TY - JOUR
T1 - Manganese-enhanced magnetic resonance imaging method detects age-related impairments in axonal transport in mice and attenuation of the impairments by a microtubule-stabilizing compound
AU - Terry, Alvin V.
AU - Beck, Wayne D.
AU - Lin, Ping Chang
AU - Callahan, Patrick M.
AU - Rudic, R. Daniel
AU - Hamrick, Mark W.
N1 - Funding Information:
The authors would like to thank Ms. Ashley Davis for her administrative assistance in preparing this manuscript. We would also like to acknowledge the contributions to the experiments described in this manuscript by the Georgia Cancer Center's Small Animal Imaging Shared Resource, Augusta University, Augusta, Georgia. This work was supported by the Institut de Recherches Servier, Croissy-sur-Seine, France, and the Medical College of Georgia Foundation, Augusta, Georgia, USA.
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/8/15
Y1 - 2022/8/15
N2 - In this study a manganese-enhanced magnetic resonance imaging (MEMRI) method was developed for mice for measuring axonal transport (AXT) rates in real time in olfactory receptor neurons, which project from the olfactory epithelium to the olfactory neuronal layer of the olfactory bulb. Using this MEMRI method, two major experiments were conducted: 1) an evaluation of the effects of age on AXT rates and 2) an evaluation of the brain-penetrant, microtubule-stabilizing agent, Epothilone D for effect on AXT rates in aged mice. In these studies, we improved upon previous MEMRI approaches to develop a method where real-time measurements (32 time points) of AXT rates in mice can be determined over a single (approximately 100 min) scanning session. In the age comparisons, AXT rates were significantly higher in young (mean age ∼4.0 months old) versus aged (mean age ∼24.5 months old) mice. Moreover, in aged mice, eight weeks of treatment with Epothilone D, (0.3 and 1.0 mg/kg) was associated with statistically significant increases in AXT rates compared to vehicle-treated subjects. These experiments conducted in a living mammalian model (i.e., wild type, C57BL/6 mice), using a new modified MEMRI method, thus provide further evidence that the process of aging leads to decreases in AXT rates in the brain and they further support the argument that microtubule-based therapeutic strategies designed to improve AXT rates have potential for age-related neurological disorders.
AB - In this study a manganese-enhanced magnetic resonance imaging (MEMRI) method was developed for mice for measuring axonal transport (AXT) rates in real time in olfactory receptor neurons, which project from the olfactory epithelium to the olfactory neuronal layer of the olfactory bulb. Using this MEMRI method, two major experiments were conducted: 1) an evaluation of the effects of age on AXT rates and 2) an evaluation of the brain-penetrant, microtubule-stabilizing agent, Epothilone D for effect on AXT rates in aged mice. In these studies, we improved upon previous MEMRI approaches to develop a method where real-time measurements (32 time points) of AXT rates in mice can be determined over a single (approximately 100 min) scanning session. In the age comparisons, AXT rates were significantly higher in young (mean age ∼4.0 months old) versus aged (mean age ∼24.5 months old) mice. Moreover, in aged mice, eight weeks of treatment with Epothilone D, (0.3 and 1.0 mg/kg) was associated with statistically significant increases in AXT rates compared to vehicle-treated subjects. These experiments conducted in a living mammalian model (i.e., wild type, C57BL/6 mice), using a new modified MEMRI method, thus provide further evidence that the process of aging leads to decreases in AXT rates in the brain and they further support the argument that microtubule-based therapeutic strategies designed to improve AXT rates have potential for age-related neurological disorders.
KW - Aging
KW - Alzheimer's disease
KW - Drug discovery
KW - Manganese-enhanced magnetic resonance imaging
KW - Therapeutic strategies
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U2 - 10.1016/j.brainres.2022.147947
DO - 10.1016/j.brainres.2022.147947
M3 - Article
C2 - 35597325
AN - SCOPUS:85130736546
SN - 0006-8993
VL - 1789
JO - Brain Research
JF - Brain Research
M1 - 147947
ER -