title: A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer's Disease.
abstract: One century after its first description, pathology of Alzheimer's disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD-related neuronal hyperexcitability cannot be accounted for by altered subthreshold dendritic signaling in these neurons but hyperexcitability is related to changes in active membrane properties and network connectivity.
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of DebrecenDebrecen, Hungary; Kenézy Gyula Hospital Ltd., Department of Emergency MedicineDebrecen, Hungary.
authors.forename: Attila
authors.initials: A
authors.lastname: Somogyi
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen Debrecen, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Katonai
authors.affiliation: MTA-SE NAP B Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of SciencesBudapest, Hungary; Department of Anatomy, Semmelweis UniversityBudapest, Hungary.
authors.forename: Alán
authors.initials: A
authors.lastname: Alpár
authors.affiliation: Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen Debrecen, Hungary.
authors.forename: Ervin
authors.initials: E
authors.lastname: Wolf
keywords: Alzheimer’s disease; compensation; computer simulations; conservation of dendritic signaling; electrotonic analysis; human amyloid precursor protein; mouse somatosensory cortex; synaptic integration