CORDIS - EU research results

Presynaptic and astrocytic role of Amyloid precursor protein signaling in the hippocampus

Final Report Summary - ABETAPRESYNASTRO (Presynaptic and astrocytic role of Amyloid precursor protein signaling in the hippocampus)

The main objective of our studies was to assess the regulation of synaptic properties by amyloid beta (Aβ)/Amyloid Precursor Protein (APP) signaling at hippocampal synapses using synaptic imaging and electrophysiological methods. Alzheimer’s disease (AD) is neurodegenerative disease, for which Aβ imbalance is considered a prime factor in the development of the disease. Accumulation of Aβ peptides, the proteolytic products of APP, induces a variety of synaptic dysfunctions ranging from network hyperactivity to synaptic depression that are postulated to cause cognitive decline in AD. Indeed, recent data revealed that brain from mouse models present network hyperactivity in early stage due to excessive synaptic inputs or synaptic excitation/inhibition imbalance. However, these studies do not investigate mechanistically what are the early cellular and molecular changes in synaptic activity that explain hippocampal hyperactivity. Based on previous results showing that amyloid beta could increase the probability of release at hippocampal synapses, we hypothesize that presynaptic loci were the plausible target of Aβ to mediate network hyperactivity.
As a first objective, we identified APP as a cognate receptor for amyloid beta. We showed using fluorescence imaging that APP is present as a complex at native hippocampal synapses in acute brain slices. Elevation in the extracellular levels of Aβ results in a change in the APP complex conformation similarly to what is observed generally in homodimer receptors. The change in APP complex dimerization correlates with the change in the amount of synaptic vesicle release following Aβ level elevation.
Our second objective was to understand in hippocampal synapses the role of presynaptic APP as a regulator of release of synaptic vesicles and short-term plasticity. We found that APP protein was lowly express in granular cells (GCs) of the dentate gyrus while pyramidal cells of CA3 and CA1 area express high levels of the protein. We checked the effects of Aβ at the synapses of two different pathways terminating on the CA3 pyramidal cells: the mossy fiber originating from the GCs and the recurrent pathway that connect CA3 pyramidal cells to each other. Surprisingly, we found that Aβ level elevation had diverse effects at the two synapses. While synapses of the recurrent pathway were insensitive to the Aβ challenge tested, mossy fiber synapses were depressed and synaptic facilitation was increased. The altered short-term synaptic plasticity in the MF synapses might altered the overall hippocampal function and leads to pattern separation deficits in mouse models and in human AD patients.

Overall, this research has significantly advanced our knowledge on the form of APP found at native hippocampal synapses and its role as a receptor of Aβ signaling. It shows that the Aβ affects differentially two synapses terminating on a same cell and provide an experimental model to understand the downstream effectors of the peptide. It has also provided the fellow with an excellent basis upon which to continue this line of research, both in terms of future experimental plans and with respect to his integration into the Israeli research community. The funding provided by the Curie Integration Grant has substantially promoted the fellow’s long-term career perspectives to establish an independent research program on the etiology of synaptic dysfunctions in Alzheimer’s disease.