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Evidence of intraneuronal Aβ accumulation preceding tau pathology in the entorhinal cortex

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Abstract

Growing evidence gathered from transgenic animal models of Alzheimer’s disease (AD) indicates that the intraneuronal accumulation of amyloid-β (Aβ) peptides is an early event in the AD pathogenesis, producing cognitive deficits before the deposition of insoluble plaques. Levels of soluble Aβ are also a strong indicator of synaptic deficits and concurrent AD neuropathologies in post-mortem AD brain; however, it remains poorly understood how this soluble amyloid pool builds within the brain in the decades leading up to diagnosis, when a patient is likely most amenable to early therapeutic interventions. Indeed, characterizing early intracellular Aβ accumulation in humans has been hampered by the lack of Aβ-specific antibodies, variability in the quality of available human brain tissue and the limitations of conventional microscopy. We therefore sought to investigate the development of the intraneuronal Aβ pathology using extremely high-quality post-mortem brain material obtained from a cohort of non-demented subjects with short post-mortem intervals and processed by perfusion-fixation. Using well-characterized monoclonal antibodies, we demonstrate that the age-dependent intraneuronal accumulation of soluble Aβ is pervasive throughout the entorhinal cortex and hippocampus, and that this phase of the amyloid pathology becomes established within AD-vulnerable regions before the deposition of Aβ plaques and the formation of tau neurofibrillary tangles. We also show for the first time in post-mortem human brain that Aβ oligomers do in fact accumulate intraneuronally, before the formation of extracellular plaques. Finally, we validated the origin of the Aβ-immunopositive pool by resolving Aβ- and APP/CTF-immunoreactive sites using super resolution structured illumination microscopy. Together, these findings indicate that the lifelong accrual of intraneuronal Aβ may be a potential trigger for downstream AD-related pathogenic events in early disease stages.

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Acknowledgements

This research is supported by the CIHR Project Grant PJT-364544 to A. Claudio Cuello, and 2017-1.2.1-NKP-2017-00002 to the Human Brain Research lab. LAW is the recipient of a Doctoral Training Fellowship from the Fonds de recherche du Québec-Santé. SDC is the holder of the Charles E. Frosst/Merck Research Associate position. ACC is the holder of the McGill University Charles E. Frosst/Merck Chair in Pharmacology and is a member of the Canadian Consortium on Neurodegeneration in Aging. We would like to thank Dr. William Klein (Northwestern University) as well as Dr. Gerhard Multhaup (McGill University) for generously providing the NU1 and pab27576 antibodies, respectively. We thank Dr. Alfredo Ribeiro-da-Silva for allowing us to use the Axio Imager M2 widefield microscope and for his guidance and assistance in acquiring the images presented above. We would also like to acknowledge Dr. Elke Küster-Schöck and the McGill University Cell Imaging and Analysis Network for their help with super resolution microscopy. The Cuello laboratory is grateful for the unrestricted support received from Dr. Alan Frosst, the Frosst family, and Merck Canada.

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Authors and Affiliations

  1. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Lindsay A. Welikovitch & A. Claudio Cuello

  2. Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada

    Sonia Do Carmo & A. Claudio Cuello

  3. Human Brain Research Laboratory, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

    Zsófia Maglóczky & Péter Szocsics

  4. Department of Psychiatry, Szent Borbála Hospital, Tatabánya, Hungary

    János Lőke

  5. Laboratory of Cerebral Cortex Research, Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary

    Tamás Freund

  6. Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada

    A. Claudio Cuello

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  1. Lindsay A. Welikovitch
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  2. Sonia Do Carmo
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  3. Zsófia Maglóczky
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  4. Péter Szocsics
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  5. János Lőke
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  6. Tamás Freund
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  7. A. Claudio Cuello
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Correspondence to A. Claudio Cuello.

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Supplemental Fig. 1 Neuronal accumulation of Aβ within the EC is ubiquitous across all non-demented cases. All control cases examined displayed appreciable iAβ accumulation across all entorhinal layers, regardless of concurrent Aβ plaque pathologies. One subject with diagnosed-AD (DEM1) also exhibited iAβ accumulation in the MTL, although McSA1-IR neurons within the EC were sparse due to extensive plaque pathology and neurodegeneration. Subjects are arranged in order of increasing neuronal McSA1-IR (scale bar = 200μm). Supplementary material 1 (PDF 1282 kb)

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Welikovitch, L.A., Do Carmo, S., Maglóczky, Z. et al. Evidence of intraneuronal Aβ accumulation preceding tau pathology in the entorhinal cortex. Acta Neuropathol 136, 901–917 (2018). https://doi.org/10.1007/s00401-018-1922-z

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  • DOI: https://doi.org/10.1007/s00401-018-1922-z

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