Figure 5.

Hypotheses regarding the possible effects of Aβ and tau on neuronal network excitability in AD. A, Hypothesis #1, Aβ and tau cooperate to lead to neuronal network hyperexcitability in AD. At early stages of AD, Aβ is more abundant in the neocortex whereas tau is localized to EC. Both Aβ and tau at early AD stages promote neuronal network hyperexcitability which not only contributes to cognitive impairments but also reciprocally increases Aβ deposition and tau release and spread to other cortical areas across connected neuroanatomical circuitry. Also, at advanced AD stages, both Aβ and tau promote neuronal network hyperexcitability, thus leading to cognitive deficit. Furthermore, Aβ-induced and tau-induced neuronal and synaptic loss, gliosis, and impaired synaptic plasticity (decreased LTP and increased LTD) contribute to neuronal network hyperexcitability and to cognitive deficits, effects also at play in scenarios illustrated in B, C. B, Hypothesis #2, Aβ enhances neuronal network hyperexcitability whereas tau suppresses excitability; the overall phenotype is hyperexcitability as Aβ effect dominates over tau effect. Aβ at early AD stages promotes neuronal network hyperexcitability which not only contributes to cognitive impairments but also increases Aβ deposition and tau release and spread to other cortical areas across connected neuroanatomical circuitry. However, tau at early AD stages suppresses neuronal activity, thus leading to silencing of neuronal networks which could also contribute to AD-related network dysfunction and cognitive deficit. Also, at advanced AD stages, Aβ enhances and tau suppresses neuronal network excitability, both leading to cognitive deficits. This could also be the case in AD patients with higher Aβ deposits than NFTs in their brains. C, Hypothesis #3, tau suppresses neuronal network excitability, whereas Aβ enhances it; the overall phenotype is suppressed excitability as tau suppressive effect dominates over Aβ enhancing effect. Tau both at early and advanced AD stages suppresses neuronal excitability thus leading to silencing of neuronal networks contributing to AD cognitive deficits. Contrarily, Aβ both at early and advanced AD stages promotes neuronal network hyperexcitability however this is dominated by tau suppressive effect. However, this hypothesis cannot explain the tau spread from EC to other cortical areas as increased neuronal activity has been identified to promote propagation of tau. Nonetheless, there could be other mediators of tau spread besides neuronal network hyperexcitability.