Computational modeling of beta amyloid effect on synaptic plasticity in hippocampal CA1 pyramidal neuron and implications for Alzheimers disease

Abstract

Background and aim: Alzheimer’s disease (AD) is steadily growing to be the leading cause of death in the 1st world countries, with incidence of dementia doubling every 10 years after the age of 60 and almost 90% suffering from it at 90 years of age. The two hallmark features of AD are beta-amyloid (Aβ) accumulation and Tau protein aggregates in the brain. Aβ increase in the brain has an effect on intra/extracellular calcium homeostasis and leads to progressive dendritic atrophy, synaptic and neuronal loss. The mechanism by which Aβ mediates cell death and initiates degenerative processes of AD continues to elude the scientific community to this day. The aim of the study is to analyze the effect of Aβ accumulation on dendritic excitability and synaptic plasticity in CA1 pyramidal neurons using computational modeling methodology. Materials and methods: We use a multicompartmental model of CA1 pyramidal neuron (Poirazi et al., Neuron, 2003) and synaptic plasticity model (Graupner and Brunel, PNAS, 2012) to investigate the influence of Aβ accumulation on intracellular calcium dynamics and synaptic plasticity at excitatory synapses in CA1 pyramidal neurons. The influence of pathological Aβ changes is modeled by blocking A-type K+ channels (IA) in pyramidal cell dendrites and increasing NMDA glutamate receptor maximal conductance in Schaffer collateral synapses. Results: Aβ accumulation leads to the enhanced CA1 pyramidal neuron dendritic excitability, increased amplitude of back-propagating action potentials, higher intracellular calcium transients and promotes long-term potentiation. Conclusions: The results show that prior to cell death Aβ accumulation alters properties of synaptic plasticity and learning in hippocampal CA1 pyramidal neurons.