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Amyloid-β assemblies: Alzheimer's disease and neurotoxicity
The way that different amyloid-β (Aβ) assemblies cause neurotoxicity depends upon their morphology, according to researchers from Boehringer Ingelheim Pharma and the University of Ulm.
It is well established that Aβ plays an important role in the pathogenesis of Alzheimer's disease but exactly how it impairs neurotransmission is not clear.
Aβ is generated by sequential proteolysis of amyloid precursor protein. The Aβ monomers then self-associate to form soluble prefibrillar Aβ. These will assemble into insoluble Aβ fibrils that eventually amass into amyloid plaques.
As a result of studies showing a lack of correlation between the number of plaques and the level of dementia, it is now believed that it is the soluble Aβ assemblies that have the most toxic effects on the brain.
In this study, various protocols were used to generate a number of prefibrillar Aβ assemblies with different morphologies and sizes. These were characterised as spheroidal, protofibrillar or fibrillar Aβ aggregates depending on the predominant Aβ assembly after self-association. Their neurotoxicity was then tested in hippocampal neuronal cultures and brain slices through neuronal binding and changes in neurotransmission.
Monomeric and fibrillar Aβ aggregates showed no binding to neurons. However, prefibrillar aggregates did bind to mature neurons, indicating potential bioactivity. Interestingly, there was no binding with young neurons for any of the Aβ aggregates.
Hippocampal neurotransmission was assessed by analysing field excitatory postsynaptic potentials (fEPSPs) of basal neurotransmission (BNT) and then after induction of long-term potentiation (LTP) by high-frequency stimuli.
The fEPSPs were carried out using Scientifica's SliceMaster multi-slice recording system to enable semi-automated simultaneous recordings of up to eight brain slices over several hours. The data acquisition equipment was a modular electrophysiology system supplied by NPI electronic.
Spheroidal Aβ aggregates inhibited NMDAR-dependent LTP, whilst protofibrillar Aβ aggregates inhibited AMPAR-dominated BNT, showing different mechanisms of neurotransmission impairment.
This suggests that multiple Aβ assemblies have important roles in Alzheimer's disease through different modalities. As a consequence of this, there is now more than one Aβ target for further therapeutic research.
Moreth J., Kroker K., Schwanzer D., Schnack C., Von Arnim C.A.F., Hengerer B., Rosenbrock H., Kussmaul L. (2013) Globular and Protofibrillar Aβ Aggregates Impair Neurotransmission by Different Mechanisms Biochemistry, 52:1466-1476 doi: 10.1021/bi3016444