Karen Ashe

Last updated

Karen Ashe
Borncirca 1955 [1]
United States
OccupationNeuroscientist
Years active1981–present
Known forAlzheimer's disease research

Karen K. Hsiao Ashe is a professor at the Department of Neurology and Neuroscience at the University of Minnesota (UMN) Medical School, where she holds the Edmund Wallace and Anne Marie Tulloch Chairs in Neurology and Neuroscience. [2] She is the founding director of the N. Bud Grossman Center for Memory Research and Care, [2] [3] and her specific research interest is memory loss resulting from Alzheimer's disease and related dementias. [2] [1] Her research has included the development of an animal model of Alzheimer's. [1] [4]

Contents

In July 2022, concerns were raised that certain images in a 2006 Nature paper [5] co-authored by Ashe and her postdoctoral student Sylvain Lesné were manipulated. [6] In May 2023, the Star Tribune reported that Ashe was using new techniques to re-do the work reported in the 2006 Nature study, this time without Lesné, and that she stated "it's my responsibility to establish the truth of what we've published". [7] The new article was published in March 2024. [8] The 2006 article was retracted in June 2024; all of the original authors except Lesné agreed with the retraction. [9] [10]

Personal life and education

Ashe's parents came to the United States from China in 1943 to pursue PhDs, before settling in the Minneapolis–Saint Paul area. Her father, C.C. Hsiao, taught aerospace engineering at the University of Minnesota, and her mother, Joyce, was a biochemist. [1] [11] She has three younger siblings. [1]

Attending the St. Paul Academy and Summit School in the 1970s, Ashe's interest in the brain began in primary school, where she excelled in math, along with music. [1] She obtained her undergraduate degree at Harvard University [2] in 1975 in chemistry and physics, [12] starting as a sophomore at the age of 17. [1] She went on to earn her PhD in brain and cognitive sciences at MIT in 1981 and her MD from Harvard in 1982. [12] [1]

Ashe's husband, James is a neurologist; she has three children (two sons and a daughter). [1]

Professional life

Early career

Between 1986 and 1989, she was a post-doctoral fellow at the University of California, San Francisco where she researched prion diseases and published with Stanley Prusiner. [2] [1] [12] In 1989, she was the first author on a  paper published in Nature , entitled "Linkage of a prion protein missense variant to Gerstmann‑Sträussler syndrome", describing the discovery of a mutation linked to a neurodegenerative disease. [13]  She was the first author on a paper published in 1990 in Science, entitled "Spontaneous neurodegeneration in transgenic mice with mutant prion protein", describing the creation of a transgenic mouse modeling a neurodegenerative disease. [14] According to the Minneapolis Star Tribune , she helped prove Prusiner's theory that prions cause neurodegenerative diseases. [1] Prusiner recognized her contribution towards the Nobel Prize he won for that work, [1] saying that Karen Hsiao "discovered a mutation in the PrP gene that caused familial disease and reproduced the disease in transgenic mice". [15]

Minnesota

Ashe joined the University of Minnesota Medical School in 1992 as an assistant professor of neurology. [1] She has also worked with the Minneapolis Veterans Affairs Health Care System. [1] She was the founding director of the N. Bud Grossman Center for Memory Research and Care. [2] [3] [16] As of 2022, she has received over $28 million in grants from the U.S. National Institutes of Health. [17]

The Minneapolis Star Tribune described Ashe as a "distinguished professor considered by many to be on the short list for a Nobel Prize for her work". [18]

Alzheimer's research

Amyloid-beta protein

In 1996—early in her career at UMN—Ashe was the first author on a paper published in Science, entitled "Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice", [19] describing a mouse model of Alzheimer's disease, which furthered her rising star as a scientist; the mice are used in research around the world, and students and scientists "come from all over the world to work with her", according to the Star Tribune. [1] In 2006, three of her research papers made a list of the eighteen papers that had contributed the most to Alzheimer's research. [20]

Ashe is a co-author on a 2006 paper published in Nature (retracted in 2024 [10] ), entitled "A specific amyloid-β protein assembly in the brain impairs memory". [6] [5] The paper describes the Aβ*56 oligomer (known as amyloid beta star 56 and Aβ*56) correlating with memory loss in mice prior to the appearance of amyloid plaques. According to a Science article, in 2022 the paper was the fifth-highest cited paper in Alzheimer's research, with approximately 2,300 other articles citing it. [6] The Guardian says the paper was "highly influential" and calls it "one of the most cited pieces of Alzheimer's disease research in the last two decades", writing that it has "dominated the field" of research. [21] The Daily Telegraph states that the "seminal research paper" led to increased drug research funding worldwide. [22] The paper was discussed at the Alzheimer Research Forum as a "star is born". [6] [23]

In 2015, Ashe was a co-author on a paper entitled "Quaternary structure defines a large class of amyloid-beta oligomers neutralized by sequestration", which defines two forms of Aβ based on quaternary structure, type 1 and type 2, that have different effects on memory function in mice. [24]  Type 1 is dispersed in the brain and associated with impaired memory. Type 2 is entrapped in amyloid plaques and does not impair memory. [24] [25] In 2020, she published a review summarizing this work, entitled "The biogenesis and biology of amyloid β oligomers in the brain". [25]

2022 investigation

In July 2022, concerns were raised by Matthew Schrag, a Vanderbilt University neuroscientist, [18] that certain images in the 2006 Nature paper were manipulated [6] in the paper co-authored by Ashe's postdoctoral Sylvain Lesné, whom she hired in 2002. [6] [26] These concerns were published in an article in Science authored by Charles Piller which questioned the association between the Aβ*56 protein and dementia symptoms. [6] Ashe stated in July 2022 via email that "it is devastating to discover that a colleague may have misled me and the scientific community [... it is also] distressing that a major scientific journal has blatantly misrepresented the implications of my work." [17] [Note 1] Ashe has stated that the edited images, which she agrees "should not have occurred", [27] do not change the conclusions of the paper. [28] No image inconsistencies have been found in other work published by Ashe without Lesné as a co-author. [6]

UMN is investigating the reports [21] as of May 2023. [29] The editors of Nature responded with a July 14, 2022 note stating they were aware of and investigating the concerns raised, that a "further editorial response [would] follow as soon as possible", and that "readers are advised to use caution when using results reported therein". [5] [17] The NIH, where Schrag lodged the whistleblower report, is also investigating the matter. [22] Retraction Watch states that Ashe co-authored with Lesné other disputed papers, and that the authors in the disputed work do not overlap except for two from UMN Department of Neuroscience. [30]

2024 retraction

In May 2023, the Star Tribune reported that Ashe was using new techniques to re-do the work reported in the 2006 Nature study, this time without Lesné, and that she stated "it's my responsibility to establish the truth of what we've published". [29] Ashe's new article was published in March 2024 in the journal iScience. [8]

In May 2024, Ashe announced that the 2006 publication would be retracted because Nature would not print a correction. [10] According to Retraction Watch, this makes it the most highly cited paper ever retracted. [10] Piller reported in Science that Ashe "and colleagues claim to confirm the findings of the 2006 paper", and Ashe states that "the manipulated images did not affect the study conclusions". [10] All of the original authors except Lesné agreed to the June 2024 retraction; [9] other researchers dispute the strength of conclusions in the new, re-worked study. [10]

Honors and awards

Ashe was awarded the Metlife Foundation Award for Medical Research in Alzheimer's Disease in 2005. [31] Ashe also earned the Potamkin Prize in 2006 for her Alzheimer's research, [32] [33] shortly after the publication of the 2006 Nature paper. [6]

In 2009, Ashe was elected to the National Academy of Medicine for her achievements in medicine. [34]

Selected publications

Notes

  1. ↑ See also Ashe's July 22 response posted on the Alzheimer Research Forum, referencing "allegations about images that may have been inappropriately altered by my former co-worker Dr. Sylvain Lesné."

Related Research Articles

<span class="mw-page-title-main">Prion</span> Pathogenic type of misfolded protein

A prion is a misfolded protein that can induce misfolding of normal variants of the same protein and trigger cellular death. Prions cause prion diseases known as transmissible spongiform encephalopathies (TSEs) that are fatal transmissible neurodegenerative diseases in humans and animals. The proteins may misfold sporadically, due to genetic mutations, or by exposure to an already misfolded protein. The consequent abnormal three-dimensional structure confers on them the ability to cause misfolding of other proteins.

<span class="mw-page-title-main">Amyloid</span> Insoluble protein aggregate with a fibrillar morphology

Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400-450 square micrometers (μm2). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

<span class="mw-page-title-main">Major prion protein</span> Protein involved in multiple prion diseases

The major prion protein (PrP) is encoded in the human body by the PRNP gene also known as CD230. Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughout the body.

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References

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  3. 1 2 "Not giving up". University of Minnesota Foundation. February 7, 2017. Archived from the original on July 12, 2017. Retrieved August 1, 2022.
  4. ↑ "University of Minnesota Academic Health Center". Archived from the original on June 10, 2010. Retrieved March 14, 2010.
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  8. 1 2 Liu P, Lapcinski IP, Hlynialuk CJ, Steuer EL, Loude TJ, Shapiro SL, Kemper LJ, Ashe KH (March 2024). "Aβ∗56 is a stable oligomer that impairs memory function in mice". iScience. 27 (3): 109239. doi:10.1016/j.isci.2024.109239. PMC   10905009 . PMID   38433923.
  9. 1 2 Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (June 24, 2024). "Retraction Note: A specific amyloid-β protein assembly in the brain impairs memory". Nature : 1. doi:10.1038/s41586-024-07691-8. ISSN   1476-4687.
  10. 1 2 3 4 5 6 Piller C (June 4, 2024). "Researchers plan to retract landmark Alzheimer's paper containing doctored images". Science . Retrieved June 4, 2024.
  11. ↑ "C.C. Hsiao memorial". umn.edu. Retrieved June 18, 2024.
  12. 1 2 3 "Karen Hsiao Ashe, M.D, Ph.D." (PDF). U. S. Department of Veteran Affairs. Retrieved August 1, 2022.
  13. ↑ Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, Westaway D, Ott J, Prusiner SB (March 1989). "Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome". Nature. 338 (6213): 342–345. Bibcode:1989Natur.338..342H. doi:10.1038/338342a0. PMID   2564168. S2CID   4319741.
  14. ↑ Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB (December 1990). "Spontaneous neurodegeneration in transgenic mice with mutant prion protein". Science. 250 (4987): 1587–1590. Bibcode:1990Sci...250.1587H. doi:10.1126/science.1980379. PMID   1980379. S2CID   45517405.
  15. ↑ "Stanley B. Prusiner: Biographical". The Nobel Prize. Retrieved August 1, 2022.
  16. ↑ "Team". N. Bud Grossman Center for Memory Research and Care: University of Minnesota. February 20, 2015. Archived from the original on July 12, 2017. Retrieved July 30, 2022.
  17. 1 2 3 Olson J (July 22, 2022). "University of Minnesota scientist responds to fraud allegations in Alzheimer's research". Star Tribune . Archived from the original on July 26, 2022. Retrieved July 26, 2022.
  18. 1 2 Olson J (July 21, 2022). "Review questions key work by University of Minnesota on Alzheimer's". Star Tribune . Archived from the original on July 24, 2022. Retrieved July 24, 2022.
  19. ↑ Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (October 1996). "Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice". Science. 274 (5284): 99–102. Bibcode:1996Sci...274...99H. doi:10.1126/science.274.5284.99. PMID   8810256. S2CID   32419070.
  20. ↑ "Taking Alzheimer's research to the next level". University of Minnesota. Archived from the original on June 14, 2010. Retrieved August 1, 2022.
  21. 1 2 Glenza J (July 23, 2022). "Critical elements of leading Alzheimer's study possibly fraudulent". The Guardian . Archived from the original on July 23, 2022. Retrieved July 23, 2022.
  22. 1 2 Knapton S (July 21, 2022). "'Manipulated' Alzheimer's data may have misled research for 16 years". The Daily Telegraph . Archived from the original on July 22, 2022. Retrieved July 23, 2022.
  23. ↑ "Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer". Alzheimer Research Forum. March 17, 2006. Retrieved August 1, 2022.
  24. 1 2 Liu P, Reed MN, Kotilinek LA, Grant MK, Forster CL, Qiang W, Shapiro SL, Reichl JH, Chiang AC, Jankowsky JL, Wilmot CM, Cleary JP, Zahs KR, Ashe KH (June 2015). "Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration". Cell Rep. 11 (11): 1760–1771. doi:10.1016/j.celrep.2015.05.021. PMC   4494129 . PMID   26051935.
  25. 1 2 Ashe KH (November 2020). "The biogenesis and biology of amyloid β oligomers in the brain". Alzheimers Dement. 16 (11): 1561–1567. doi:10.1002/alz.12084. PMC   7984270 . PMID   32543725.
  26. ↑ Lesné SE (2013). "Breaking the Code of Amyloid-β Oligomers" (PDF). International Journal of Cell Biology. 2013. OMICS Group Conferences: 950783. doi: 10.1155/2013/950783 . PMC   3773433 . PMID   24072999. Archived from the original (PDF) on July 27, 2022. Retrieved July 27, 2022.
  27. ↑ Olson J (July 30, 2022). "University of Minnesota researcher seeks to sustain Alzheimer's findings amid image scandal". Star Tribune . Archived from the original on July 31, 2022. Retrieved July 31, 2022.
  28. ↑ Alltucker K, Weintraub K (July 29, 2022). "Investigation into pivotal Alzheimer's study raises questions on suspected disease culprit" . USA Today . Retrieved July 29, 2022.
  29. 1 2 Olson J (May 13, 2023). "University of Minnesota researcher seeks to put tarnished Alzheimer's discoveries back on track". Star Tribune. Retrieved May 14, 2023.
  30. ↑ Marcus A (June 21, 2022). "Papers on Alzheimer's slapped with expressions of concern". Retraction Watch. Archived from the original on June 30, 2022. Retrieved July 23, 2022.
  31. ↑ "MetLife Foundation Awards for Medical Research in Alzheimer's Disease" (PDF). Met Life Foundation. 2016. p. 13. Archived from the original (PDF) on October 13, 2018.
  32. ↑ Jucker M, Beyreuther K, Haas C, eds. (2006). Alzheimer: 100 Years and Beyond. Springer Science and Business Media. p.  466. ISBN   978-3540376514.
  33. ↑ "Past recipients: Making a difference". The Potamkin Prize. Retrieved August 1, 2022.
  34. ↑ "National Academy of Medicine (formerly Institute of Medicine)". University of Minnesota. Retrieved August 1, 2009.


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