Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

Abstract

Tauopathies, the most common of which is Alzheimer's disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process. A major challenge that contributes to the definition of an early therapeutic window is limited technologies. To address these challenges, we modified and adapted a manganese-enhanced magnetic resonance imaging (MEMRI) approach to provide sensitive and quantitative power to detect changes in broad neuronal function in aging mice. Considering that tau tangle burden correlates well with cognitive impairment in Alzheimer's patients, we performed our MEMRI approach in a time course of aging mice and an accelerated mouse model of tauopathy. We measured significant changes in broad neuronal function as a consequence of age, and in transgenic mice, before the deposition of bona fide tangles. This MEMRI approach represents the first diagnostic measure of neuronal dysfunction in mice. Successful translation of this technology in the clinic could serve as a sensitive diagnostic tool for the definition of effective therapeutic windows.

Keywords: Alzheimer; MEMRI; Manganese; Tangles; Tau; rTg4510.

Figure 1

Pre and post-manganese parametric ΔR1 maps of a non-transgenic mouse. A) High resolution R1 mapping from baseline scans; regions of interest are denoted. B) Same mouse, R1 maps from scan taken 6h post-manganese injection.

Figure 2

MEMRI detects age-related changes in manganese uptake in non-transgenic mice. (A–D) Representative MEMRI R1 map of littermate control mice at A) 2mo, B) 3mo, C) 6mo, and D) 10mo. Quantification of ΔR1 values in E) CA3 F) CA1 G) dentate gyrus (DG) and H) superior medial cortex (CTX). (I–J) ΔR1 and one-way ANOVA analysis using Tukey’s multiple comparisons test of different brain regions (DG, CA1, CA3, and CTX) in (I) 2mo, (J) 3mo, (K) 6mo, and (L) 10mo control mice. All values are mean ± SEM, n= at least 6 per group.

Figure 3

Significant MEMRI changes in in aged tauopathic mice. Representative R1 maps of MEMRI-scans of 10mo littermate control (A) and 10mo rTg4510 (Tg) mice (B). C) Quantification of ΔR1 values in CA3, CA1, dentate gyrus (DG), and superior medial cortex (CTX). All values are mean ± SEM, n= 6, *p<0.05.

Figure 4

MEMRI-R1 detects early signs of neuronal dysfunction in transgenic rTg4510 mice prior to the onset of cognitive deficits. (A–D) Representative R1 map of A) 2mo littermate control B) 3mo littermate control C) 2mo rTg4510 mouse (Tg) and D) 3mo rTg4510 mouse (Tg). Quantification of ΔR1 values in E) CA1 F) CA3 G) dentate gyrus (DG), and H) superior medial cortex (CTX). (I) ΔR1 comparison between different brain regions (CA3, CA1, DG, and CTX) in 3mo and 10mo rTg4510. All values are mean ± SEM, n= at least 4. ***p<0.001, **p<0.01 *p<0.05.

Figure 5

MEMRI coincides with increased signal of the earliest marker of tau pathology. (A–H) Representative immunohistochemistry micrographs (20x objective) from 2- and 3mo rTg4510 stained with MC1 tau. (I) Quantification of MC1 levels in CA1, CA3, DG, and CTX. Data are mean ± SEM, n=3 mice per group and 2–4 slices per mouse, *p<0.05. (J–L) Representative immunohistochemistry micrographs of 3mo rTg4510 mice in the regions denoted (CA3, DG, CTX) that were statistically significantly different and show tangle-bearing neurons and filaments (60x objective).