Amyloid β Oligomers Decrease Hippocampal Spontaneous Network Activity in an Age-Dependent Manner

Abstract

Soluble amyloid beta (Abeta) oligomers might trigger early cognitive impairment in Alzheimer's Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Abeta(25-35) affects the spontaneous activity in hippocampal slices, when was added to the bath, at high nanomolar concentrations. In the present study, we aimed to characterize the effects of the oligomerized full length sequence Abeta(1-42) on the spontaneous network activity in the CA1 hippocampal area testing whether such effects are age dependent. By performing extracellular field recordings of spontaneous network activity of hippocampal slices, we found that an oligomerized solution of Abeta(1-42) (osAbeta) potently inhibit, in a dose-dependent manner, the spontaneous hippocampal network activity with an IC(50) of 0.4 +/- 3.2 nM and a maximal effect reached around 10 nM. While spontaneous hippocampal network activity is unaffected by age, the sensitivity of spontaneous hippocampal network activity to osAbeta (10 nM) appears to be increased in slices from older animals. Moreover, to see a significant reduction in spontaneous network activity in slices from animals in their second week of life 100nM osAbeta was needed. The osAbeta-induced reduction in hippocampal network activity is accompanied by a presynaptic reduction in both spontaneous and miniature synaptic potentials. Finally, we demonstrated that the effect produced by osAbeta on spontaneous network activity was specific, reversible and unrelated with cell death. In conclusion, our data show that osAbeta alters hippocampal network activity at concentrations commonly observed in AD patients and that such effect of osAbeta increase with age.

Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

“…Spontaneous prefrontal network recordings in slices showed low-voltage neuronal activity that includes a broad range of frequency components (Figure 1; n = 10; meaning 10 slices obtained from 10 animals, with only one slice per animal). As previously shown for other neuronal networks [34–37], this activity is reduced by the application of 30 nM A β (Figure 1, representative traces and power spectra). Analysis of the integrated power (from 1 to 120 Hz) showed a significant reduction of the prefrontal spontaneous network activity 60 min after A β application (to 63.2 ± 8.5% of basal activity, p < 0.05; n = 10) (Figure 1, inset bar graph).…”

“…This latter effect might contribute to the A β -induced action potential desynchronization in the hippocampus that contributes to the inhibition of its neural network activity [45]. Aside from the changes in cell excitability, the inhibition of neural network activity induced by A β has also been related to a reduction in both excitatory [34, 37, 47, 48] and inhibitory [47, 48] synaptic transmission. In fact, these findings are consistent with the observation that A β reduced cholinergic modulation of the inhibitory transmission in the PFC [17].…”

“…The oligomerization procedure was performed as previously described [33, 34]. Briefly, solid A β 1-42 peptide was dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to a final concentration of 1 mM.…”

“…A β oligomers found in the supernatant were collected and maintained at 4°C until being used for experiments. Previous characterization of our solution indicates that it contains a mixture of A β aggregates, with hexamers as the main A β oligomeric form present [34]. …”

Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer’s Disease

“…This paradoxical situation might be explainable given the sophisticated pathophysiology of the septohippocampal system and the heterogeneity, that is, dualistic theory of hippocampal theta activity, that is, hippocampal theta being differentiated into atropine-insensitive type I and atropine-sensitive type II theta [40, 60]. It has been reported that A β can modulate cholinergic and glutamatergic neurons in the septohippocampal system [61–64] and that the presence of A β in both the medial septum and the hippocampus can dampen theta rhythm in vitro and in vivo [62, 65–69] which is associated with cognitive impairment.…”