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Key pathways in Alzheimer’s disease

The incidence of neurodegenerative disorders such as Alzheimer’s disease (AD) is rising due to an increase in the ageing population. Understanding the molecular mechanism of neuronal degeneration could lead to new interventions.
Key pathways in Alzheimer’s disease
Amyloid precursor protein (APP) is a membrane protein that is mainly located in neuronal synapses and plays a central role in synapse formation and neural plasticity. Proteolytic cleavage of APP produces amyloid beta (Aβ) peptides that under physiological conditions display various functions. In AD, Aβ peptides misfold, aggregate and accumulate into plaques, causing synaptic dysfunctions and cognitive decline.

The primary objective of the EU-funded ABETAPRESYNASTRO (Presynaptic and astrocytic role of amyloid precursor protein signaling in the hippocampus) project was to investigate how Aβ and APP signalling regulated synaptic properties in the hippocampus. Accumulating evidence from animal models indicated that early stage AD presents with network hyperactivity due to an imbalance in synaptic excitation and inhibition. However, there was no information regarding the cellular and molecular changes in synaptic activity responsible for this hippocampal hyperactivity. ABETAPRESYNASTRO scientists hypothesised that Aβ could mediate network hyperactivity by increasing the release of neurotransmitter vesicles at synapses.

Using fluorescence imaging at hippocampal brain synapses, they observed that APP was present as a complex and its conformation was affected by an elevation in the extracellular levels of Aβ. This had an immediate effect in synaptic vesicle release and hence synaptic activity.

After localising APP expression in a certain part of hippocampus, scientists went on to examine the impact of Aβ peptide at different synapses. They discovered a differential effect of Aβ peptide on synapses terminating at the same cell. In particular, Aβ peptide induced a depressive effect on mossy fibre synapses and altered short-term plasticity, potentially affecting overall hippocampus function.

Apart from fundamental knowledge into the APP downstream signalling events, the study provided experimental tools that could be utilised in the future to study synaptic dysfunction in neurodegenerative disorders.

Related information

Subjects

Life Sciences

Keywords

Alzheimer’s disease, amyloid precursor protein, synapse, amyloid beta peptide, hippocampus, mossy fibre
Record Number: 188745 / Last updated on: 2016-10-27
Domain: Biology, Medicine
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