Computational Modeling of Alzheimer’s Disease in Hippocampal CA1 Pyramidal Neurons

Abstract

The most common form of dementia in the world is Alzheimer’s disease (AD), a degenerative and irreversible brain illness. Despite the fact that the number of AD patients is rising, no ground-breaking treatments have been suggested recently. In order to understand the intricate molecular, synaptic, cellular, neuronal, and network level causes of impaired learning and memory in the AD, a new multidisciplinary approach is required. We use an integrated experimental and computational modelling approach to explore and better understand the impairment in synaptic plasticity caused by AD-related peptides at hippocampal CA1-CA3 synapses in early AD disease. Amyloid beta (Aβ), Amyloid eta (Aβ), and the Amyloid APP intracellular domain are among the AD-related peptides that are produced as a result of altered amyloid precursor protein (APP) processing and clearance in the early stages of the disease (AICD). While high concentrations of AICD cause LTP disruption and leave LTD intact at glutamatergic synapses, Aβ inhibits long-term potentiation (LTP) and promotes long-term depression (LTD) in hippocampal CA1 pyramidal neurons. The aim of this study is to investigate the joint effect of AICD and Aβ on LTP and LTD at hippocampal CA1-CA3 synapses applying computational modeling approach. We used a newly developed NMDAr-dependent voltage-based model of synaptic plasticity along with a compartmental model of a CA1 pyramidal neuron. The increased AICD levels were modeled, by adjusting the conductances of SK channels, L-type calcium channels, and the contribution of GluN2Bcontaining NMDA receptor. The heightened levels of Aβ were modeled as increased extracellular glutamate concentration, endocytosis of synaptic AMPA receptors, decreased synaptic density, and altered GluN2B-containing NMDA receptor-mediated activation of calcium/calmodulin-dependent kinase II (CaMKII). Our modeling results show that increased AICD levels disrupt LTP while LTD is unaffected, while increased Aβ levels disrupt LTP and enhance LTD, mirroring the experimental results. Simulation with both AICD and Aβ having pathological concentrations disrupt synapse ability to potentiate weight. Computational modeling study sheds light on the AICD- and Aβ-induced complex processes and their interactions in shaping synaptic plasticity at the hippocampal synapses.