Abstract
Alzheimer’s disease (AD) is caused by the accumulation of the amyloid- (Aβ) peptide within the brain extracellular space. Aβ is produced within neurons then secreted into the extracellular fluid. Normally, Aβ is found as a soluble, monomeric peptide within the brain interstitial fluid (ISF) and cerebrospinal fluid. During the pathogenesis of AD, however, Aβ changes conformation then aggregates into toxic higher ordered species, including soluble oligomers and insoluble plaques, which appear to underlie the etiology of AD. Conversion into these toxic species of Aβ appears to be concentration dependent and, at least partially, occurs within the ISF. Consequently, understanding the metabolic processes that regulate Aβ generation, particularly within the ISF, has implications for understanding pathogenesis as well as treatment. In order to study ISF Aβ metabolism in a physiological setting, several groups have utilized in vivo microdialysis both in animal models of disease as well as human patients. Synaptic transmission, the events that underlie brain function, directly leads to Aβ generation in vivo; suppressing synaptic activity rapidly reduces ISF Aβ levels whereas increasing activity increases Aβ levels. In mouse models of AD, behaviors such as stress and sleep/wake cycles also dynamically modulate ISF Aβ generation. Following traumatic brain injury, cortical ISF Aβ levels in humans is correlated with neurological status and synaptic transmission; comatose patients with initially low synaptic activity have low ISF Aβ levels which rise as neurological status improve. Conversely, in humans 10 % of individuals with temporal lobe epilepsy (TLE) develop Aβ plaques. The absolute concentration of Aβ within the ISF appears directly related to whether a brain region will develop plaques or not. Microdialysis provides a powerful tool to assess brain ISF Aβ levels longitudinally through a wide variety of experimental and behavioral paradigms.
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Cirrito, J.R. (2013). Extracellular Amyloid-β Protein Dynamics in Alzheimer’s Disease. In: Müller, M. (eds) Microdialysis in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4815-0_9
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