Field Says Farewell to Neuropathologist Yasuo Ihara, 78

The Alzheimer’s field mourns the loss of Yasuo Ihara of Doshisha University in Kizugawa, Japan, who died June 10 at the age of 78 after a long illness. Ihara did pioneering work characterizing pathologic Aβ and tau in the AD brain, and trained a generation of scientists who continue to carry the field forward. He received several honors during his lifetime, including the 1995 Potamkin Prize and the 1996 Metlife Foundation Award.

Yasuo Ihara, whose pioneering work characterized amyloid and tau deposits in Alzheimer’s disease brain. [Courtesy of Ryoko Ihara.] [Courtesy of Ryoko Ihara.]

“[Yasuo] belonged to that rare species of AD researchers who are both ‘tauist’ and ‘βabtist.’ He put Japan on the list of leading countries in AD research,” Konrad Beyreuther at the University of Heidelberg, Germany, and Colin Masters at the University of Melbourne, Australia, wrote to Alzforum.

Dennis Selkoe at Brigham and Women’s Hospital, Boston, agreed. “Yasuo was widely recognized as the premier basic scientist of Alzheimer’s disease in Japan, and was among a handful of world leaders in this challenging field … We would not be where we are today without Yasuo Ihara’s brilliant contributions and intellectual leadership,” Selkoe wrote (comments below).

Regarding Aβ pathology, Ihara first identified Aβ40 and Aβ42 as components of amyloid plaques 30 years ago, and more recently reported that the proportion of these peptides can be used to stage plaque maturity (Iwatsubo et al., 1994; Kakuda et al., 2020). He is perhaps best known for his discovery that γ-secretase gives rise to different Aβ peptides by chewing off three- to four-peptide chunks in succession, helping explain how familial AD mutations change the ratio of long and short Aβ peptides (Gu et al., 2001; Takami et al., 2009).

“Yasuo Ihara was a great biochemist, and his dissection of the mechanism of presenilin/γ-secretase cleavage (with cuts every three-residue helical turn) is really beautiful work,” John Hardy at University College London wrote to Alzforum. “This mechanism is elegant and gives direct insight into the biochemistry of the initiation of Alzheimer’s disease.”

Yasuo Ihara (seated, with flowers), receiving The Order of the Sacred Treasure in Japan in 2018. [Courtesy of Taisuke Tomita.]

Regarding tau, Ihara pinpointed the protein as a component of paired helical filaments in AD brain (Nukina and Ihara, 1986; Ihara et al., 1986). He was also the first to report the presence of ubiquitin in these deposits (Mori et al., 1987). Ihara studied other types of protein deposit as well, reporting the ubiquitination of Lewy bodies and identifying α-synuclein in amyloid plaques (Kuzuhara et a., 1988; Uéda et al., 1993).

Ihara Lab, Tokyo, 1987. Clockwise from top left: Hiroshi Mori, Yasuo Ihara, Akira Tamaoka, Carmela Abraham, Dennis Selkoe. [Courtesy of Carmela Abraham.]

Colleagues appreciated his intellectual rigor and kindness. “I admired Yasuo for his highly respectful treatment of all scientists, regardless if they were established leaders or, like myself at the time, just very young beginners,” Christian Haass at Ludwig Maximilians University in Munich wrote to Alzforum. Kenneth Kosik at the University of California, Santa Barbara, remembered Ihara’s insatiable curiosity and intuitive sense of where answers might lie. “Yasuo sped from the centrifuge to the laboratory bench beating a path that you did not want to obstruct. Although he gave the impression he was in a great hurry, he always had time for a scientific discussion,” Kosik wrote (comments below).

Ihara is survived by his wife, Keiko, and children Ryoko and Tomo. His funeral was held June 13 in Japan. If you would like to share a memory or photo of Ihara, please use the comment function below.—Madolyn Bowman Rogers

Comments

    • User Profile Image Dennis Selkoe
      Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
    • Posted:

    As a career-long friend, admirer, and early collaborator of Ihara-sensei, I am deeply saddened by his passing. I knew he was ill in recent years and had also overcome a serious immune disorder decades ago that interrupted his work. Yet he came back from that earlier illness, and with his talented colleagues, he elegantly deciphered the molecular mechanism of the pathogenically critical “processive” APP cleavages by the presenilin/γ-secretase complex. This was truly brilliant work, and it matters more than ever today.

    In 1980, Yasuo was the first scientist from overseas to join my fledging lab at McLean Hospital. He had been directed to me by my postdoctoral mentor, Mike Shelanski. Yasuo and I, then at the same point in our respective careers, quickly formed a camaraderie, and we worked alongside Carmela Abraham and Ken Kosik. The four of us had exciting times in those early days deciphering the molecular pathology of AD. Our first joint paper (Selkoe et al., 1982) revealed the unusual insolubility of paired helical filaments (PHF) in SDS and urea, and Yasuo used these properties to define a method to purify PHFs from AD cortex. He hypothesized that the unknown subunit protein of PHF was, in part, covalently crosslinked, and he suggested e(γ-glutamyl)lysine crosslinks created by transglutaminase, a topic we quickly developed (Selkoe et al., 1982). Then, he led the development of the first antisera to PHF (Ihara et al., 1983). Yasuo was a gifted experimentalist; he was deeply knowledgeable in protein biochemistry and in the mechanisms of neurodegeneration. These were heady days for us, and I was disappointed that after a little less than two years at McLean, Professor Mannen, head of Neurology at Tokyo University, called Yasuo back to assume a joint clinical and research position in that prestigious department.

    Yasuo and I kept in close touch, and I soon found my way to Tokyo for the first of several visits. I met Yasuo’s talented fellows, some of whom came to my lab (now at the the Brigham) for postdoctoral training. At Tokyo Metropolitan Geriatric Hospital, Yasuo did pioneering studies on the nature of post-translational modifications of tau, which he and Nobuyuki Nukina (alongside three other labs) had identified as the PHF subunit in 1985 (Nukina and Ihara, 1985). There were many other insights on the molecular pathology of tau tangles and amyloid plaques made by Ihara and colleagues. And his later work on the mechanism of presenilin proteolysis exemplified the innovative, clever biochemistry Yasuo pursued throughout his career.

    Yasuo was widely recognized as the premier basic scientist of Alzheimer’s disease in Japan and was among a handful of world leaders in this challenging field. He was a warm and collegial person and a highly respected scientist, mentor, and collaborator. We would not be where we are today without Yasuo Ihara’s brilliant contributions and intellectual leadership. I will miss his sage comments and pleasant companionship at many international meetings.   

    I extend my condolences to Yasuo’s lovely wife and lifelong companion, Keiko, and his accomplished children, Ryoko and Tomo, all of whom spent happy hours with my family in our early Boston days. Yasuo, I so wish we had had more time together over these four decades.

    References:

    Selkoe DJ, Ihara Y, Salazar FJ. Alzheimer's disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Science. 1982 Mar 5;215(4537):1243-5. PubMed.

    Selkoe DJ, Abraham C, Ihara Y. Brain transglutaminase: in vitro crosslinking of human neurofilament proteins into insoluble polymers. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6070-4. PubMed.

    Ihara Y, Abraham C, Selkoe DJ. Antibodies to paired helical filaments in Alzheimer's disease do not recognize normal brain proteins. Nature. 1983 Aug 25-31;304(5928):727-30. PubMed.

    Nukina N, Ihara Y. Proteolytic fragments of Alzheimer's paired helical filaments. J Biochem. 1985 Dec;98(6):1715-8. PubMed.

    View all comments by Dennis Selkoe
    • User Profile Image Kenneth Kosik
      University of California, Santa Barbara
    • Posted:

    Yasuo's death brings a flood of memories from the beginning of our careers when he arrived in the Selkoe lab at McLean Hospital, Belmont, Massachusetts, where I was fresh out of a neurology residency without a clue about how to do research. Yasuo knew precisely what he was doing. With a single-minded doggedness he quickly proved that Alzheimer’s neurofibrillary tangles were insoluble under the harshest conditions. That finding in 1982 was an important advance in the biophysical characterization of tangles. At that time, we had no idea what the tangles were made of. No one knew anything about tau protein. By 1986 we did know that tau was the major component of neurofibrillary tangles based on work in several labs all appearing at about the same time. With Yasuo’s amazingly intuitive sense of where the answers lie, we contributed to the early identification of tau in tangles. Later Yasuo went on to prove directly, and definitively, that the neurofibrillary tangles were made of tau by using mass spectroscopy and he made the significant discovery that tau in tangles was bound to ubiquitin, both mono- and polyubiquitinated chains. Yasuo sped from the centrifuge to the laboratory bench beating a path that you did not want to obstruct. Although he gave the impression he was in a great hurry, he always had time for a scientific discussion, patiently listened, and in his concise manner, insightfully responded.

    From the time Yasuo returned to Japan he became a leader in the neuropathology community, devoted to studies of both tau and amyloid in whichever direction his insatiable curiosity led. In 1998, he published one of the earliest consensus reports on molecular and biochemical markers of Alzheimer’s disease, along with other eminent neuropathologists whose ranks are sadly now thinning. Yasuo will now join these luminaries in the field that include Peter Davies, Sid Gilman, Allen Roses, John Blass, John Trojanowski, and Henry Wisniewski.

    View all comments by Kenneth Kosik

  3. Dr. Yasuo Ihara was one of the pioneer researchers in the AD field in Japan and he made many important discoveries that have linked classical pathology to molecular pathology. He trained many Japanese researchers and established the foundation of basic AD research in Japan.

    When I started my research on Alzheimer's disease at Dr. Takeshi Iwatsubo’s Lab in 1994, we did not yet have laboratory space. So, we began experiments at a part of Yasuo’s Lab. At that time, his lab had many researchers who had established the current biochemical and molecular biological research on AD, such as Drs. Hiroshi Mori, Katsuhiko Yanagisawa, Maho Morishima-Kawashima, and Masato Hasegawa. As a beginner, I learned many things, such as how to conduct biochemical experiments, discussions, and presentations. Yasuo was always teaching me very carefully, gently, and sometimes strictly, how to do enzymology and biochemistry as I began my research on γ-secretase. Although I was not directly affiliated with the Ihara Lab, I was fortunate to have the opportunity to receive direct guidance from him. I can say that Yasuo is one of my “elementary school teachers” in my research career.

    Yasuo is a father to many Japanese dementia biochemistry researchers. He devoted his life deeply to the basic science of disease. I heard that he wrote in a letter to the future at the Tsukuba Expo in 1985, “I wonder what dementia research will be like in the future when this letter reaches us.” Yasuo may have been relieved when he heard the news of lecanemab in this year, 2023. We will continue our research to overcome dementia. Please rest in peace.

    View all comments by Taisuke Tomita

  4. Yasuo Ihara, who died on June 10, aged 78, made seminal contributions to our understanding of the composition of the abnormal filaments that accumulate in the brains of individuals with neurodegenerative diseases. He referred to this work as “product analysis.” Yasuo is perhaps best known for his pioneering studies on hyperphosphorylated and ubiquitinated tau, which is the major component of the neurofibrillary lesions of Alzheimer’s and many other neurodegenerative diseases (Nukina and Ihara, 1986; Mori et al., 1987; Kondo et al., 1988; Murayama et al., 1990; Hasegawa et al., 1992; Morishima-Kawashima et al., 1993; Yoshida and Ihara, 1993). But he also contributed in important ways to studies on Aβ (Iwatsubo et al., 1994; Takami et al., 2009) and on what is now known as α-synuclein (Uéda et al., 1993). Yasuo’s work is continued by his talented and loyal students, many of whom have prominent academic positions in Japan.

    References:

    Hasegawa M, Morishima-Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J Biol Chem. 1992 Aug 25;267(24):17047-54. PubMed.

    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994 Jul;13(1):45-53. PubMed.

    Kondo J, Honda T, Mori H, Hamada Y, Miura R, Ogawara M, Ihara Y. The carboxyl third of tau is tightly bound to paired helical filaments. Neuron. 1988 Nov;1(9):827-34. PubMed.

    Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 1987 Mar 27;235(4796):1641-4. PubMed.

    Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Titani K, Ihara Y. Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments. Neuron. 1993 Jun;10(6):1151-60. PubMed.

    Murayama S, Mori H, Ihara Y, Tomonaga M. Immunocytochemical and ultrastructural studies of Pick's disease. Ann Neurol. 1990 Apr;27(4):394-405. PubMed.

    Nukina N, Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem. 1986 May;99(5):1541-4. PubMed.

    Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.

    Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282-6. PubMed.

    Yoshida H, Ihara Y. Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J Neurochem. 1993 Sep;61(3):1183-6. PubMed.

    View all comments by Michel Goedert
    • User Profile Image Christian Haass
      Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
    • Posted:

    I met Yasuo more than three decades ago when I was still working in Boston. He was one of the most thoughtful and “quiet” scientists I ever met. With Yasuo’s passing, not only a brilliant scientist, but also a leader in the field, has left us.

    I admired Yasuo for his highly respectful treatment of all scientists, regardless of whether they were established leaders or, like myself at the time, just very young beginners. As a young scientist I was proud to have the opportunity to discuss with him the existence of intracellular Aβ and the mechanisms of intramembrane proteolysis. He knew all the little details and was always happy to share his knowledge and experience with his colleagues all over the world. We will all miss Yasuo!

    View all comments by Christian Haass

  6. Yasuo Ihara (1945-2023): Pioneer Alzheimer’s disease researcher.

    We first met and got to know Yasuo Ihara, and realized his deep insight into Alzheimer’s disease, at the 11th meeting of the International Society for Neurochemistry (ISN) held at the Maputo Sheraton Hotel in La Guaita, Venezuela, May 31, 1987. The president of the ISN invited one of us (Konrad) to organize a session on molecular genetics of nervous system disease. Yasuo Ihara was, therefore, asked to present his newest findings on paired helical filaments, and Colin was invited to present a paper with the title “Molecular Biology of Alzheimer’s Disease Specific Amyloid” covering our discoveries of Aβ42/43 and the cloning of APP that had been published in Nature a few months earlier. Yasuo presented his newest findings showing that paired helical filaments contained proteolytic fragments of tau, that phosphorylated tau is integrated into paired helical filaments, and that ubiquitin is a component of paired helical filaments in AD. After our session, we discussed the finer points around tau and Aβ patho-biology, in depth, until the early hours of the next morning at the Maputo Sheraton bar. We agreed that the key to understanding AD lay in the brains of the patients, and that the study of these brains would have priority for all three of us in the years to come. We both were surprised how well Yasuo tolerated alcohol and it was way after midnight when we retired to our rooms.

    After this Venezuela meeting, Yasuo continued to publish novel, outstanding, and relevant papers on topics including the first description of the ubiquitination of Lewy bodies in diffuse LBD and Parkinson’s disease (Kazuhara et al., 1988). Over his productive lifetime, he published many outstanding papers. Our in-house bibliography of AD has his first contribution in 1981 and his last in 2021. These include studies of the tau fragments in paired helical filaments derived from the carboxyterminal third of tau (Kondo et al., 1988); massive somatodendritic sprouting of cortical neurons in AD (Ihara, 1988); the initial deposition of Aβ42/43 in diffuse plaques that were devoid of Aß40 using C-terminal specific monoclonals (Iwatsubo et al., 1994); the first description of the longer Aβ species 1-43, 1-45, 1-46 and 1-48 produced by presenilin (Qi-Takahara et al., 2005); and the identification of the successive tri-peptide and tetra-peptide release form C-99 (Takami et al., 2009). In 2020, Yasuo published, as senior author, perhaps his major legacy, that β-secretase activity associates with Braak senile plaque status (Kakuda et al., 2020).

    This is just a short recollection of the seminal discoveries of Yasuo, who belonged to that rare species of AD researchers who are both “tauist" and “βabtist.” He put Japan on the list of leading countries in AD research, and some his former coworkers are well on the pathway to fulfill his legacy, to lead to a deep understanding of the mechanisms leading to AD and neurodegeneration.

    References:

    Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1988;75(4):345-53. PubMed.

    Kondo J, Honda T, Mori H, Hamada Y, Miura R, Ogawara M, Ihara Y. The carboxyl third of tau is tightly bound to paired helical filaments. Neuron. 1988 Nov;1(9):827-34. PubMed.

    Ihara Y. Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease. Brain Res. 1988 Aug 30;459(1):138-44. PubMed.

    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994 Jul;13(1):45-53. PubMed.

    Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. PubMed.

    Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.

    Kakuda N, Yamaguchi H, Akazawa K, Hata S, Suzuki T, Hatsuta H, Murayama S, Funamoto S, Ihara Y. γ-Secretase Activity Is Associated with Braak Senile Plaque Stages. Am J Pathol. 2020 Jun;190(6):1323-1331. Epub 2020 Mar 20 PubMed.

    View all comments by Konrad Beyreuther View all comments by Colin Masters

  7. Yasuo was a major contributor to the AD field in so many ways and will be greatly missed. Some of the very fundamental biochemical mechanisms that underlie how tau and other proteins are involved in neuropathology will always be part of Yasuo's legacy. His contributions were expansive and many of the things we take for granted now, such as the ability to understand and detect paired helical filaments, are due to work he contributed. Yasuo, you will be greatly missed.

    View all comments by RR Robert Rissman

  8. I was one of the early students of Yasuo after he came back to the University of Tokyo as the chair of neuropathology. When I discussed my research topic for thesis work, he said “I’m focusing on the pathobiology of tau and neurofibrillary changes. I don’t have a general interest in Alzheimer’s. If you agree with my view, I can suggest you a research topic.” I started a study “to visualize the regenerative aspects of Alzheimer’s neuropathological changes.” This idea came from the findings that AD brains express fetal antigens, including phosphorylated tau, neuropil threads, and tau-positive abnormal curly fibers, in AD cortices, which sometimes looked like sprouting neurites. Yasuo suggested that “if you can visualize the new and old parts of the tau deposits in the threads, you can estimate the direction of the sprouting neurites that harbor the tau threads,” and recommended a combination of immunolabeling for the tau N terminus and ubiquitin. I double stained the AD tissue sections, examined them under a confocal microscope, and found that some of the tau-positive threads were devoid of ubiquitin at the end, as Yasuo predicted. When I reported the results, Yasuo was calmly satisfied, and told me to further examine the pathology in detail. While looking at more neuropil threads, I became puzzled. Some neuropil threads were negative for ubiquitin at both ends: so, which is the real direction of neurite growth? I came to the conclusion that neuropil threads may simply represent tau deposits that arose within thin neurites, which extend to the proximal and distal directions within the narrow caliber neurites. Yasuo was very reluctant to accept my view. “We have ample evidence supporting the hypothesis that robust sprouting activity takes place in AD brains!” he said, turning red, and insisting on his hypothesis. Two days later, he dropped by my bench, and said: “Well, I’ve been thinking about our discussion for two whole days, I came to be convinced that your interpretation can better explain the tau pathology, and may be correct. I will change my hypothesis.” We wrote a short paper on this finding, which became a part of my thesis (Iwatsubo et al., 1992). Yasuo was always fair and dedicated to science.

    Many years later when I took over the position of Yasuo’s, I often called him at his new lab in the southern outskirts of Kyoto and discussed many things, including AD research and the politics of science. He loved his new office, overlooking a beautiful bamboo grove; “I love this scenery, it reminds me of the McLean hospital in Boston where I started research with Dennis,” he said.

    Yasuo always encouraged me to conduct J-ADNI, to prepare for the clinical trials of disease-modifying therapies of AD. It might not be a coincidence that he passed away at the same time when the approval of lecanemab was unanimously recommended by the advisory committee in the U.S. I deeply regret our too-early loss of Yasuo, but his spirit in advancing AD research is carried on by all his students, friends, and collaborators.

    Yasuo Ihara (right) with John Trojanowski, Virginia Lee, and Takeshi Iwatsubo on a Sunday afternoon in 1993, discussing a collaboration on Lewy bodies at Yasuo’s office in the University of Tokyo.

    References:

    Iwatsubo T, Hasegawa M, Esaki Y, Ihara Y. Lack of ubiquitin immunoreactivities at both ends of neuropil threads. Possible bidirectional growth of neuropil threads. Am J Pathol. 1992 Feb;140(2):277-82. PubMed.

    View all comments by Takeshi Iwatsubo
    • User Profile Image Todd E. Golde
      Goizueta Institute @ Emory Brain Health
    • Posted:

    I first met Yasuo Ihara during my M.D., Ph.D. training with Steve Younkin at Case Western. Yasuo was visiting Case Western to give a talk, after which he, Steve, and I had lunch. As a young and ambitious but inexperienced student, I was impressed by Yasuo’s kindness, generosity, and scientific insights. This was in the early days, when many of us were trying to understand APP processing, and I just remember how the scientific discussion was thoughtful, open, and inspiring. I think the discussion lasted for over two hours. Many years later our work intersected as both our labs were focused on understanding how the different species of Aβ were generated by γ-secretase. Indeed, the Takami et al., 2009, J. Neuroscience paper, wherein his lab reported how successive cleavage of APP CTF leads to various Aβ peptides, is to me a tour de force of protein biochemistry (Takami et al., 2009). That paper to me epitomized Yasuo’s approach to science and is just one facet of the many major contributions he made to the Alzheimer’s field.

    References:

    Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.

    View all comments by Todd E. Golde

  10. International luminaries have already attested here about Yasuo’s scientific talents and achievements. He pioneered the study of plaques and tangles in the early '80s as a postdoctoral fellow in the Selkoe lab, and continued, in Tokyo, to contribute to the understanding of their biochemistry and metabolism in AD. He also focused on aggregates that accumulate in other neurodegenerative diseases. He was a mentor to many who became famous researchers over the years.

    But, here, I wanted to mention some anecdotes. We first met in 1981 in the Selkoe lab at McLean hospital in Belmont, Massachusetts. We were new to the United States and discovered, to our surprise, that I understood Yasuo's pronunciation of chemical names better than the locals did. For example, Xylene is pronounced in Hebrew and Japanese the same, and very differently than in English. The same is true for names of enzymes.

    Yasuo was a superb biochemist and neuropathologist, but despite arriving in Boston in his 30s, he didn’t know how to drive. So, I drove him to a driving school near McLean hospital until he got his license.

    When Yasuo arrived, Dennis took us to a Japanese restaurant, a first for me. If I remember correctly, there was only one such restaurant in Boston in 1981, near the ocean. I love avocado, so when I saw the small green mass, I put it all in my mouth. It was wasabi, which I had not encountered before. I cried for a long time…

    Finally, I have to mention that Yasuo was an extremely gracious host when Dennis and I visited Tokyo and Hakone in 1987. He took care of all our needs, organized beautiful tours for us, a tea ceremony, a visit to the silk museum in Yokohama, and asked two of his then-postdocs, Hiroshi Mori and Akira Tamaoka, to accompany us everywhere we went so we didn’t get lost. This was my first trip to Japan and I returned to Boston completely charmed and captivated by the beauty of this country, all thanks to Yasuo. Rest in peace, my dear friend. 

    View all comments by Carmela Abraham
    • User Profile Image Masato Hasegawa
      Tokyo Metropolitan Institute of Medical Science
    • Posted:

    Professor Yasuo Ihara was my mentor. He introduced me to dementia research and taught me logical thinking, as well as the rigors of research.

    I met Yasuo in 1988, after completion of my master’s degree. I visited his laboratory at the Tokyo Metropolitan Institute of Gerontology, following the introduction by Dr. Takao Arai, who had taught me how to make monoclonal antibodies. After Yasuo had talked about his own research, using some technical terms, he said: “When can you start to work here?” Perhaps he intended to accept me as a Ph.D. student all along.

    Yasuo gave me a copy of his review (Ihara, 1985), in which he wrote: “Alzheimer’s disease is a kind of accumulation disease. The approach is simple: Just examine the accumulated products.” Looking back, I believe that Yasuo was essentially correct. Thirty-five years later, cryo-EM has revealed the high-resolution structures of amyloid filaments extracted from the brains of individuals with many different neurodegenerative diseases.

    For much of Yasuo’s work he analysed the brains of individuals with neurodegenerative diseases at the level of neuropathology and biochemistry. By doing so, he also trained the next generation of researchers. Yasuo, thank you so very much for all your guidance and encouragement. Please rest in peace.

    References:

    Ihara Y. [Alzheimer paired helical filament]. Seikagaku. 1985 Oct;57(10):1390-6. PubMed.

    View all comments by Masato Hasegawa

  12. The late Professor Ihara was a great teacher to all neuroscientists and neuropathologists in Japan. He helped us build, from the ground up, the Brain Bank for Aging Research, the first and only brain bank dedicated to Alzheimer’s disease and aging research in Japan. And, with his own living will, he donated his brain and body to the bank at the end of his life. Receiving his baton, we will continue the relay to find the cure for Alzheimer’s disease. We express our sincere thanks to him, and pray for him to rest in peace.

    View all comments by Yuko Saito View all comments by Shigeo Murayama

  13. It is extremely sad to hear about the passing of Ihara-sensei, who was a long-term Professor of Neuropathology at University of Tokyo Graduate School of Medicine when I was a medical student there. Ihara-sensei has been my role model as a premier biochemist, neuropathologist, and a distinguished medical school alumnus.

    I had a chance to give a talk at his department in 2007, and presented the study of tau-tubulin kinase-1 (TTBK1) that our laboratory cloned as a neuron-specific tau kinase on tau phosphorylation and axonal degeneration (https://pubmed.ncbi.nlm.nih.gov/16923168/). After the presentation, Ihara-sensi suggested to study collapsin response mediator protein-2 (CRMP2), which is also enriched in the growth cone and is the substrate of the sequential phosphorylation by cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3 (GSK3B). I contacted Dr. Kozo Kaibuchi at Nagoya University, and obtained the necessary reagents to determine that TTBK1 is upstream of CDK5 and GSK3B for the phosphorylation of CRMP2 at Ser 522 and Thr 514, respectively (https://pubmed.ncbi.nlm.nih.gov/32019603/). I sent this paper to Ihara-sensi after its acceptance, and was glad to hear that he liked the study. At a later meeting in Japan, I leaned that he was then focusing on developing a drug to halt tau pathology progression to take a responsibility “Kejime” of the research field, in which he had been profoundly engaged.

    Ihara-sensei was an inspiration to many researchers in the world, including myself, as one of the giants in the dementia society, although he was rarely able to go abroad during the later years of his life. He is truly missed.

    View all comments by Tsuneya Ikezu

  14. In Yasuo Ihara, I lost my lifetime mentor. I kept thinking that I would like to talk to him just one more time, but that dream did not come true.

    In the 1990s, I got into Alzheimer's from basic research on proteolysis. The motivation for this was my encounter with Professor Ihara. At that time, he was a professor at the Department of Neuropathology, Faculty of Medicine, University of Tokyo, and I was a researcher at the Tokyo Metropolitan Institute of Medical Medicine (located in Komagome at the time). When I was studying the relationship between cerebral ischemia and Alzheimer's disease, Dr. Seiichi Kawashima, who was heading the laboratory I belonged to, introduced me to Dr. Ihara. I will omit the details, but Dr. Ihara and I were involved in proving the hypothesis that the chemical structure of Aβ peptide, which had been established as a causative agent of Alzheimer's disease, was different from what was thought at the time.

    I performed experiments by myself every day, and once a week I brought the data from Komagome (Tokyo Metropolitan Institute) to Hongo (University of Tokyo) by bicycle. I lost track of time and had discussions, which often lasted over two hours. It was truly the happiest season of my research career. I co-authored the research with Professors Ihara and Kawashima and published it in Neuron (Saido et al., 1995). I can confidently say that I wouldn't be where I am today without my encounter with Professor Ihara. In total, Professor Ihara and I published 12 papers together in English (Saido et al., 1995; Saido et al., 1994; Yamazaki et al., 1997; Funato et al., 1998; Oyama et al., 1998; Yamaguchi et al., 1998; Sawamura et al., 2000; Funamoto et al., 2004; Qi-Takahara et al., 2005; Sato et al., 2005; Saito et al., 2011; Funamoto et al., 2013) and one review in Japanese (Morishima-Kawashima et al., 2001). 

    After that, we continued to interact not only in research but also in the management of the Japan Dementia Research Society. Sadly, after Dr. Ihara retired from the University of Tokyo and moved to Doshisha University in Kyoto, his health gradually deteriorated, and finally he had to receive hospital treatment, and the chance to see him decreased.

    On May 28, 2016, Dr. Ihara, who was in his hospital bed, called me out of the blue from his mobile phone and said, "I don't have much time left, so I'd like to ask you to do work for developing dementia research in Japan." I took it seriously and emailed researchers around the world. In the end, Dr. Ihara made a full recovery and I was relieved, but I deeply regretted having spread such inaccurate information.

    After that, I visited him with Dr. Maho Morishima, one of Dr. Ihara's beloved disciples. This was the last time I met with him. The fact that this visit was restricted due to the coronavirus crisis was also an obstacle.

    Ihara-sensei's wake was held on June 12, his funeral ceremony on June 13. Researchers around the world requested live streaming, so with the bereaved family's permission, we shared the live information and recordings on Zoom. Dr. Ihara was the first researcher in the world to discover that tau protein is a component of neurofibrillary tangles. Everyone involved in Alzheimer's disease research knows him. It's exactly a "giant star falling."

    In addition to his research, he was instrumental in reforming and developing the Japanese Dementia Research Society. June 10 has become the saddest day for me. I sincerely pray for the repose of his soul.

    References:

    Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron. 1995 Feb;14(2):457-66. PubMed.

    Saido TC, Yokota M, Maruyama K, Yamao-Harigaya W, Tani E, Ihara Y, Kawashima S. Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. J Biol Chem. 1994 May 27;269(21):15253-7. PubMed.

    Yamazaki T, Haass C, Saido TC, Omura S, Ihara Y. Specific increase in amyloid beta-protein 42 secretion ratio by calpain inhibition. Biochemistry. 1997 Jul 8;36(27):8377-83. PubMed.

    Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, Okeda R, Ihara Y. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol. 1998 Apr;152(4):983-92. PubMed.

    Oyama F, Sawamura N, Kobayashi K, Morishima-Kawashima M, Kuramochi T, Ito M, Tomita T, Maruyama K, Saido TC, Iwatsubo T, Capell A, Walter J, Grünberg J, Ueyama Y, Haass C, Ihara Y. Mutant presenilin 2 transgenic mouse: effect on an age-dependent increase of amyloid beta-protein 42 in the brain. J Neurochem. 1998 Jul;71(1):313-22. PubMed.

    Yamaguchi H, Sugihara S, Ogawa A, Saido TC, Ihara Y. Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol. 1998 Mar;95(3):217-22. PubMed.

    Sawamura N, Morishima-Kawashima M, Waki H, Kobayashi K, Kuramochi T, Frosch MP, Ding K, Ito M, Kim TW, Tanzi RE, Oyama F, Tabira T, Ando S, Ihara Y. Mutant presenilin 2 transgenic mice. A large increase in the levels of Abeta 42 is presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin. J Biol Chem. 2000 Sep 8;275(36):27901-8. PubMed.

    Funamoto S, Morishima-Kawashima M, Tanimura Y, Hirotani N, Saido TC, Ihara Y. Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry. 2004 Oct 26;43(42):13532-40. PubMed.

    Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci. 2005 Jan 12;25(2):436-45. PubMed.

    Sato T, Tanimura Y, Hirotani N, Saido TC, Morishima-Kawashima M, Ihara Y. Blocking the cleavage at midportion between gamma- and epsilon-sites remarkably suppresses the generation of amyloid beta-protein. FEBS Lett. 2005 May 23;579(13):2907-12. PubMed.

    Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC. Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci. 2011 Aug;14(8):1023-32. PubMed.

    Funamoto S, Sasaki T, Ishihara S, Nobuhara M, Nakano M, Watanabe-Takahashi M, Saito T, Kakuda N, Miyasaka T, Nishikawa K, Saido TC, Ihara Y. Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase. Nat Commun. 2013;4:2529. PubMed.

    Morishima-Kawashima M, Saido TC, Ihara Y. [Alzheimer's disease and the proteins]. Tanpakushitsu Kakusan Koso. 2001 Aug;46(11 Suppl):1798-804. PubMed.

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References

Paper Citations

  1. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron. 1994 Jul;13(1):45-53. PubMed.
  2. Kakuda N, Yamaguchi H, Akazawa K, Hata S, Suzuki T, Hatsuta H, Murayama S, Funamoto S, Ihara Y. γ-Secretase Activity Is Associated with Braak Senile Plaque Stages. Am J Pathol. 2020 Jun;190(6):1323-1331. Epub 2020 Mar 20 PubMed.
  3. Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y. Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch. J Biol Chem. 2001 Sep 21;276(38):35235-8. PubMed.
  4. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009 Oct 14;29(41):13042-52. PubMed.
  5. Nukina N, Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem. 1986 May;99(5):1541-4. PubMed.
  6. Ihara Y, Nukina N, Miura R, Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem. 1986 Jun;99(6):1807-10. PubMed.
  7. Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science. 1987 Mar 27;235(4796):1641-4. PubMed.
  8. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1988;75(4):345-53. PubMed.
  9. Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282-6. PubMed.

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