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Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease

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Abstract

Background

Mutations in the presenilin proteins cause early-onset, familial Alzheimer’s disease (FAD).

Materials and Methods

We characterized the cellular localization and endoproteolysis of presenilin 2 (PS2) and presenilin 1 (PS1) in brains from 25 individuals with presenilin-mutations causing FAD, as well as neurologically normal individuals and individuals with sporadic Alzheimer’s disease (AD).

Results

Amino-terminal antibodies to both prese-nilins predominantly decorated large neurons. Regional differences between the broad distributions of the two presenilins were greatest in the cerebellum, where most Purkinje cells showed high levels of only PS2 immunoreactivity. PS2 endoproteolysis in brain yielded multiple amino-terminal fragments similar in size to the PS1 amino-terminal fragments detected in brain. In addition, two different PS2 amino-terminal antibodies also detected a prominent 42 kDa band that may represent a novel PS2 form in human brain. Similar to PS1 findings, neither amino-terminal nor antiloop PS2 antibodies revealed substantial full-length PS2 in brain. Immunocytochemical examination of brains from individuals with the N141I PS2 mutation or eight different PS1 mutations, spanning the molecule from the second transmembrane domain to the large cytoplasmic loop domain, revealed immunodecoration of no senile plaques and only neurofibrillary tangles in the M139I PS1 mutation stained with PS1 antibodies.

Conclusions

Overall presenilin expression and the relative abundance of full-length and amino-terminal fragments in presenilin FAD cases were similar to control cases and sporadic AD cases. Thus, accumulation of full-length protein or other gross mismetabolism of neither PS2 nor PS1 is a consequence of the FAD mutations examined.

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Acknowledgments

This work was supported by a LEAD (leadership and Excellence in Alzheimer Disease) grant from the NIA (R. N. and A. C.; AG10916) and a NRSA fellowship (P. M.; NS09848). Human brain tissue was provided in part by the Harvard Brain Tissue Resource Center, which is supported in part by the PHS grant number MH/NS 31862 and the Kathleen Price Bryan Brain Bank at Duke University Medical Center. We wish to thank Drs. Gopal Thinakaran and Sangram Sisodia for providing us with the N2a cell extracts and the anti-loop PS2 polyclonal antibody.

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Authors and Affiliations

  1. The Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, New York, 10962, USA

    Paul M. Mathews, Anne M. Cataldo, Benjamin H. Kao, Anna G. Rudnicki, Xi Qin, John L. Yang, Ying Jiang, Melanie Picciano & Ralph A. Nixon

  2. Kathleen Price Bryan Brain Bank, Bryan Alzheimer’s Disease Research Center, Duke University Medical Center, Durham, North Carolina, USA

    Christine Hulette

  3. Department of Neurology, Medical College of Pennsylvania, Philadelphia, Pennsylvania, USA

    Carol F. Lippa

  4. Neurology and Medical Genetics, Veterans Administration Medical Center, Seattle, Washington, USA

    Thomas D. Bird

  5. Department of Pathology, University Of Washington School of Medicine, Seattle, Washington, USA

    David Nochlin

  6. Department of Molecular Biology, Central Institute of Mental Health, Mannheim, Germany

    Jochen Walter & Christian Haass

  7. Centre for Research in Neurodegenerative Disorders, University of Toronto, Toronto, Ontario, Canada

    Lyne Lévesque & Paul E. Fraser

  8. Department of Neurology, Harvard Medical School, Department of Biomedical Science, Eunice Kennedy Shriver Center, Waltham, Massachusetts, USA

    Athena Andreadis

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  1. Paul M. Mathews
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Correspondence to Paul M. Mathews.

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Mathews, P.M., Cataldo, A.M., Kao, B.H. et al. Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease. Mol Med 6, 878–891 (2000). https://doi.org/10.1007/BF03401825

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