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Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer’s disease by whole blood exchange

Abstract

Alzheimer’s disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD. In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40–80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.

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Fig. 1: Blood exchange treatment decreases the accumulation of cerebral amyloid plaques.
Fig. 2: Blood exchange treatment improves spatial memory.
Fig. 3: Sustained reduction in the cerebral amyloid deposition by blood exchange treatment.
Fig. 4: Reduction in insoluble Aβ levels in Tg2576 mice receiving blood exchange treatment.
Fig. 5: Plasma concentrations of total Aβ increased soon after blood exchange.
Fig. 6: Changes in the cerebral amyloid burden by blood exchange treatment in aged Tg2576 mice after the onset of cerebral plaque pathology.
Fig. 7: Changes in the spatial memory by blood exchange treatment after the onset of cerebral plaque pathology.

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Acknowledgements

This study was supported by the Mitchell Foundation and R01AG059321 to CS.

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AU developed the concept, designed the study, performed all blood exchange experiments, analyzed the histological data, prepared the final version of the figures, and wrote the paper. VK performed biochemical and behavioral studies and analyzed the data. DM-S and IM-G participated in histological image processing. SP participated in producing the revised version of this paper, figures and editing the paper. CS developed the concept, wrote the paper, managed peer-review process and provided funding for the study. All authors discussed the results and critically reviewed the paper. AU and CS are equally privileged on this work.

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Correspondence to Akihiko Urayama or Claudio Soto.

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Urayama, A., Moreno-Gonzalez, I., Morales-Scheihing, D. et al. Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer’s disease by whole blood exchange. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01679-4

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