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Treatment Strategy of Alzheimer Disease: Pause of Clinical Trials of Aβ Vaccine and Next Steps Shigeki Kuzuhara 1 1Department of Medical Welfare, Faculty of Health Science, Suzuka University of Medical Science Keyword: Alzheimer disease , treatment , vaccine , amyloid , tau , prevention pp.659-666
Published Date 2010/7/1
DOI https://doi.org/10.11477/mf.1416100710
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Abstract

 The important pathognomonic features of Alzheimer disease (AD) brain are the occurrence of abundant neurofibrillary tangles (NFTs) in neurons and presence of extracellular deposits of β-amyloid (Aβ)- senile plaques. In the early 1980s, the NFTs were characterized, and cerebral amyloid was purified; further the amino acid sequences of the tau protein in the NFTs and of Aβ were identifed. Immunohistochemical studies with antibodies to tau and Aβ revealed that extracellular accumulation of Aβ precedes that of tau in neurons. Molecular genetic studies revealed that abnormal gene mutations of familial AD accelerate Aβ production. On the basis of these findings, the amyloid cascade hypothesis that Aβ accumulation is the primary cause of neuronal degeneration and induces accumulation of tau in the AD brain was proposed and widely accepted. Thus, on the basis of this hypothesis, transgenic AD mice were treated with Aβ vaccine; the Aβ amyloid plaques were eliminated, and a dramatic improvement of the behavioral deficits was observed in the treated mice.

 The great success of preclinical studies promoted clinical trials of the Aβ vaccine in AD patients. However, the clinical trials were discontinued because of the occurrence of severe meningoencephalitis. Postmortem examination of the brains of the vaccinated patients with high titer of the anti- Aβ antibody in the serum revealed elimination of the Aβ plaques along with presence of cerebral inflammation. However, in autopsy-proven cases, assessment of the clinical and cognitive functions of the patients did not provide any evidence for improved survival or prolongation of the time to severe dementia. Thus, anti-Aβ antibody could eliminate the accumulated Aβ but could not rescue the degenerated neurons. Thus, the AD treatment strategy should be converted from repair and cure of AD to prevention. Anti-Aβ therapy must be started at the preclinical stage, and it is necessary to focus on tau and other proteins, mitochondria, glial cells, and other factors that influence the degeneration of neurons.


Copyright © 2010, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1344-8129 印刷版ISSN 1881-6096 医学書院

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