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Neurobiol Dis ; 63: 62-73, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24291517

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 ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-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 Aß 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.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Cerebral Cortex/pathology , Plaque, Amyloid/etiology , Age Factors , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Cell Death/physiology , Cerebral Cortex/metabolism , Conditioning, Psychological , Disease Models, Animal , Fear , Fourier Analysis , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation/genetics , Neurons/metabolism , Neurons/pathology , Plaque, Amyloid/genetics , Presenilin-1/genetics , Thallium
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