Obituary for the late Yasuo Ihara
Professor Yasuo Ihara, who guided a number of researchers including myself to a career in research on AD, passed away on June 10, 2023. He was 78 years old.
It was the 1990s, over 30 years ago, when I got into Alzheimer’s disease (AD) research via basic research on proteolysis. The motivation for this was my encounter with Professor Ihara. At that time, Prof. Ihara was Chairman of the Department of Neuropathology, Faculty of Medicine, University of Tokyo (located in Hongo, Tokyo), and I was a research scientist at the Tokyo Metropolitan Institute of Medical Science (located in Komagome, Tokyo). Prof. Ihara and I were involved in proving the hypothesis that the chemical structure of Aβ, which had been established as a causative agent of AD, 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 to Hongo by bicycle. The discussions often lasted over two hours; it was a dreamy time, and truly the happiest period in my research career. I co-authored the research with Prof. Ihara and published it in Neuron,1 which later led to development of donanemab by Lilly2?–4 and has been approved by FDA.
I can confidently say that I would not be where I am today without my encounter with Prof. Ihara. In total, he and I published 12 papers together in English1,5?–15 and one review in Japanese.16
After that, we continued to interact not only in research but also in the management of the Japan Dementia Research Society. However, after Prof. 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, meaning that opportunities to see him diminished. The fact that visits were restricted due to the COVID-19 pandemic was also an obstacle. Professor Ihara’s wake was held on June 12, and his funeral ceremony was held on June 13, 2023. Researchers around the world requested live streaming, so with the permission of his close family members, we shared the live information and recordings on Zoom. Prof. Ihara was one of the first researchers in the world to discover that tau protein is a component of neurofibrillary tangles.17,18 He also pioneered in elucidation of the serial cleavages of APP C-terminal fragment by γ-secretase.15,19 Everyone involved in AD research has heard of him. It is exactly as if “a giant star has fallen”.
In addition to his research, he was instrumental in reforming and developing the Japanese Dementia Research Society. June 10th became the saddest day for me. I sincerely pray for the repose of his soul.
Takaomi C. Saido
RIKEN Center for Brain Science
Wako, Japan.
Photo by TC Saido
REFERENCES
[1] | Saido TC , Iwatsubo T , Mann DM , et al. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron (1995) ; 14: : 457–466. |
[2] | Mintun MA , Lo AC , Duggan Evans C , et al. Donanemab in early Alzheimer’s disease. N Engl J Med (2021) ; 384: : 1691–1704. |
[3] | Demattos RB , Lu J , Tang Y , et al. A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice. Neuron (2012) ; 76: : 908–920. |
[4] | Sims JR , Zimmer JA , Evans CD , et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA (2023) ; 330: : 512–527. |
[5] | Saido TC , Yokota M , Maruyama K , et al. Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. J Biol Chem (1994) ; 269: : 15253–15257. |
[6] | Yamazaki T , Haass C , Saido TC , et al. Specific increase in amyloid beta-protein 42 secretion ratio by calpain inhibition. Biochemistry (1997) ; 36: : 8377–8383. |
[7] | Funato H , Yoshimura M , Yamazaki T , et al. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol (1998) ; 152: : 983–992. |
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[9] | Yamaguchi H , Sugihara S , Ogawa A , et al. Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol (1998) ; 95: : 217–222. |
[10] | Sawamura N , Morishima-Kawashima M , Waki H , et al. 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) ; 275: : 27901–27908. |
[11] | Funamoto S , Morishima-Kawashima M , Tanimura Y , et al. Truncated carboxyl-terminal fragments of beta-amyloid precursor protein are processed to amyloid beta-proteins 40 and 42. Biochemistry (2004) ; 43: : 13532–13540. |
[12] | Qi-Takahara Y , Morishima-Kawashima M , Tanimura Y , et al. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci (2005) ; 25: : 436–445. |
[13] | Sato T , Tanimura Y , Hirotani N , et al. Blocking the cleavage at midportion between gamma- and epsilon-sites remarkably suppresses the generation of amyloid beta-protein. FEBS Lett (2005) ; 579: : 2907–2912. |
[14] | Saito T , Suemoto T , Brouwers N , et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci (2011) ; 14: : 1023–1032. |
[15] | Funamoto S , Sasaki T , Ishihara S , et al. Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase. Nat Commun (2013) ; 4: : 2529. |
[16] | Morishima-Kawashima M , Saido TC and Ihara Y. [Alzheimer’s disease and the proteins]. Tanpakushitsu Kakusan Koso (2001) ; 46: : 1798–1804. |
[17] | Ihara Y , Nukina N , Miura R , et al. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J Biochem (1986) ; 99: : 1807–1810. |
[18] | Nukina N and Ihara Y. One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem (1986) ; 99: : 1541–1544. |
[19] | Takami M , Nagashima Y , Sano Y , et al. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci (2009) ; 29: : 13042–13052. |
