research into AD Spread
Many current and former Alzheimer’s Disease Research (ADR) grantees are looking into possible explanations of how Alzheimer’s disease (AD) starts and possibly spreads to different regions of the brain through misfolded protein particles, which are variously called “prions” or “prion-like particles” or “seeds.”
In 1997, Stanley Prusiner, MD, at the University of California, San Francisco (UCSF), won the Nobel Prize in Physiology/Medicine “for his discovery of Prions – a new biological principle of infection.” About a decade earlier, his career and investigation into these contaminant particles was boosted by BrightFocus ADR grant funding to develop his prion theory as a model for AD.
Now an honorary board member of BrightFocus Foundation, Dr. Prusiner’s research into prions continues today. In addition, the following individuals have received ADR grants to investigate the spread of AD in this manner:
Jiri Safar, MD (Case Western, ADR 2016-19)
Stephen Strittmatter, MD, PhD (Yale, ADR 2013-16)
David Harris, MD, PhD (Boston University, ADR 2013-16)
Peter Tessier, PhD (Rensselaer Polytechnic Institute, ADR 2011-14)
Marc Diamond, MD (ADR 2010-13 and mentor to ADR grantee Kristen Funk, PhD ADR 2014-16, both at Washington University in St. Louis). Dr. Diamond is now at the University of Texas Southwestern Medical Center.
A research team at University College London (UCL) recently published results of experiments that provide the first causal evidence that amyloid-beta (Aβ) pathology may have been transmitted between humans through a contaminated growth hormone injection in the 1980s.
Scary as it may sound, the study by Purro et al published in Nature provided no immediate cause for alarm.
“Although we generated evidence that Alzheimer’s pathology may be transmissible, there is no suggestion, in our work or in anyone else’s, that Alzheimer’s disease is contagious,” commented the lead scientist on the project, John Collinge, MD, in a press conference covered by the UK’s Guardian newspaper. “You can’t catch it with intimate contact as a carer or a loved one of someone with Alzheimer’s. It is only transmitted as a result of a particular medical procedure.” Collinge led the investigation at UCL and was senior author on the Nature report.
In that same issue of Nature, David Holtzman, MD, chairman of Neurology at Washington University School of Medicine in St. Louis, and Tien-Phat V. Huynh, PhD, a student there, published a News & Views article that commented on the findings. Dr. Holtzman chairs the BrightFocus Alzheimer’s Disease Research (ADR) Scientific Review Committee.
In that article, they remind that there are universal standard precautions in place during surgery and medical procedures to protect against the possible spread of Aβ “seeds” or any other potential biological contaminants through cross-contamination of instruments. These universal precautions are likely to be effective against the threat of AD transmission through “seeding,” and yet they may need to be reemphasized, they advised.
“It is crucial that surgical instruments that come into contact with the human brain are appropriately treated to remove seeds of misfolded forms of peptides and proteins,” the authors wrote.
The Back Story
In 2015, Collinge et al published their findings of the only known cases of suspected AD transmission in humans (Jaunmuktane et al, Nature, 2015). These cases involve individuals who, as children, were treated with a type of growth hormone made from large amounts of pooled donor tissue, eg, pituitary glands removed from human cadavers. That cadaver-derived growth hormone (c-hGH) was used from 1958-85, and discontinued when it was linked to a brain-wasting disease in humans known Creutzfeldt-Jakob disease (CJD). Similar to mad cow disease, CJD is transmitted through contaminated protein fragments known as prions. Because of the risk it might contain prions, C-hGH was replaced in the mid-80s with a synthetically-derived growth hormone that is still in use today.
Since then, for several decades now, scientists have been tracking individuals who received c-hGH because of their risk of developing CJD. Then, in 2015, came the startling discovery by Collinge and colleagues that there may be another potential hazard connected to the long-since discontinued use of c-hGH. Findings from brain autopsies revealed that in a fraction of individuals who had received impure c-hGH, amyloid-beta (Aβ) plaques had formed near neurons and also were lining the walls of brain blood vessels and compromising blood flow (a condition known as cerebral amyloid angiopathy, or CAA). Aβ plaques and CAA are linked with AD and neurodegeneration.
That discovery gave rise to speculation about Aβ “seeding,” ie, that c-hGH may have been contaminated not only with prions that cause CJD, but also with cellular fragments containing “seeds” of misshapen Aβ linked to Alzheimer’s. It was some of the first evidence that AD might be transmissible. A BrightFocus commented on the emerging story, and relayed the consensus view among leading scientists that the public had very little to fear. AD transmission would be a very rare event indeed, with the risk mostly confined to surgical procedures, and even then only if existing safeguards were ignored and contaminated brain tissue came into contact with healthy tissue.
Very little about that has changed today.
More About the Recent Findings
In the intervening years since 2015, Dr. Collinge and the team of UCL researchers set out to test the hypothesis of “Aβ seeding,” ie, the idea that c-hGH containing misfolded Aβ proteins may have given rise to the growth of Aβ plaques, possibly signaling the spread of AD to affected individuals. As one of the first steps, they analyzed vials of c-hGH dating back to the 1980s and confirmed they did contain Aβ contaminants. (As a side note, some experiments for this project were performed by a recent BrightFocus grantee, Dominic Walsh, PhD, and colleagues, at Brigham and Women’s Hospital, affiliated with Harvard; see 2014-16 ADR grant project.)
Next, in experiments performed at UCL, the researchers injected samples of the same contaminated c-hGH into an animal model designed to mimic human AD. Animals inoculated with c-hGH developed Aβ plaques and CAA, in contrast to animals inoculated with synthetic growth hormone. It appears that Aβ particles found in c-hGH were acting as Aβ seeds, and that even after decades in storage they were potent agents spurring growth of Aβ plaques and CAA seen in Alzheimer’s.
As an important sidelight, Walsh, at Harvard, also found misfolded tau proteins in the stored c-hGH samples. However, no animals developed tau tangles in response to c-hGH inoculation; nor were tau tangles found in the autopsied brains of people who received c-hGH. A possible explanation could be that tau deposits take longer to form than Aβ plaques, and the people whose brains were autopsied may not have lived long enough for that to happen. Some experts, including past BrightFocus grantee Marc Diamond, MD, think it’s possible that tau may seed in the same fashion, and BrightFocus funds research in this area (see sidebar at end).
Call to Action
Responding to the news, Dr. Holtzman and others have called for a whole new research agenda. Among other things, they want to learn whether there’s a certain volume or threshold concentration of Aβ seeds needed to spur the development of plaques and CAA, and whether route of administration matters (eg, brain, intravenous, or intramuscular injections, this latter method being the one used for c-hGH treatments). They called for ongoing surveillance to see if tau tangles or any other brain pathologies develop in c-hGH recipients.
And finally, because the evidence shows that Aβ seeds are remarkably stable and capable of transmitting AD pathology even after several decades of being stored at room temperature, scientists have called on the medical and scientific communities to combat this potential threat by reinforcing, and even beefing up, existing precautions. Current standards call for not using biological material prepared from the human central nervous system for injection or transplantation into patients during neurosurgical or medical procedures, unless those materials are adequately screened or there is no other option; and making sure that surgical instruments that come into contact with the human brain are appropriately treated to remove seeds of misfolded forms of peptides and proteins, such as Aβ, tau, or prion proteins.
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