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Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques

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Abstract

Background

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production.

Method

Using the proband’s samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1.

Results

The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased.

Conclusion

Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

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Acknowledgments

This work was supported by a grant from the Japanese Millennium Project. We thank Norihiro Ogawa for technical assistance in the pathological study. We are most grateful to all participants in the study.

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory Science, Tenri University, Nara, Japan

    Hidehisa D. Yamagata & Tomoya Fukuoka

  2. Choju Medical Institute, Fukushimura Hospital, Aichi, Japan

    Hiroyasu Akatsu, Takayuki Yamamoto, Akira Hori & Yoshio Hashizume

  3. Matsuyama Memorial Hospital, Matsuyama, Ehime, Japan

    Akito Wake, Ichiro Watanabe & Naoto KImura

  4. Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Touon-shi, Ehime, Japan

    Tetsuro Miki

  5. Department of Pathology, Ehime University Graduate School of Medicine, Touon-shi, Ehime, Japan

    Kazuo Kamada & Tatsuhiko Miyazaki

  6. Department of Aging Neurobiology, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi, Japan

    Naoyuki Sato

  7. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan

    Maya Mimuro & Mari Yoshida

Authors
  1. Hidehisa D. Yamagata
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  2. Hiroyasu Akatsu
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Contributions

HDY: study design, genetic analysis. HA, AW, IW, NK, TeM: data collection. TF: drafting and revising manuscript. KK, TaM, TY, AH, MM, MY, YH: pathological studies. NS: functional assay. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hidehisa D. Yamagata.

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Ethical approval

All procedures used in this research were approved by the Ethics Committee of Ehime University School of Medicine and were conducted according to the principles of the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individuals included in this study.

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None.

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Yamagata, H.D., Akatsu, H., Fukuoka, T. et al. Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques. Neurol Sci (2024). https://doi.org/10.1007/s10072-024-07537-1

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