Abstract
Onset and progression of Alzheimer’s disease (AD) pathophysiology differs between brain regions. The neocortex, for example, is a brain region that is affected very early during AD. NMDA receptors (NMDARs) are involved in mediating amyloid beta (Aβ) toxicity. NMDAR expression, on the other hand, can be affected by Aβ. We tested whether the high vulnerability of neocortical neurons for Aβ-toxicity may result from specific NMDAR expression profiles or from a particular regulation of NMDAR expression by Aβ. Electrophysiological analyses suggested that pyramidal cells of 6-months-old wildtype mice express mostly GluN1/GluN2A NMDARs. While synaptic NMDAR-mediated currents are unaltered in 5xFAD mice, extrasynaptic NMDARs seem to contain GluN1/GluN2A and GluN1/GluN2A/GluN2B. We used conditional GluN1 and GluN2B knockout mice to investigate whether NMDARs contribute to Aβ-toxicity. Spine number was decreased in pyramidal cells of 5xFAD mice and increased in neurons with 3-week virus-mediated Aβ-overexpression. NMDARs were required for both Aβ-mediated changes in spine number and functional synapses. Thus, our study gives novel insights into the Aβ-mediated regulation of NMDAR expression and the role of NMDARs in Aβ pathophysiology in the somatosensory cortex.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease defined by the occurrence of amyloid beta (Aβ) plaques and tau tangles in the brain
To test whether specific expression and/or regulation of NMDA receptors (NMDARs) subunits contribute to the early neuronal Aβ-toxicity in the neocortex, we investigated NMDAR-mediated currents in neocortical neurons with virus-mediated Aβ-overexpression as well as in neocortical neurons of the 5xFAD mouse model
Given that Aβ-expression, onset, and severity of Aβ-pathology differs between brain regions with early onset and severity in the cortex of 5xFAD mice [7,47], we investigated whether signs of Aβ-overexpression can be observed in the somatosensory cortex of 6-months-old 5xFAD mice
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease defined by the occurrence of amyloid beta (Aβ) plaques and tau tangles in the brain. Memory deficits occur as early symptoms in AD patients, Aβ plaques occur in the hippocampus, a brain area involved in memory formation, later than in the neocortex [3,4,5,6] In line with these findings from AD patients, the 5xFAD AD mouse model shows spine loss and neuron loss in the neocortex earlier than in the hippocampus [7]. To test whether specific expression and/or regulation of NMDAR subunits contribute to the early neuronal Aβ-toxicity in the neocortex, we investigated NMDAR-mediated currents in neocortical neurons with virus-mediated Aβ-overexpression as well as in neocortical neurons of the 5xFAD mouse model. We found changes in the decay and deactivation kinetics consistent with an upregulation of extrasynaptic GluN2B-containing NMDARs. The contribution of NMDARs to Aβ-toxicity in adult neocortical neurons was investigated using conditional knockout of GluN1, GluN2A, or GluN2B. Our study gives novel insights into the regulation and role of NMDARs in AD pathophysiology
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