Impaired memory storage and recall in a hippocampal CA1 network in early Alzheimer’s disease

Abstract

Alzheimer’s Disease (AD) affects millions of individuals, and is one of the main causes of dementia and neurodegeneration worldwide. No significant progress has been made in the treatment of this condition. The molecular mechanisms leading to neurodegeneration in AD are still far from being clear. Alterations in the Amyloid Precursor Protein (APP) processing and clearance have been observed in early stages of AD. Increased levels of specific APP fragments, such as Amyloid β peptide (Aβ) and Amyloid APP Intra-Cellular Domain (AICD), are believed to play an important role in impairment of learning and memory in AD (Opazo et al, Cell Reports 2018; Pousinha et al, Elife 2017). We present a computational study on the effects of the Aβ-induced alterations in synaptic plasticity at a network level. We use a hippocampal CA1-CA3 network which consists of 100 CA1 pyramidal neurons with inhibitory interneurons, medial septum inputs, entorhinal cortex inputs and Schaffer collateral inputs from CA3 neurons. We employ a newly developed NMDAr-dependent voltage-based model of synaptic plasticity that implements the experimentally observed effects of increased levels of AICD and Aβ on long-term potentiation (LTP) and long-term depression (LTD) at CA1- CA3 synapses (Dainauskas et al, Front. Comput. Neurosci. 2023) We illustrate the influence of Aβ-induced alterations in synaptic plasticity on the pattern storage and recall ability of the network. We demonstrate that altered LTP impairs memory storage and recall in hippocampal CA1 network in AD, the process that can be prevented by pharmacological blockage of GluN2B-NMDA receptor. Computational modeling study allows integration of the complex effects of AD related peptides at molecular, synaptic, neuron and network levels, and explains the impaired memory formation and retrieval in the hippocampal networks in AD.