Fig. 4: A hypothetical pathogenic mechanism for neuronal network changes in AD based on PV neuron dysfunction.

Neuronal hyperexcitability and network dysfunction are commonly observed in AD patients and in mouse models of AD. Taken together, published data seem to support a model in which interneurons, in particular PV interneurons, play a key role. Early in disease pathogenesis, before any significant aggregation of Aβ into plaques, soluble Aβ causes an aberrant increase in the excitability of PV cells and a corresponding increase in network inhibition. This is accompanied by an increase in perineuronal nets around PV cells, possibly to support the increased energy demand due to higher activity. Pyramidal cells at this stage seem unaffected, possibly because they are less vulnerable or less sensitive to Aβ toxicity. At a later stage, pyramidal cells also show increased excitability, possibly as a homeostatic response to restore excitation/inhibition balance. Increasing Aβ concentrations and Aβ aggregation may contribute to the increased excitability of pyramidal cells. Finally, PV cells become hypoactive while pyramidal cells remain hyperexcitable due to increasing Aβ pathology, resulting in an overall network hyperexcitability. The reduced activity of PV neurons is linked to a reduced expression and/or function of Nav1.1 and Kv3 channels. This stage is supported by both patient and mouse data showing reduced gamma oscillations and increased epileptic activity.