The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease

Abstract

Multivariate biomarkers are needed for detecting Alzheimer’s disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination—through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy.

Identifying Vulnerable Brain Networks in Mouse Models of Genetic Risk Factors for Late Onset Alzheimer’s Disease

“…This allows to model the human innate immune response, in particular with respect to the redox microenvironment, and NO production (Hoos et al, 2014). Mouse models on this genetic background expressing APP mutations present multiple AD like phenotypes (Wilcock et al, 2008;Colton et al, 2014;Kan et al, 2015;Badea et al, 2016). Here we assessed the differential effects of the interaction of the humanized NOS background with APOE3 and APOE4 alleles.…”

Synaptic Pruning in Alzheimer’s Disease: Role of the Complement System

“…Evidence indicates the APPSwDI/Nos2−/− ( CVN-AD) mouse model replicates multiple AD pathologies [ 31 ] , Badea et al (2016) identified multivariate biomarkers that appear to predict cognitive decline. One of these biomarkers is the fornix.…”

Optimizing Diffusion Imaging Protocols for Structural Connectomics in Mouse Models of Neurological Conditions

“…Further reductions in acquisition times come from compressed sensing [28], which several groups have implemented for mouse MRI [29][30][31]. Such advances can help translate diffusion protocols into population studies [32] incorporating multiple biomarkers from morphometry [33], microstructural properties based on diffusion [13] or magnetic susceptibility [34], or network properties [35]. Such integrative studies may better predict changes in behaviors, modeling those observed in humans with neurodegenerative conditions [34].…”

“…We need to compare 2-mm linear dimension voxel sizes in humans (corresponding to 8-mm 3 voxel volumes), vs. 0.2-0.043-mm linear dimension voxel sizes (corresponding to ∼8 × 10 −2 -8 × 10 −5 -mm 3 voxel volumes) required to distinguish similar levels of anatomical detail in mouse brains [6][7][8][9][10][11]. This increased resolution enables the observation of brain architecture at the level of cellular layers, which, therefore, can help us gain insight into the mechanistic drivers behind the etiology and progression of disease, using animal models where axonal dimensions are relatively similar to humans [12,13].…”