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Precocious White Matter Inflammation and Behavioural Inflexibility Precede Learning and Memory Impairment in the TgAPP21 Rat Model of Alzheimer Disease

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Abstract

Neuroinflammation and behavioural inflexibility are both common in late adulthood but far more profound in Alzheimer disease (AD). To investigate the relationship between ageing, AD, neuroinflammation, and behavioural flexibility, male wild-type Fischer 344 (Wt) and the transgenic APP21 (TgAPP21) rats were aged to 4, 8, 13, and 22 months and evaluated for neuroinflammation and cognitive impairment. TgAPP21 rats overexpress a pathogenic variant of the human amyloid precursor protein (hAPP; Swedish and Indiana mutations) but do not spontaneously develop overt pathology related to AD. In both genotypes, learning and memory were similarly impaired in older rats. However, at 8 months of age, TgAPP21 rats demonstrated behavioural inflexibility in set shifting, reversal, and the Morris water maze, while Wt rats showed inflexibility at 13 and 22 months of age. This early inflexibility in TgAPP21 rats was accompanied by a precocious increase in microglia activation within the corpus callosum; 8- and 13-month-old TgAPP21 rats had similar levels of microglia activation as 13- and 22-month-old Wt rats, respectively. However, while neuroinflammation within the white matter continued to progress with age, behavioural inflexibility peaked in 8-month-old TgAPP21 rats; in older TgAPP21 rats, memory and learning impairments masked inflexibility. These findings suggest that the behavioural inflexibility and white matter inflammation seen in normal ageing are accelerated in AD and may precede impairments of learning and memory.

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Data Availability

The datasets generated and analysed for the current study are available from the corresponding author on a reasonable request.

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Acknowledgements

We would like to thank Dr. Lynn Wang, Shikhar Maheshwari, and UWO’s Animal Care and Veterinary Services staff for their technical assistance.

Funding

This work was supported in part by research grants from the Natural Sciences and Engineering Research Council of Canada to Brian L. Allman (435819) and to Shawn N. Whitehead (418489); the Canadian Consortium on Neurodegeneration in Aging, the Canadian Institutes of Health Research (126127), and the Canadian Foundation for Innovation (34213) to Shawn N. Whitehead.

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Authors and Affiliations

  1. Vulnerable Brain Laboratory, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada

    Alexander Levit, Andrew Gibson, Olivia Hough, Youngkyung Jung, Brian L. Allman & Shawn N. Whitehead

  2. Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA

    Yuksel Agca & Cansu Agca

  3. Department of Clinical Neurological Sciences, University Hospital, University of Western Ontario, London, ON, N6A 5C1, Canada

    Vladimir Hachinski & Shawn N. Whitehead

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  1. Alexander Levit
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  2. Andrew Gibson
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  3. Olivia Hough
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  4. Youngkyung Jung
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  5. Yuksel Agca
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  6. Cansu Agca
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  7. Vladimir Hachinski
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  8. Brian L. Allman
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  9. Shawn N. Whitehead
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by AL, AG, OH, and YJ. The first draft of the manuscript was written by AL and SNW and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shawn N. Whitehead.

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Animal ethics and procedures were approved by the Animal Care Committee at Western University (protocol 2014–016) and are in compliance with Canadian and National Institute of Health Guides for the Care and Use of Laboratory Animals (NIH Publication #80–23).

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Levit, A., Gibson, A., Hough, O. et al. Precocious White Matter Inflammation and Behavioural Inflexibility Precede Learning and Memory Impairment in the TgAPP21 Rat Model of Alzheimer Disease. Mol Neurobiol 58, 5014–5030 (2021). https://doi.org/10.1007/s12035-021-02476-w

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