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bioRxiv · 10.1101/2020.04.27.064634

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

Al-Amin, M. M.·Grandjean, J.·Klohs, J.·Kim, J.
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Abstract

Although amyloid beta (A{beta}) deposition is one of the major causes of white matter (WM) alterations in Alzheimers disease (AD), little is known about the underlying basis of WM damage and its association with global structural connectivity and network topology. We aimed to dissect the contributions of WM microstructure to structural connectivity and network properties in the ArcA{beta} mice model of A{beta} amyloidosis. We acquired diffusion-weighted images (DWI) of wild type (WT) and ArcA{beta} transgenic (TG) mice using a 9.4 T MRI scanner. Fixel-based analysis (FBA) was performed to measure fiber tract-specific properties. We also performed three complementary experiments; to identify the global differences in structural connectivity, to compute network properties and to measure cellular basis of white matter alterations. Transgenic mice displayed disrupted structural connectivity centered to the entorhinal cortex (EC) and a lower fiber density and fiber bundle cross-section. In addition, there was a reduced network efficiency and degree centrality in weighted structural connectivity in the transgenic mice. To further examine the underlying neuronal basis of connectivity and network deficits, we performed histology experiments. We found no alteration in myelination and an increased level of neurofilament light (NFL) in the brain regions with disrupted connectivity in the TG mice. Furthermore, TG mice had a reduced number of perineuronal nets (PNN) in the EC. The observed FDC reductions may indicate a decrease in axonal diameter or axon count which would explain the basis of connectivity deficits and reduced network efficiency in TG mice. The increase in NFL suggests a breakdown of axonal integrity, which would reduce WM fiber health. Considering the pivotal role of the EC in AD, A{beta} deposition may primarily increase NFL release, damaging PNN in the entorhinal pathway, resulting in disrupted structural connectivity.

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Al-Amin, M. M., Grandjean, J., Klohs, J., Kim, J.. 2020-04-28. Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis. https://doi.org/10.1101/2020.04.27.064634

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