Impaired hippocampal synaptic plasticity in Alzheimer's disease: Integrating experimental data and computational modeling

Abstract

Alzheimer’s disease (AD) has a long preclinical stage and, before any clinical symptoms appear, pathological processes are observed in the hippocampus. Recent experimental evidence supports the fundamental role of AD-related peptides early in the pathology: in particular the most widely studied Amyloid beta (Abeta), and the less investigated Amyloid precursor protein (APP) C-terminal peptide (AICD). The aim of this project is to understand the AD-related peptide-induced mechanisms of impaired learning and memory in hippocampal CA1 region in early pathology of AD by applying the integrated experimental and computational modelling approach. We investigated the effects of Abeta and AICD on intrinsic excitability of hippocampal CA1 pyramidal neurons and synaptic plasticity at hippocampal CA1-CA3 synapses in early pathology of AD. We developed data-driven in silico models of the hippocampal learning in CA1 region under AD conditions, and 1) extended the experimental evidence of Abeta, AICD-related changes in the properties of hippocampal CA1 pyramidal neuron synaptic plasticity, synaptic signal integration and neuronal excitability; 2) incorporated the effects of AD-related peptides into computational models of hippocampal synaptic plasticity to determine and explain the mechanisms of altered hippocampal function that leads to impaired learning in AD; 3) assessed the potential targets for innovative treatment of AD. We used Human Brain Project Brain Simulation Platform to perform computational modeling. The modeling results support the experimental evidence that pathological concentrations of Aβ and AICD cause long-term potentiation (LTP) impairment. Long-term depression (LTD) enhancement was observed in Abeta conditions. Synaptic plasticity was strongly dependent on GluN2B-NMDA receptor subunit functioning, and rescued by its partial blockade in AD. The modeling study provides insight into the complex interactions in AD pathophysiology, and suggests the conditions under which synaptic plasticity is restored. The inter-disciplinary analysis, bringing together experimentalists and modelers, helps to further unravel the neuronal mechanisms most affected by AD, build a biologically-plausible computational models of the hippocampal CA1 area under AD conditions, and suggest potential targets for pharmacological treatment of AD.