사람에서 가장 일반적인 유전적 CJD의 원인으로 알려진 프리온 단백질 유전자의 E200K 부위에서 특징적인 병원성 돌연변이에서 amyloid β(Aβ) plaques가 축적된다는 사실을 최초로 보고한 논문입니다.
[ Arch Neurol] 2009년 10월호에 실렸는데요… 프리온 유전자 200번 코돈의 E/K 이형성과 129번 코돈의 MM 동질접합체를 가진 가족성 CJD(Familial Creutzfeldt-Jakob Disease)의 뇌를 부검한 결과 베타 아밀로이드반(amyloid β plaques)가 축적된다는 사실을 확인함으로써 CJD와 알츠하이머병이 서로 연관이 있을 수 있다는 주장에 힘을 실어준 연구라고 해석할 수 있습니다.
앞으로 후속 연구가 더 이루어지면 크로이츠펠트-야콥병과 알츠하이머병의 연관관계에 대한 규명을 좀 더 분명하게 알 수 있으리라 생각합니다.
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Codistribution of Amyloid β Plaques and Spongiform Degeneration in Familial Creutzfeldt-Jakob Disease With the E200K-129M Haplotype
Nupur Ghoshal, MD, PhD; Ignazio Cali, MS; Richard Justin Perrin, MD, PhD; S. Andrew Josephson, MD; Ning Sun, MD, PhD; Pierluigi Gambetti, MD; John Carl Morris, MD
출처 : Arch Neurol. 2009;66(10):1240-1246.
http://archneur.ama-assn.org/cgi/content/abstract/66/10/1240?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Ghoshal+N&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
Background Dominantly inherited Creutzfeldt-Jakob disease (CJD) represents 5% to 15% of all CJD cases. The E200K mutation in the prion protein (PrP) gene (PRNP) is the most frequent cause of familial CJD. Coexistent amyloid β (Aβ) plaques have been reported in some transmissible spongiform encephalopathies but to date have not been reported in familial CJD with the E200K mutation.
Objective To characterize a family with CJD in which Aβ plaques codistribute with spongiform degeneration.
Design Clinicopathologic and molecular study of a family with CJD with the E200K-129M haplotype.
Setting Alzheimer disease research center.
Participants Two generations of a family.
Main Outcome Measures Clinical, biochemical, and neuropathologic observations in 2 generations of a family.
Results In this kindred, 3 autopsied cases showed pathologic changes typical for the E200K-129M haplotype, including spongiform degeneration, gliosis, neuronal loss, and PrP deposition. Moreover, 2 of these cases (ages 57 and 63 years) showed numerous Aβ plaques codistributed with spongiform degeneration. APOE genotyping in 2 cases revealed that Aβ plaques were present in the APOE 4 carrier but not in the APOE 4 noncarrier. Two additional cases exhibited incomplete penetrance, as they had no clinical evidence of CJD at death after age 80 years but had affected siblings and children.
Conclusions To our knowledge, this is the first description of Aβ plaques in familial CJD with the E200K mutation. The codistribution of plaques and CJD-associated changes suggests that PrP plays a central role in Aβ formation and that Aβ pathology and prion disease likely in fluence each other. The kindred described herein provides support that PrPE200K may result in increased Aβ deposition.
Author Affiliations: Department of Neurology and Alzheimer’s Disease Research Center (Drs Ghoshal, Perrin, and Morris) and Division of Neuropathology, Department of Pathology and Immunology (Drs Perrin and Morris), Washington University School of Medicine, St Louis, Missouri; National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio (Mr Cali and Dr Gambetti); Department of Neurology, University of California, San Francisco (Dr Josephson); and DuPage Neurological Associates, Willowbrook, Illinois (Dr Sun).
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Family’s inherited condition links prion diseases, Alzheimer’s
December 9, 2009 By Michael Purdy
www.physorg.com/
(PhysOrg.com) — A laboratory connection between Alzheimer’s disease and brain-wasting diseases such as the human form of mad cow disease has moved into the clinic for what is believed to be the first time, manifesting itself in the brains of patients with a rare inherited disorder.
In three cases from an Illinois family, researchers at Washington University School of Medicine in St. Louis report that brain regions harmed by an inherited form of Creutzfeldt-Jakob disease (CJD) also have amyloid plaques identical to those found in the same brain areas in Alzheimer’s patients.
The finding adds to other, earlier evidence suggesting that the misfolded protein believed to cause CJD, known as a prion, appears to play a role in the Alzheimer’s disease process.
“This interplay between amyloid and the prion protein raises questions about whether these diseases are really all that different, and whether there are common pathways involved in both conditions that can provide an avenue for new treatments,” says lead author Nupur Ghoshal, M.D., Ph.D., an investigator at Washington University’s Alzheimer’s Disease Research Center (ADRC).
Ghoshal’s research, published in Archives of Neurology, began with the autopsy of a patient who died from inherited CJD more than two decades ago after being followed clinically by senior author John C. Morris, M.D., now the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the ADRC. The autopsy revealed not only the expected brain changes inflicted by CJD but also amyloid brain plaques, even though the patient was younger than the age at which Alzheimer’s typically occurs.
CJD and other spongiform encephalopathies rapidly plunge patients into dementia, causing death in a few months to years. They have been associated with rare genetic mutations typically found in a handful of ethnic groups that includes some Jewish sects and some Eastern European lineages. In recent decades, sporadic cases of CJD-like diseases have been associated with consumption of brain and spinal tissues from cows with a brain-wasting condition called mad cow disease. These cases helped spur development of a theory that a misfolded protein known as a prion causes inherited and transmissible forms of diseases like CJD.
Healthy organisms normally make the prion protein, which in its regular configuration contributes in a yet-to-be-identified way to the function of nerve cells. Researchers believe misfolded copies of the prion protein can cause other nearby copies of the protein to misfold, triggering a harmful chain reaction that leads to conditions like CJD.
Ghoshal’s analysis showed that the amyloid detected in the initial CJD patient’s autopsy was the same type found in the brains of patients with Alzheimer’s. The amyloid appeared in regions of the brain most often harmed by CJD and Alzheimer’s disease.
With help from the National Prion Disease Surveillance Center and the archives of the neuropathology division at Barnes-Jewish Hospital and the School of Medicine, she then tracked down and analyzed brain tissue samples from two other members of the same family who died from inherited CJD. They also had deposits of the same form of amyloid in the same brain regions.
Ghoshal considered other possible explanations for the presence of amyloid besides CJD. Amyloid deposits may naturally accrue in healthy aging brains, but that type of buildup normally doesn’t appear until age 65 or over, and all three patients were younger than this when they died. Amyloid has also been linked to traumatic brain injury, but none of the patients had experienced such an injury.
“This all becomes very interesting in light of several recent discoveries that have suggested CJD and Alzheimer’s have important links,” Ghoshal says. “For example, a genetic risk factor for inherited CJD was recently linked to increased risk of Alzheimer’s disease.”
A recent Yale study suggested that the amyloid plaques of Alzheimer’s disease only harm brain cells if the prion protein is present at synapses, the junctures where two nerve cells communicate. Ghoshal recommends further study of patients with inherited and spontaneous CJD to clarify the links between the two diseases and develop new approaches to treating them.
More information: Ghoshal N, Cali I, Perrin RJ, Josephson SA, Sun N, Gambetti P, Morris JC. Codistribution of amyloid beta plaques and spongiform degeneration in familial Creutzfeldt-Jakob disease with the E200K-129M haplotype. Archives of Neurology, Oct. 2009.
Provided by Washington University School of Medicine in St. Louis
