Changes in extracellular space size and geometry in APP23 transgenic mice: A model of Alzheimer's disease
- Eva Syková*,†,‡,
- Ivan Voříšek*,†,
- Tatiana Antonova*,†,
- Tomáš Mazel*,†,
- Melanie Meyer-Luehmann§,
- Mathias Jucker§,
- Milan Hájek†,¶,
- Michael Or∥,**, and
- Jan Bureš∥
- *Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic; †Department of Neuroscience and Center for Cell Therapy and Tissue Repair, Charles University, Second Medical Faculty, Vúvalu 84, 150 06 Prague 5, Czech Republic; §Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Muller Strasse 27, D-72076 Tübingen, Germany; ¶Department of Radiology, Institute for Clinical and Experimental Medicine, Vídeňská 1958, 140 21 Prague 4, Czech Republic; ∥Institute of Physiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic; and **Department of Psychiatry, Charles University, First Medical Faculty, Ke Karlovu 2, 128 08 Prague 2, Czech Republic
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Contributed by Jan Bures, November 21, 2004
Abstract
Diffusion parameters of the extracellular space (ECS) are changed in many brain pathologies, disturbing synaptic as well as extrasynaptic “volume” transmission, which is based on the diffusion of neuroactive substances in the ECS. Amyloid deposition, neuronal loss, and disturbed synaptic transmission are considered to be the main causes of Alzheimer's disease dementia. We studied diffusion parameters in the cerebral cortex of transgenic APP23 mice, which develop a pathology similar to Alzheimer's disease. The real-time tetramethylammonium (TMA) method and diffusion-weighted MRI were used to measure the ECS volume fraction (α = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADCTMA), diffusing exclusively in the ECS and of water (ADCW). Measurements were performed in vivo in 6-, 8-, and 17- to 25-month-old hemizygous APP23 male and female mice and age-matched controls. In all 6- to 8-month-old APP23 mice, the mean ECS volume fraction, ADCTMA, and ADCW were not significantly different from age-matched controls (α = 0.20 ± 0.01; ADCTMA, 580 ± 16 μm2·s-1; ADCW, 618 ± 19 μm2·s-1). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADCW, significantly greater in females than in males, but no changes in ADCTMA. ECS volume fraction increased (0.22 ± 0.01) and ADCTMA decreased (560 ± 7 μm2·s-1) in aged APP23 mice. The impaired navigation observed in these animals in the Morris water maze correlated with their plaque load, which was twice as high in females (20%) as in males (10%) and may, together with changed ECS diffusion properties, account for the impaired extrasynaptic transmission and spatial cognition observed in old transgenic females.
Footnotes
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↵ ‡ To whom correspondence should be sent at the * address. E-mail: sykova{at}biomed.cas.cz.
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Author contributions: E.S. and J.B. designed research; I.V., T.A., T.M., M.M.-L., and M.O. performed research; E.S., I.V., T.M., M.M.-L., M.J., M.H., M.O., and J.B. analyzed data; and E.S., I.V., T.M., and J.B. wrote the paper.
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Abbreviations: ADC, apparent diffusion coefficient; MR, magnetic resonance; TMA, tetramethylammonium; ADCTMA, ADC of TMA; ADCW, ADC of water; ECS, extracellular space; ISM, ion-selective microelectrode; DW-MRI, diffusion-weighted MRI.
- Copyright © 2005, The National Academy of Sciences
