講師の部屋

English

Takeshi Kawarabayashi, M.D., Ph.D.
Department of Neurology,
Institute of Brain Science, Hirosaki University Graduate School of Medicine
5 Zaifu, Hirosaki, Aomori 036-8216, Japan
Tel: +81-172-39-5142
Fax: +81-172-39-5143
Email: tkawara@hirosaki-u.ac.jp

CURRICULUM VITAE
EDUCATION and DEGREES:
1983 M.D. Gunma University School of Medicine
1993 Ph.D. Gunma University School of Medicine, Maebashi
PROFESSIONAL TRANING AND EMPLOYMENT:
2007- Lecturer, Department of Neurology, Hirosaki University Graduate School of Medicine
2006-2007 Assistant, Department of Neurology, Hirosaki University Graduate School of Medicine
2005-2006 Assistant, Department of Neurology, Okayama University Graduate School of Medicine
2002-2005 Clinical Fellow, Department of Neurology, Okayama University Graduate School of Medicine
2000-2002 Clinical Fellow, Sawarabi Spring Hospital
1997-2000 Visiting scientist, Alzheimer Research Center, Department of Pharmacology, Mayo Clinic Jacksonville
1983-1997 Resident, Department of Neurology, Gunma University School of Medicine
AWARDS AND HONORS:
2008 Presentation Award, Hirosaki Medical Society
2001 Presentation Award, Japanease Society for Neurology
1997 Japanese longevity science Foundation
1996 Novartis Foundation
MAJOR RESEARCH INTERESTS:
Clinical Neurology, Alzheimer’s disease, non-AD dementia, Neurodegenerative disease Development of Biomarkers of Neurodegenerative disease
Development of Animal model
Development of disease modifying drugs
Pathogenesis of Alzheimer’s disease
MEMBERSHIPS:
Japanease Society for Dementia (Councilor)
The Japan Geriatrics Society (Councilor)
Japanease Society for Neurology
Japanease Society for Internal Medicine
Society for Neuroscience
CURRENT GRANT FUNDING:
Position: Principal Investigator
Number: 24591246
Grantor: Grant-in-Aid for Scientificy Research (C) from JSPS
Period: 2004-2005
Total Amount: ¥3,900,000
PATENTS:
2009 Transformed soybean plant which stores vaccine, and use thereof (PCT/JP200906997)

PUBLICATIONS:
  • Takamura A, Sato Y, Watabe D, Okamoto Y, Nakata T, Kawarabayashi T, Oddo S, Laferla FM, Shoji M, Matsubara E, Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways. Life Sci. 2012; 91(23-24):1177-1186.
  • Watanabe M, Adachi Y, Jackson M, Yamamoto-Watanabe Y, Wakasaya Y, Shirahama I, Takamura A, Matsubara E, Kawarabayashi T, Shoji M. An unusual case of elderly-onset CADASIL with multiple cerebrovascular risk factors. J Stroke Cerebrovasc Dis. 2012;21(2):143-145.
  • Takamura A, Kawarabayashi T, Yokoseki T, Shibata M, Morishima-Kawashima M, Saito Y, Murayama S, Ihara Y, Abe K, Shoji M, Michikawa M, and Matsubara E, Dissociation of Aβ from lipoprotein in cerebrospinal fluid from Alzheimer’s disease accelerates Aβ42 assembly. J Neurosci Res. 2011;89(6):815-821.
  • Takamura A, Okamoto Y, Kawarabayashi T, Yokoseki T, Shibata M, Mouri A, Nabeshima T, Sun H, Abe K, Urisu T, Yamamoto N, Shoji M, Yanagisawa K, Michikawa M, Matsubara E, Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer’s disease model mouse. Mol Neurodegener, 2011;6(1):20.
  • Wakasaya Y, Kawarabayashi T, Watanabe M, Yamamoto-Watanabe Y, Takamura A, Kurata T, Murakami T, Abe K, Yamada K, Wakabayashi K, Sasaki A, Westaway D, St.George-Hyslop P, Matsubara E, Shoji M, Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy. J Neurosci Res. 2011;89(4):576-584.
  • Seino Y, Kawarabayashi T, Wakasaya Y, Takamura A, Nakahata N, Watanabe M, Yamamoto-Watanabe Y, Matsubara E, Westaway D, Davis P, St.George-Hyslop P, Shoji . Aß amyloid accelerates accumulation of phosphorylated tau in neuronal cytoplasm and processes of double transgenic mice.J Neurosci Res. 2010;88(16):3547-3554.
  • Yamamoto-Watanabe Y, Watanabe M, Jackson M, Akimoto H, Sugimoto K, Yasujima M, Wakasaya Y, Matsubara E, Kawarabayashi T, Harigaya Y, Lyndon AR, Shoji M. Quantification of cystatin C in cerebrospinal fluid from various neurological disorders and correlation with G73A polymorphism in CST3 . Brain Res. 2010;1361:140-145.
  • Yamamoto-Watanabe Y, Watanabe M, Hikichi M, Ikeda Y, Jackson M, Wakasaya Y, Matsubara E, Kawarabayashi T, Kannari K, Shoji M. Prevalence of autosomal dominant cerebellar ataxia in Aomori, the northernmost prefecture of Honshu, Japan.Internal Med. 2010; 49(22):2409-2414.
  • Yamamoto-Watanabe Y, Watanabe M, Okamoto K, Fujita Y, Jackson M, Ikeda M, Nakazato Y, Ikeda Y, Matsubara E, Kawarabayashi T, Shoji M. A Japanese ALS6 family with mutation R521C in the FUS/TLS gene: a clinical, pathological and genetic report. J Neurol Sci. 2010; 296(1-2): 59-63.
  • Wakasaya Y, Watanabe M, Tomiyama M, Suzuki C, Jackson M, Fujimuro M, Kimura T, Seino Y, Kawarabayashi T, Yamamoto-Watanabe Y, Matsubara E, Shirahama I, Takamura A, Nakahata N, Shoji M. An unusual case of chronic relapsing tetanus associated with mandibular osteomyelitis. Intern Med. 2009;48(15):1311-1313.
  • Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, Shoji M, Takahashi M, Nakashima M. A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P+A53T transgenic mice. Parkinsonism Relat Disord. 2009;15(9):649-654.
  • Ikeda M, Kawarabayashi T, Harigaya Y, Sasaki A, Yamada S, Matsubara E, Murakami T, Tanaka Y, Kurata T, Wuhua X, Ueda K, Kuribara H, Ikarashi Y, Nakazato Y, Okamoto K, Abe K, Shoji M. Motor impairment and aberrant production of neurochemicals in human alpha-synuclein A30P+A53T transgenic mice with alpha-synuclein pathology. Brain Res 2009;1250:232-241.
  • Wati H, Kawarabayashi T, Matsubara E, Kasai A, Hirasawa T, Kubota T, Harigaya Y, Shoji M, Maeda S, Transthyretin accelerates vascular Aß deposition in a mouse model of Alzheimer’s disease. Brain Pathol. 2009 Jan;19(1):48-57.
  • Watanabe M, Monai N, Jackson M, Yamamoto-Watanabe Y, Ikeda Y, Suzuki C, Tomiyama M, Kawarabayashi T, Kimura T, Seino Y, Wakasaya Y, Miki Y, Matsubara E, Shoji M, A small trinucleotide expansion in the TBP gene gives rise to a sporadic case of SCA17 with abnormal putaminal findings on MRI. Intern Med. 2008;47(24):2179-2182.
  • Suzuki C, Watanabe M, Tomiyama M, Sugimoto K, Nanba E, Jackson M, Kimura T, Seino Y, Wakasaya Y, Kawarabayashi T, Miki Y, Yamamoto-Watanabe Y, Shoji M, A novel mutation in the arylsulfatase A gene associated with adult-onset metachromatic leukodystrophy without clinical evidence of neuropathy. Eur Neurol. 2008;60(6):310-311.
  • Kurata T, Hayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Kawarabayashi T, Takao Y, Ohta T, Harigaya Y, Manabe Y, Kamiya T, Shoji M, Abe K, Differentiation of PA from early PSP with different patterns of symptoms and CBF reduction. Neurol Res. 2008;30(8):860-867.
  • Xu W, Kawarabayashi T, Matsubara E, Deguchi K, Murakami T, Harigaya Y, Ikeda M, Amari M, Kuwano R, Abe K, Shoji M, Plasma antibodies to Aß40 and Aß42 in patients with Alzheimer’s disease and normal controls. Brain Res. 2008;1219:169-179.
  • Arai A, Tomiyama M, Kannari K, Kimura T, Suzuki C, Watanabe M, Kawarabayashi T, Shen H, Shoji M, Reuptake of L-DOPA-derived extracellular DA in the striatum of a rodent model of Parkinson’s disease via norepinephrine transporter. Synapse. 2008;62(8):632-635.
  • Sasaki A, Kawarabayashi T, Murakami T, Matsubara E, Ikeda M, Hagiwara H, Westaway D, St.George-Hyslop P, Shoji M, Nakazato Y, Microglial activation in brain lesions with tau deposits: comparison of human tauopathies and tau transgenic mice TgTauP301L. Brain Res. 2008;1214:159-168.
  • Kawarabayashi T, Shoji M, Plasma biomarkers of Alzheimer’s disease. Curr Opin Psychiatry. 2008;21(3):260-267.
  • Tomiyama M, Arai A, Kimura T, Suzuki C, Watanabe M, Kawarabayashi T, Shoji M, Exacerbation of chronic pancreatitis induced by anticholinesterase medications in myasthenia gravis. Eur J Neurol. 2008;15(5):e40-41.
  • Kurata T,Kawarabayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Ikeda M, Matsubara E, Westaway D, St.George-Hyslop P, Harigaya Y, Kamiya T, Shoji M, Abe K. Enhanced accumulation of phosphorylated a-synuclein in double transgenic mice expressing mutant ßAPP and presenilin-1. J Neurosci Res. 2007;85(10):2246-2252.
  • Murakami T, Moriwaki Y, Kawarabayashi T, Nagai M, Ohta Y, Deguchi K, Kurata T, Takehisa Y, Matsubara E, Ikeda M, Harigaya Y, Shoji M, Takahashi R, Abe, K. PINK1, a gene product of PARK6, accumulates in a-synucleinopathy brains. J Neurol Neurosurg Psychiatry. 2007;78(6):653-654.
  • Murakami T, Paitel E, Kawarabayashi T, Ikeda M, Chishti MA, Janus C, Matsubara E, Sasaki A, Kawarai T, Phinney AL,
    Harigaya Y, Horne P, Egashira N, Mishima K, Hanna A, Yang J, Iwasaki, K, Takahashi M, Fujiwara M, Ishiguro K, Bergeron C, Carlson GA, Abe K, Westaway D, St.George-Hyslop P, Shoji M, Cortical neuronal and glial pathology in
    TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation, Am J Pathol. 2006;169(4):1365-1375.
  • Samura E, Shoji M, Kawarabayashi T, Sasaki A, Matsubara E, Murakami T, Wuhua X, Tamura S, Ikeda M, Ishiguro K, Saido TC, Westaway D, St George Hyslop P, Harigaya Y, Abe K, Enhanced accumulation of tau in doubly transgenic mice expressing mutant ßAPP and presenilin-1. Brain Res. 2006;1094(1):192-199.
  • Harigaya Y, Tomidokoro Y, Ikeda M, Sasaki A, Kawarabayashi T, Matsubara E, Kanai M, Saido TC, Younkin SG, Shoji M Type-specific evolution of amyloid plaque and angiopathy in APPsw mice. Neurosci Lett. 2006;395(1):37-41.
  • Ikeda M, Shoji M, Kawarai T, Kawarabayashi T, Matsubara E, Murakami T, Sasaki A, Tomidokoro Y, Ikarashi Y, Kuribara H, Ishiguro K, Hasegawa M, Yen SH, Chishti MA, Harigaya Y, Abe K, Okamoto K, St George-Hyslop P, Westaway D, Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice. Am J Pathol. 2005;166(2):521-531.
  • Ohyagi Y, Asahara H, Chui DH, Tsuruta Y, Sakae N, Miyoshi K, Yamada T, Kikuchi H, Taniwaki T, Murai H, Ikezoe K, Furuya H, Kawarabayashi T, Shoji M, Checler F, Iwaki T, Makifuchi T, Takeda K, Kira JI, Tabira T, Intracellular Aß42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB J. 2005;19(2):255-257.
  • Kawarabayashi T, Shoji M, Younkin LH, Wen-Lang L, Dickson DW, Murakami T, Matsubara E, Abe K, Ashe KH, Younkin SG, Dimeric amyloid ß protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci. 2004;24(15):3801-3809.
  • Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R, Abe K, Pael-R is accumulated in Lewy bodies of Parkinson’s disease. Ann Neurol, 2004;55(3):439-442.
  • Matsubara E, Sekijima Y, Tokuda T, Urakami K, Amari M, Shizuka-Ikeda M, Tomidokoro Y, Ikeda M, Kawarabayashi T, Harigaya Y, Ikeda S, Murakami T, Abe K, Otomo E, Hirai S, Frangione B, Ghiso J, Shoji M, Soluble Aß homeostasis in AD and DS: impairment of anti-amyloidogenic protection by lipoproteins. Neurobiol Aging. 2004;25(7):833-841.
  • Ikarashi Y, Harigaya Y, Tomidokoro Y, Kanai M, Ikeda M, Matsubara E, Kawarabayashi T, Kuribara H, Younkin SG, Shoji M, Decreased level of brain acetylcholine and memory disturbance in APPsw mice. Neurobiol Aging. 2004;25(4):483-490.
  • Sasaki A, Shoji M, Harigaya Y, Kawarabayashi T, Ikeda M, Naito M, Matsubara E, Abe K, Nakazato Y, Amyloid cored plaques in Tg2576 transgenic mice are characterized by giant plaques, slightly activated microglia, and the lack of paired helical filament-typed, dystrophic neuritis. Virchows Arch. 2002;441(4):358-367.
  • Shoji M, Fukushima K, Wakayama M, Shizuka-Ikeda M, Ikeda Y, Kawakami A, Sakazume Y, Ikeda M, Harigaya Y, Matsubara E, Kawarabayashi T, Murakami T, Nagano I, Manabe Y, Abe K, Intellectual faculities in patients with Alzheimer’s disease regress to the level of a 4-5-year old child. Geriatrics and Gerontology International. 2002;2:143-147.
  • Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH, Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci. 2002;22(15):6331-6335.
  • Shizuka-Ikeda M, Matsubara E, Ikeda M, Kanai M, Tomidokoro Y, Ikeda Y, Watanabe M, Kawarabayashi T, Harigaya Y, Okamoto K, Maruyama K, Castaño EM, St. George-Hyslop P, Shoji M, Generation of amyloid ß protein from a presenilin-1 and ßAPP complex. Biocem Biophys Res Commun. 2002;292(2):571-578.
  • Shoji M, Matsubara E, Murakami T, Manabe Y, Abe K, Kanai M, Ikeda M, Tomidokoro Y, Shizuka M, Watanabe W, Amari M, Ishiguro K, Kawarabayashi T, Harigaya Y, Okamoto K, Nishimura T, Nakamura Y, Takeda M, Urakami K, Adachi Y, Nakashima K, Arai H, Sasaki H, Kanemaru K, Yamanouchi H, Yoshida Y, Ich K, Yoshida H, Toji H, Nakamura S, Hirai H, Cerebrospinal fluid tau in dementia disorders: A large scale multicenter study by a Japanese study group. Neurobiol Aging. 2002;23(3):363-370.
  • Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH, The relationship between Aß and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci. 2002;22(5):1858-1867.
  • Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG, Golde TE, Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis. 2002;9(1):11-23.
  • Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG, Age-dependent changes in brain, CSF, and plasma amyloid ß protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci. 2001;21(2):372-381.
  • Yu H, Saura CA, Choi S, Sun LD, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson MA, Younkin S, Kandel ER, Kirkwood A, Shen J, APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron. 2001;31(5):713-726.
  • Tomidokoro Y, Harigaya Y, Matsubara E, Ikeda M, Kawarabayashi T, Shirao T, Ishiguro K, Okamoto K, Younkin SG, Shoji M, Brain Aß amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau. J Pathol. 2001;194(4):500-506.
  • Tomidokoro Y, Ishiguro K, Harigaya Y, Matsubara E, Ikeda M, Park JM, Yasutake K, Kawarabayashi T, Okamoto K, Shoji M, Aß amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice. Neurosci Lett. 2001;299(3):169-172.
  • Tomidokoro Y, Harigaya Y, Matsubara E, Ikeda M, Kawarabayashi T, Okamoto K, Shoji M, Impaired neurotransmitter systems by Aß amyloidosis in APPsw transgenic mice overexpressing amyloid ß protein precursor. Neurosci Lett. 2000;292(3):155-158.
  • Tucker HM, Kihiko M, Caldwell JN, Wright S, Kawarabayashi T, Price D, Walker D, Scheff S, McGillis JP, Rydel RE, Estus S, The plasmin system is induced by and degrades amyloid-ß aggregates. J Neurosci. 2000;20(11):3937-3946.
  • Shoji M, Kawarabayashi T, Matsubara E, Ikeda M, Ishiguro K, Harigaya Y, Okamoto K, Distribution of amyloid ß protein precursor in the Alzheimer’s disease brain. Psychiatry Clin Neurosci. 2000;54(1):45-54.
  • Shoji M, Kawarabayashi T, Sato M, Sasaki A, Saido TC, Matsubara E, Tomidokoro Y, Kanai M, Shizuka M, Ishiguro K, Ikeda M, Harigaya Y, Okamoto K, Hirai S, Age-related amyloid ß protein accumulation induces cellular death and macrophage activation in transgenic mice. J Pathol. 2000;191(1):93-101.
  • Tomidokoro Y, Ishiguro K, Igeta Y, Matsubara E, Kanai M, Shizuka M, Kawarabayashi T, Harigaya Y, Kawakatsu S, Ii K, Ikeda M, St George-Hyslop PH, Hirai S, Okamoto K, Shoji M, Carboxyl-terminal fragments of presenilin-1 are closely related to cytoskeletal abnormalities in Alzheimer’s brains. Biochem Biophys Res Commun. 1999;256(3):512-518.
  • Shoji M, Matsubara E, Kanai M, Watanabe M, Nakamura T, Tomidokoro Y, Shizuka M, Wakabayashi K, Igeta Y, Ikeda Y, Mizushima K, Amari M, Ishiguro K, Kawarabayashi T, Harigaya Y, Okamoto K, Hirai S, Combination assay of CSF tau, Aß1-40 and Aß1-42(43) as a biochemical marker of Alzheimer’s disease. J Neurol Sci. 1998;158(2):134-140.
  • Kanai M, Matsubara E, Isoe K, Urakami K, Nakashima K, Arai H, Sasaki H, Abe K, Iwatsubo T, Kosaka T, Watanabe M, Tomidokoro Y, Shizuka M, Mizushima K, Nakamura T, Igeta Y, Ikeda Y, Amari M, Kawarabayashi T, Ishiguro K, Harigaya Y, Wakabayashi K, Okamoto K, Hirai S, Shoji M, Longitudinal study of cerebrospinal fluid levels of tau, Aß1-40, and Aß1-42(43) in Alzheimer’s disease: a study in Japan. Ann Neurol. 1998;44(1):17-26.
  • Shoji M, Kawarabayashi T, Sato M, Sasaki A, Matsubara E, Igeta Y, Kanai M, Tomidokoro Y, Shizuka M, Ishiguro K, Harigaya Y, Okamoto K, Hirai S, Accumulation of amyloid ß protein in transgenic mice. Neurobiol Aging. 1998;19(1 Suppl):S59-63.
  • Igeta Y, Kawarabayashi T, Sato M, Yamada N, Matsubara E, Ishiguro K, Kanai M, Tomidokoro Y, Osuga J, Okamoto K, Hirai S, Shoji M, Apolipoprotein E accumulates with the progression of Aß deposition in transgenic mice. J Neuropathol
    Exp Neurol. 1997;56(11):1228-1235.
  • Kawarabayashi T, Igeta Y, Sato M, Sasaki A, Matsubara E, Kanai M, Tomidokoro Y, Ishiguro K, Okamoto K, Hirai S, Shoji M, Lysosomal generation of amyloid ß protein species in transgenic mice. Brain Res. 1997;765(2):343-348.
  • Sato M, Kawarabayashi T, Shoji M, Kobayashi T, Tada N, Matsubara E, Hirai S, Neurodegeneration and gliosis in transgenic mice overexpressing a carboxy-terminal fragment of Alzheimer amyloid-ß protein precursor. Dement
    Geriatr Cogn Disord. 1997;8(5):296-307.
  • Kawarabayashi T, Shoji M, Sato M, Sasaki A, Ho L, Eckman CB, Prada CM, Younkin SG, Kobayashi T, Tada N, Matsubara E, Iizuka T, Harigaya Y, Kasai K, Hirai S, Accumulation of ß-amyloid fibrils in pancreas of transgenic mice. Neurobiol Aging. 1996;17(2):215-222.
  • Iizuka T, Shoji M, Kawarabayashi T, Sato M, Kobayashi T, Tada N, Kasai K, Matsubara E, Watanabe M, Tomidokoro Y, Hirai S, Intracellular generation of amyloid ß-protein from amyloid beta- and gamma-secretase. Biochem Biophys Res Commun. 1996;218(1):238-242.
  • Shoji M, Kawarabayashi T, Sato M, Sasaki A, Matsubara E, Iizuka T, Harigaya Y, Hirai S, Systemic overexpression of a C-terminal fragment of human amyloid ß-protein precursor causes accumulation of Alzheimer ß-amyloid fibrils in pancreas of transgenic mice. Gerontology. 1996;42 (Suppl 1):48-56.
  • Iizuka T, Shoji M, Harigaya Y, Kawarabayashi T, Watanabe M, Kanai M, Hirai S, Amyloid ß-protein ending at Thr43 is a minor component of some diffuse plaques in the Alzheimer’s disease brain, but is not found in cerebrovascular amyloid. Brain Res. 1995;702(1-2):275-278.
  • Harigaya Y, Shoji M, Kawarabayashi T, Kanai M, Nakamura T, Iizuka T, Igeta Y, Saido TC, Sahara N, Mori H, Hirai S, Modified amyloid ß protein ending at 42 or 40 with different solubility accumulates in the brain of Alzheimer’s disease. Biochem Biophys Res Commun. 1995;211(3):1015-1022.
  • Yamaguchi H, Yamazaki T, Kawarabayashi T, Sun X, Sakai Y, Hirai S, Localization of Alzheimer amyloid ß protein precursor and its relation to senile plaque amyloid. Gerontology. 1994;40(Suppl 2):65-70.
  • Yamaguchi H, Ishiguro K, Sugihara S, Nakazato Y, Kawarabayashi T, Sun X, Hirai S, Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer ß-amyloid deposition. Acta
    Neuropathol. 1994;88(5):413-419.
  • Yamazaki T, Yamaguchi H, Kawarabayashi T, Hirai S, Ultrastructural localization of amyloid ß/A4 protein precursor in the normal rat brain. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993;63(3)173-180.
  • Kawarabayashi T, Shoji M, Yamaguchi H, Tanaka M, Harigaya Y, Ishiguro K, Hirai S, Amyloid ß protein precursor accumulates in swollen neurites throughout rat brain with aging. Neurosci Lett. 1993;153(1):73-76.
  • Ikeda M, Shoji M, Yamaguchi H, Matsubara E, Amari M, Ishiguro K, Kawarabayashi T, Harigaya Y, Hirai S, Diagnostic significance of skin immunolabelling with antibody against native cerebral amyloid in Alzheimer’s disease. Neurosci Lett.
    1993;150(2):159-161.
  • Ishiguro K, Shoji M, Yamaguchi H, Matsubara E, Ikeda M, Kawarabayashi T, Harigaya Y, Okamoto K, Hirai S, Differential expression of alpha 1-antichymotrypsin in the aged human brain. Virchows Arch B Cell Pathol Incl Mol Pathol. 1993;64(4):221-227.
  • Yamazaki T, Yamaguchi H, Nakazato Y, Ishiguro K, Kawarabayashi T, Hirai S, Ultrastructural characterization of cerebellar diffuse plaques in Alzheimer’s disease. J Neuropathol Exp Neurol. 1992;51(3):281-286.
  • Kawarabayashi T, Shoji M, Harigaya Y, Yamaguchi H, Hirai S, Expression of APP in the early stage of brain damage. Brain Res. 1991;563(1-2):334-338.
  • Kawarabayashi T, Shoji M, Harigaya Y, Yamaguchi H, Hirai S, Amyloid ß/A4 protein precursor is widely distributed in both the central and peripheral nervous systems of the mouse. Brain Res. 1991;552(1):1-7.
  • Yamaguchi H, Nakazato Y, Kawarabayashi T, Ishiguro K, Ihara Y, Morimatsu M, Hirai S, Extracellular neurofibrillary tangles associated with degenerating neurites and neuropil threads in Alzheimer-type dementia. Acta Neuropathol.1991;81(6):603-609.
  • Okamoto K, Hirai S, Ishiguro K, Kawarabayashi T, Takatama M, Light and electron microscopic and immunohistochemical observations of the Onuf’s nucleus of amyotrophic lateral sclerosis. Acta Neuropathol. 1991;81(6):610-614.
  • Yamaguchi H, Nakazato Y, Yamazaki T, Shoji M, Kawarabayashi T, Hirai S, Subpial ß/A4 amyloid deposition occurs between astroglial processes in Alzheimer-type dementia. Neurosci Lett. 1991;123(2):217-220.
  • Shoji M, Kawarabayashi T, Harigaya Y, Yamaguchi H, Hirai S, Kamimura T, Sugiyama T, Alzheimer amyloid ß-protein precursor in sperm development. Am J Pathol. 1990;137(5):1027-1032.
  • Shoji M, Hirai S, Harigaya Y, Kawarabayashi T, Yamaguchi H, The amyloid ß-protein precursor is localized in smooth muscle cells of leptomeningeal vessels. Brain Res. 1990;530(1):113-116.
  • Shoji M, Hirai S, Yamaguchi H, Harigaya Y, Kawarabayashi T, Amyloid ß-protein precursor accumulates in dystrophic neurites of senile plaques in Alzheimer-type dementia. Brain Res. 1990;512(1):164-168.
  • Tanaka M, Suzuki H, Kawarabayashi T, Morimatsu M, Hirai S, Palatal myoclonus disappears in sleep. Neurology. 1984;34(3):406-407.

研究紹介

認知症患者の数は世界中で増加を続けており、2030年には7600万人に、2050年には1億3500万人にもなると予想され、大きな社会問題になっています。2013年12月11日には初のG8 Dementia SummitがLondonで開催され、2025年までに認知症の治療または病態修飾療法を同定し、その目的を達成するために、認知症に関する研究を進めることが宣言されました。

当研究室では認知症の臨床研究、基礎研究を一貫して行ってきました。早期診断のための診断マーカーの開発、モデルマウスを用いた病態の解析、および疾患修飾薬の開発などを行っており、今年度からは家族性アルツハイマー病の発症前診断および発症前からの治療法を目指すDominantly Inherited Alzheimer Network (DIAN)研究に参加しています。

  1. 認知症診断マーカーの開発
    当研究室では脳脊髄液中のアミロイドß蛋白(Aß)およびタウの測定がアルツハイマー病の早期診断に有用なことを世界に先駆けて示しました。また、血液中のAßがアルツハイマー病の発症予測のマーカーであることも示しています。現在は新たな疾患マーカーの開発を行っています。
    Kanai K, et al., Ann Neurol 1998
    Shoji M, et al., Ann Neurol 2000
    Shoji M, et al., Neurobiol Aging 2001
    Shoji M, et al., Neurobiol Aging 2002
  2. 疾患モデルマウスの確立
    当研究室ではtransgenic mouseを用いた疾患モデルマウスの作製とこれを用いた疾患の病態解析と治療法開発を行ってきました。
    1) アルツハイマー病モデルマウス アミロイドß蛋白前駆体蛋白(APP)を発現します。
    ① NOR-ß, deltaNOR-ß, deltaNL-ß 当科にて作製しました。
    ß-actin promotorの下にAPPのC末部分を発現させました。Aßは脳を始めとして全身に発現し、膵臓にAß アミロイドの蓄積と著明な細胞死、マクロファージの活性化を再現しました。ニューヨーク大学でもこのマウスを用いた解析を行っています。
    Kawarabayashi T, et al., Neurobiol Aging 1996
    Shoji M, et al., Neurobiol Aging 1998
    Igeta Y, et al., J Neuropathol Exp Neurol 1997
    ② Tg2576 hamster prion promotorの下でSweden型の家族性アルツハイマー病の遺伝子変異をもつAPP695を発現します。 Minnesota,大学のAshe KH教授らが作製し、アメリカ留学中から解析を担当しました。学習障害は6月齢から、8月齢から脳アミロイドが沈着し、アルツハイマー病の多くの変化を再現することから、現在最も広く使われているアルツハイマー病モデルマウスです。
    Kawarabayashi T, et al., J Neurosci 2000
    Westerman MA, et al., J Neurosci 2002
    ③ TgCRND8 Toronto大学のSt George-Hyslop P教授らが作製した家族性アルツハイマー病の変異を2つ持つマウスで、2月齢から脳アミロイドが蓄積して学習障害を起こします。後述する経口免疫療法の開発に使用しています。
    2) タウオパチーモデルマウス
    パーキンソニズムを伴う家族性前頭側頭型認知症の遺伝子変異をそれぞれ1つづつ組み込んだタウをhamster prion promotorの下に発現するTgTauP301LおよびTgTauR406Wという2種類のマウスをSt George-Hyslop P教授らと共同開発しました。これらのマウスでは神経原線維変化、神経細胞死、行動障害を再現することができ、APP発現マウスでは再現できない神経細胞死がタウによって起こることが示されました。
    Murakami T, et al., Am J Pathol 2006
    Ikeda M, et al., Am J Pathol 2005
    Wakasaya Y, et al., J Neurosci Res 2011
    3) パーキンソン病、レヴィー小体型認知症モデルマウス
    家族性パーキンソン病の遺伝子変異を2つ組み込んだα-synucleinを発現するTgαSYNを当科にて作製しました。このマウスではパーキンソン病に特徴的に蓄積するLewy body様の封入体と線条体のドパミン減少、行動障害を再現することができました。またchaperon蛋白であるsodium 4-phenylbutyric acidの投与がリン酸化αSYNの蓄積を減少させ,線条体dopamineの減少を予防し、自発運動も改善することから、パーキンソン病治療に有望な薬剤であることが示されました。
    Ikeda M, et al., Brain Res. 2009
    Ono K, et al., Parkinsonism Relat Disord.2009
  3. アルツハイマー病発症におけるlipid raftsの関与の解明
    Lipid raftsとはglycosphingolipidとcholesterolに富み,それらの凝集によって形成されるmembrane microdomainで、細胞膜の脂質の海の上を筏(rafts)のように漂っていることから命名されました。そこにはcaveolin,flotillinなどの鋳型蛋白,プリオンなどのGPI anchor proteinや信号伝達系分子などの多くの蛋白が特異的に集積しており、蛋白,脂質輸送,信号伝達、細胞接着、貪食等の様々な機能が想定されています.
    私たちはモデルマウスや細胞系を用いて、lipid raftsがAßの産生部位であること、神経毒性の高いアミロイドß蛋白オリゴマーが早期から蓄積すること、この蓄積によってfynやグルタミン酸受容体の信号伝達系に変調を来すことを報告してきました。さらに近年Aß、タウやα-synucleinは異常プリオン蛋白のように脳内で神経細胞から分泌されて次の神経細胞に伝播していくことが示されましたが、この伝播への関与も疑われています。私たちはこの機序を明らかにすると共にlipid rafts標的療法の開発を行っております。
    Wahrle S, et al., Neurobiol Dis 2002
    Kawarabayashi T, et al., J Neurosci 2004
  4. アルツハイマー病免疫療法の開発
    アルツハイマー病の疾患修飾薬の中で最も有望視されているのが免疫療法です、当研究室ではアルツハイマー病モデルマウスを用いてAß免疫療法の開発を行っています。
    1. Aßワクチン療法
      Aß42ペプチドの経皮免疫によってTg2576マウスの脳アミロイド蓄積の減少が認められました
    2. Aß抗体療法 BAM-10
      AßのN末抗体BAM-10のTg2576マウスへの2週間投与により脳アミロイド沈着を変化させずに行動障害の改善が示されました。
      Kotilinek LA, et al., J Neurosci 2002
    3. Aß抗体療法 BC05
      Aß42特異抗体BC05の投与によりTg2576マウスで血中Aß42の著明な増加と脳Aß量とAßアミロイド沈着の減少が認められました。
      Asami-Odaka A, et al., Neurodegener Dis 2005
    4. Aß抗体療法 抗Aß oligomer特異抗体
      Aß oligomer特異抗体を作製し、Tg2576マウスへの投与により脳Aß oligomerの減少と学習障害の改善が認められました。現在は大分大学神経内科で松原教授が開発を続けており、臨床治験も近々行われるそうです。
      Takamura A, et al., Mol Neurodegener 2011
    5. Aß経口免疫療法
      AßのN末部位を組み込んだ組み換え大豆蛋白をTgCRND8マウスに経口投与することで学習障害の改善と脳Aß蓄積および脳Aß oligomerの減少を認めました。経口免疫療法はアルツハイマー病予防の安全な治療法として注目されています。現在論文作製中です。