title: Changes in extracellular space size and geometry in APP23 transgenic mice: a model of Alzheimer's disease.
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 (alpha = ECS volume/total tissue volume) and the apparent diffusion coefficients (ADCs) of TMA (ADC(TMA)), diffusing exclusively in the ECS and of water (ADC(W)). 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, ADC(TMA), and ADC(W) were not significantly different from age-matched controls (alpha = 0.20 +/- 0.01; ADC(TMA), 580 +/- 16 microm(2).s(-1); ADC(W), 618 +/- 19 microm(2).s(-1)). Aging in 17- to 25-month-old controls was accompanied by a decrease in ECS volume fraction and ADC(W), significantly greater in females than in males, but no changes in ADC(TMA). ECS volume fraction increased (0.22 +/- 0.01) and ADC(TMA) decreased (560 +/- 7 microm(2).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.
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic. sykova@biomed.cas.cz
authors.forename: Eva
authors.initials: E
authors.lastname: Syková
authors.forename: Ivan
authors.initials: I
authors.lastname: Vorísek
authors.forename: Tatiana
authors.initials: T
authors.lastname: Antonova
authors.forename: Tomás
authors.initials: T
authors.lastname: Mazel
authors.forename: Melanie
authors.initials: M
authors.lastname: Meyer-Luehmann
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Milan
authors.initials: M
authors.lastname: Hájek
authors.forename: Michael
authors.initials: M
authors.lastname: Ort
authors.forename: Michael
authors.initials: M
authors.lastname: Or
authors.forename: Jan
authors.initials: J
authors.lastname: Bures
mesh_terms: D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000209:etiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D004058:Diffusion; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000644:Quaternary Ammonium Compounds / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000644:Quaternary Ammonium Compounds; C027917:tetramethylammonium