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Aβ and Tau Prions Causing Alzheimer’s Disease

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Alzheimer’s Disease

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2561))

Abstract

Studies show that patients with Alzheimer’s disease (AD) have both Aβ and tau prions, and thus, AD is a double-prion disease. AD patients with the greatest longevity exhibited low levels of both Aβ and tau prions; tau prions were nearly absent in the brains of almost half of the patients who lived beyond 80 years of age. Using cellular bioassays for prions in postmortem samples, we found that both Aβ and tau proteins misfold into prions leading to AD, which is either a sporadic or familial dementing disorder. Although AD is transmissible experimentally, there is no evidence that AD is either communicable or contagious. Since the progression of AD correlates poorly with insoluble Aβ in the central nervous system (CNS), it was difficult to distinguish between inert amyloids and Aβ prions. To measure the progression of AD, we devised rapid bioassays to measure the abundance of isoform-specific Aβ prions in the brains of transgenic (Tg) mice and in postmortem human CNS samples from AD victims and people who died of other neurodegenerative diseases (NDs). We found significant correlations between the longevity of individuals with AD, sex, and genetic background, despite the fact that all postmortem brain tissue had essentially the same confirmed neuropathology.

Although brains from all AD patients had measurable levels of Aβ prions at death, the oldest individuals had lower Aβ prion levels than the younger ones. Additionally, the long-lived individuals had low tau prion levels that correlated with the extent of phosphorylated tau (p-tau). Unexpectedly, a longevity-dependent decrease in tau prions was found in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the tau prion levels decreased exponentially with respect to the age at death with a half-time of approximately one decade, and this correlated with the abundance of phosphorylated tau.

Even though our findings with tau prions were not unexpected, they were counterintuitive; thus, tau phosphorylation and tau prion activity decreased exponentially with longevity in patients with AD ranging from ages 37 to 99 years. Our findings demonstrated an inverse correlation between longevity in AD patients and the abundance of neurotoxic tau prions. Moreover, our discovery may have profound implications for the selection of phenotypically distinct patient populations and the development of diagnostics and effective therapeutics for AD.

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Acknowledgments

This work was supported by grants from the National Institutes of Health (NIH) (AG002132 and AG031220) and by support from the Dana Foundation, the Rainwater Charitable Foundation, and the Sherman Fairchild Foundation. Human brain tissue was received from the UCSF Neurodegenerative Disease Brain Bank, which is supported by the NIH (AG023501 and AG19724 to W.W.S.), the Tau Consortium, and the Consortium for Frontotemporal Dementia Research. Human brain tissue provided by the Brain Bank at Karolinska Institutet (KI), Stockholm, Sweden, received financial support from StratNeuro at KI, Swedish Brain Power, and Stockholm County Council. Human brain tissue provided by the Massachusetts Alzheimer’s Disease Research Center (Director: Matthew P. Frosch) received financial support from the NIH (P50 AG005134). Autopsy tissue obtained from the University of Washington Neuropathology Core is supported by the Alzheimer’s Disease Research Center (AG05136), the Adult Changes in Thought Study (AG006781), and the Morris K. Udall Center of Excellence for Parkinson’s Disease Research (NS062684). Autopsy tissue was also supplied by the King’s College London (Department of Clinical Neuroscience), the University of Edinburgh (Department of Neuropathology), and the Manchester Brain Bank (University of Manchester), which is part of the Brains for Dementia Research Initiative, jointly funded by Alzheimer’s Society and Alzheimer’s Research UK. We thank the Queen Square Brain Bank for Neurological Disorders (supported by the Reta Lila Weston Trust for Medical Research, the Progressive Supranuclear Palsy [Europe] Association, and the Medical Research Council) at the UCL Institute of Neurology, University College London, for provision of the UK human brain tissue samples. The Sydney Brain Bank is supported by Neuroscience Research Australia and the University of New South Wales. Glenda M. Halliday is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (1079679). Human brain tissue provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center (Director: David A. Bennett) [122], received financial support from the NIH (P30AG10161 and R01AG15819).

Competing Interests

S.B.P. is the founder of Prio-Pharma, which has not contributed financial or any other support to these studies. W.F.D. is a member of the scientific advisory boards of Alzheon Inc., Pliant, Longevity, CyteGen, Amai, and ADRx Inc., none of which have contributed financial or any other support to these studies.

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Author notes

  1. Carlo Condello and Atsushi Aoyagi contributed equally with all other contributors.

Authors and Affiliations

  1. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

    Carlo Condello, Gregory E. Merz, Atsushi Aoyagi, William F. DeGrado & Stanley B. Prusiner

  2. Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA

    Carlo Condello & Stanley B. Prusiner

  3. Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Atsushi Aoyagi

  4. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA

    William F. DeGrado

  5. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA

    Stanley B. Prusiner

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  1. Carlo Condello
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  2. Gregory E. Merz
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  3. Atsushi Aoyagi
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  4. William F. DeGrado
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  5. Stanley B. Prusiner
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Corresponding authors

Correspondence to Carlo Condello or Stanley B. Prusiner .

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Editors and Affiliations

  1. Translational Neuroscience Initiative, Neuroscience Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA

    Jerold Chun

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Condello, C., Merz, G.E., Aoyagi, A., DeGrado, W.F., Prusiner, S.B. (2023). Aβ and Tau Prions Causing Alzheimer’s Disease. In: Chun, J. (eds) Alzheimer’s Disease. Methods in Molecular Biology, vol 2561. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2655-9_16

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  • DOI: https://doi.org/10.1007/978-1-0716-2655-9_16

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