MILEDI, Multiscale Modelling of Impaired LEarning in Alzheimer’s Disease and Innovative Treatments

Alzheimer’s disease (AD) affects over 46 million people worldwide, estimated to triple by the year 2050. It has a long preclinical stage and, before any clinical symptoms appear, pathological processes are observed in the hippocampus and entorhinal cortex, key brain structures responsible for memory encoding and retrieval. AD cannot be prevented, halted or cured today, and new interdisciplinary ways are urgently needed for the understanding and treatment of this devastating disease.

Recent experimental evidence supports the fundamental role of AD-related peptides early in the pathology: in particular the most widely studied Amyloid beta (Aβ), and the less investigated Amyloid eta (Aη) and Amyloid precursor protein (APP) C-terminal peptide (AICD). Their differential effects on synaptic function and intrinsic excitability of hippocampal CA1 pyramidal neuron at a single cell level are currently being investigated. However, the dose-dependent impact and complex interaction effects of Aβ, Aη, AICD on hippocampal synaptic plasticity, CA1 network activity, memory encoding and retrieval capacity and dynamics remain largely unknown.

An interdisciplinary consortium will perform ex-vivo whole-cell patch clamp electrophysiology recordings in hippocampus CA1 (Dr. Hélène Marie, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France), computational modeling of hippocampal synaptic plasticity (Prof Ausra Saudargiene, Lithuanian University of Health Sciences, Kaunas, Lithuania), of neuronal excitability and large scale network (Dr. Michele Migliore, Institute of Biophysics, Palermo, Italy) under control and Alzheimer’s disease conditions.

The main project objectives are:

  1. Extend the experimental evidence of Amyloid beta (Aβ), Amyloid eta (Aη), AICD-related changes in the properties of hippocampal CA1 pyramidal neuron synaptic plasticity, synaptic signal integration and neuronal excitability.
  2. Incorporate the dose-dependent effects of AD-related peptides into computational models of hippocampal synaptic plasticity, CA1 pyramidal neurons and CA1 network (Figure 1); identify and suggest experimentally testable predictions on the molecular, synaptic, cellular, network-level mechanisms of altered hippocampal function that leads to impaired learning and progressive irreversible memory loss in Alzheimer’s disease.
  3. Identify and assess experimentally and by computational modeling potential targets for innovative treatment of Alzheimer’s disease.

The project has received funding from the FLAG-ERA III Joint Call 2019.