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.

Analysis Of Brain Functional Connectivity By Frequent Pattern Mining In Graphs. Application To The Characterization Of Murine Models

“…A second network (graph g 1 ), that appears significantly less frequently in Alz mice than Ctrl mice, is of particular interest since it gather key regions involved in memory, namely the hippocampus (CA1, CA2, CA3, DG), the entorhinal (ENT) and perirhinal (PERI) cortex, and the subiculum (SUB). This is consistent with microstructural alterations that were detected in the main connection pathway of these regions for the same mice, as well as a significantly higher concentration of pathologi-cal proteins in the hippocampus [7]. These alterations could therefore reflect an overall dysfunction of the memory network, that may be responsible of potential memory disturbances at more advanced stages of the pathology.…”

“…The study focuses on a mouse model of Alzheimer's disease (Thy-Tau22) [7]. A group of n Alz = 16 Alzheimer's mice is compared to a group of n Ctrl = 13 control mice.…”

“…rsfMRI were acquired on a 7T MR scanner (BioSpec 70/30, Bruker, Germany) using a GE-EPI sequence with the following parameters: 500 volumes, TE: 15ms, TR: 2000ms, 27 axial slices, slice thickness: 0.4mm, in-plane spatial resolution: 0.14x0.22mm. Data were preprocessed with SPM8 1 and SPMmouse 2 libraries according to the following pipeline: (i) motion correction, (ii) affine registration on the Allen Brain atlas 3 , (iii) Gaussian spatial filtering (FWHM: 2mm), (iv) temporal bandpass filtering (0.01-0.1Hz) and (v) regressing out the signal of the cerebrospinal fluid (see [7] for details).…”

Early memory deficits and extensive brain network disorganization in the AppNL-F/MAPT double knock-in mouse model of familial Alzheimer’s disease

“…This suggests that perturbations in resting state FC may predict memory FC perturbations, but do not directly mirror them. Moreover, the mouse models used to evaluate pre-aggregate resting state FC presented either amyloid pathology (Shah et al, 2016;Shah et al, 2018) or tau pathology (Degiorgis et al, 2020) but not both concurrently. It has been shown with combined resting state fMRI and PET imaging in humans that increased Aβ alone is associated with hyperconnectivity of the DMN while combined Aβ and Tau pathologies reveal hypoconnectivity (Schultz et al, 2017).…”

“…Initial stages of AD are inevitably linked to discrete physiological and neuroanatomical perturbations, which should be more easily investigated in mouse models of AD (Scearce-Levie et al, 2020). Using fMRI on young AD transgenic mice, increased soluble Aβ (Shah et al, 2016;Shah et al, 2018), and regionally specific increases in neuroinflammation and phospho-tau (Degiorgis et al, 2020) have been linked to disruptions in resting state functional networks. As fMRI/EEG/MEG methods are currently difficult to implement in freely moving mice, ex-vivo imaging based on quantification of activity regulated expression of immediate early genes (IEG; c-fos, Egr1 and arc) may be used to evaluate memory related neural activation (Kinnavane et al, 2015).…”