Disrupted cross-laminar cortical processing in beta amyloid pathology precedes cell death

作者：Lison H; Happel M F K; Schneider F; Baldauf K; Kerbstat S; Seelbinder B; Schneeberg J; Zappe M; Goldschmidt J; Budinger E; Schroeder U H; Ohl F W; Schilling S; Demuth H U; Scheich H; Reymann K G; Roenicke R^*

来源：Neurobiology of Disease, 2014, 63: 62-73.

DOI：10.1016/j.nbd.2013.11.014

• beta amyloid
• Cortical column
• Glutaminyl cyclase
• Network disruption
• Thallium uptake

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 S-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical S-amyloidosis with still few plagues in the transgenic5xFAD 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 A beta 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.

• 出版日期2014-3