The Amyloid precursor protein intracellular domain affects hippocampal synaptic plasticity in Alzheimer’s disease: a computational modeling study

Abstract

Alzheimer’s disease (AD) is an irreversible and incurable brain disorder, characterized by progressive memory loss and cognitive dysfunction. In early AD, the alterations in amyloid precursor protein (APP) processing and clearance of APP peptides are observed. Increased APP levels lead to the production of AD related peptides such as amyloid beta, and the amyloid APP intracellular domain (AICD) at higher concentrations [1]. It was recently shown that AICD modifies intrinsic excitability of hippocampal CA1 pyramidal neuron and impairs synaptic plasticity in AD [1]. The aim of this study is to investigate the effect of the pathological AICD levels on long-term potentiation (LTP) and long-term depression (LTD) in a detailed computational model of a CA1 pyramidal neuron. We used a detailed compartmental model [2] and included the influence of the elevated AICD levels by increasing the conductances of SK channels and L-type calcium channels. At a synaptic level, the contribution of the GluN2B-containing NMDA receptor (NMDAr) was also increased. A modified NMDAr dependent voltage-based model of synaptic plasticity [3] was used to analyse synaptic strengths at clustered Shaffer collateral synapses. The results support the experimental indication that pathological concentration of AICD leads to LTP disruption and leaves LTD intact in AD. The model provides insight into the complex interactions in AD pathophysiology and suggest the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree can concur in generating the observed signal at the soma after a LTP conditioning period.