title: Restricted diffusion in the brain of transgenic mice with cerebral amyloidosis.
abstract: A prominent hallmark of Alzheimer's disease pathology is cerebral amyloidosis. However, it is not clear how extracellular amyloid-beta peptide (A beta) deposition and amyloid formation compromise brain function and lead to dementia. It has been argued that extracellular amyloid deposition is neurotoxic and/or that soluble A beta oligomers impair synaptic function. Amyloid deposits, by contrast, may affect diffusion properties of the brain interstitium with implications for the transport of endogenous signalling molecules during synaptic and/or extrasynaptic transmission. We have used diffusion-weighted magnetic resonance imaging to study diffusion properties in brains of young (6-month-old) and aged (25-month-old) APP23 transgenic mice and control littermates. Our results demonstrate that fibrillar amyloid deposits and associated gliosis in brains of aged APP23 transgenic mice are accompanied by a reduction in the apparent diffusion coefficient. This decrease was most pronounced in neocortical areas with a high percentage of congophilic amyloid and was not significant in the caudate putamen, an area with only modest and diffuse amyloid deposition. These findings suggest that extracellular deposition of fibrillar amyloid and/or associated glial proliferation and hypertrophy cause restrictions to interstitial fluid diffusion. Reduced diffusivity within the interstitial space may alter volume transmission and therefore contribute to the cognitive impairment in Alzheimer's disease.
authors.affiliation: Discovery Technologies, Novartis Institute for Biomedical Research, CH-4002 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueggler
authors.forename: Melanie
authors.initials: M
authors.lastname: Meyer-Luehmann
authors.forename: Martin
authors.initials: M
authors.lastname: Rausch
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D004058:Diffusion; D004195:Disease Models, Animal; D005911:Gliosis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid
chemical_list: D016564:Amyloid beta-Protein Precursor