title: Disrupted cross-laminar cortical processing in β amyloid pathology precedes cell death.
abstract: Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological β-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical β-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aβ are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Lison
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: M F K
authors.initials: MF
authors.lastname: Happel
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schneider
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Baldauf
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kerbstat
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Seelbinder
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Schneeberg
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zappe
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Goldschmidt
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Budinger
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: U H
authors.initials: UH
authors.lastname: Schröder
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: F W
authors.initials: FW
authors.lastname: Ohl
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schilling
authors.affiliation: Probiodrug AG, Weinbergweg 22, 06120 Halle (Saale), Germany.
authors.forename: H-U
authors.initials: HU
authors.lastname: Demuth
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Scheich
authors.affiliation: Leibniz-Institute for Neurobiology, Brenneckestr. 6, 39118 Magdeburg, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany.
authors.forename: K G
authors.initials: KG
authors.lastname: Reymann
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), c/o Universitätsklinikum Magdeburg, Leipziger Strasse 44/Haus 64, 39120 Magdeburg, Germany; Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. Electronic address: raik.roenicke@med.ovgu.de.
authors.forename: R
authors.initials: R
authors.lastname: Rönicke
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D005239:Fear; D005583:Fourier Analysis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000209:etiology* / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D013793:Thallium
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D013793:Thallium
keywords: (AD); (APP); (CSD); (FFT); (ICMS); (LFP); (QC); (Tl-AMG); (TlDDC); Alzheimer's disease; Cortical column; Fast Fourier Transformation; Glutaminyl cyclase; Network disruption; Thallium uptake; current source density; glutaminyl cyclase; intracortical microstimulation; local field potential; thallium autometallography; thallium diethyl-dithiocarbamate; β amyloid; β-amyloid precursor protein