Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer’s disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
An established memory can be made transiently labile if retrieved or reactivated. Over time, it becomes again resistant to disruption and this process that renders the memory stable is termed reconsolidation. The reasons why a memory becomes labile after retrieval and reconsolidates still remains debated. Here, using inhibitory avoidance learning in rats, we provide evidence that retrievals of a young memory, which are accompanied by its reconsolidation, result in memory strengthening and contribute to its overall consolidation. This function associated to reconsolidation is temporally limited. With the passage of time, the stored memory undergoes important changes, as revealed by the behavioral outcomes of its retrieval. Over time, without explicit retrievals, memory first strengthens and becomes refractory to both retrieval-dependent interference and strengthening. At later times, the same retrievals that lead to reconsolidation of a young memory extinguish an older memory. We conclude that the storage of information is very dynamic and that its temporal evolution regulates behavioral outcomes. These results are important for potential clinical applications.
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