Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice.

Abstract

In Alzheimer's disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer's disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus-encompassing dorsal HIP-SS communication-in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

• Authors: Laetitia Degiorgis, Meltem Karatas, Marion Sourty, Emilie Faivre, Julien Lamy, Vincent Noblet, Thomas Bienert, Marco Reisert, Dominik von Elverfeldt, Luc Buée, David Blum, Anne-Laurence Boutillier, Jean-Paul Armspach, Frédéric Blanc, Laura-Adela Harsan
• Journal: Brain : a journal of neurology (Brain) Vol. 143 Issue 12 Pg. 3748-3762 (12 01 2020) ISSN: 1460-2156 [Electronic] England
• PMID: 33184651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• tau Proteins

Topics

• Animals
• Astrocytes (pathology)
• Brain (diagnostic imaging, pathology)
• Cognitive Dysfunction (genetics, psychology)
• Connectome
• Disease Progression
• Gliosis (pathology)
• Humans
• Image Processing, Computer-Assisted
• Magnetic Resonance Imaging
• Memory Disorders (etiology, pathology, psychology)
• Mice
• Mice, Transgenic
• Nerve Net (diagnostic imaging, pathology)
• Tauopathies (complications, diagnostic imaging, pathology, psychology)
• tau Proteins (metabolism)