Submicromolar Aß42 Reduces Hippocampal Glutamate Receptors and Presynaptic Markers in an Aggregation-Dependent Manner

UNCP Author/Contributor (non-UNCP co-authors, if there are any, appear on document)
Dr . Ben Bahr, William C. Friday Chair and Professor of Molecular Biology and Biochemistry (Creator)
The University of North Carolina at Pembroke (UNCP )
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Abstract: Synaptic pathology in Alzheimer's disease brains is thought to involve soluble Aß42 peptide. Here, sterile in-cubation in PBS caused small Aß42 oligomer formation as well as heterogeneous, 6E10-immunopositive ag-gregates of 80–100 kDa. The high molecular weight aggregates (H-agg) formed in a time-dependent manner over an extended 30-day period. Interestingly, an inverse relationship between dimeric and H-agg formation was more evident when incubations were performed at 37 °C as compared to 23 °C, thus providing an exper-imental strategy with which to address synaptic compromise produced by the different Aß aggregates. H-agg species formed faster and to higher levels at 37 °C compared to 23 °C, and the two aggregate preparations were evaluated in hippocampal slice cultures, a sensitive system for monitoring synaptic integrity. Applied daily at 80–600 nM for 7 days, the Aß42 preparations caused dose-dependent and aggregation-dependent declines in a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits as well as in presynaptic components. Unlike the synaptic effects, Aß42 induced only trace cellular degeneration that was CA1 speci?c. The 37 °C preparation was less effective at decreasing synaptic markers, corresponding with its reduced levels of Aß42 monomers and dimers. Aß42 dimers decayed signi?cantly faster at 37 °C than 23 °C, and more rapidly than monomers at either temperature. These ?ndings indicate that Aß42 can self-aggregate into potent synaptotoxic oligomers as well as into larger aggregates that may serve to neutralize the toxic formations. These results will add to the growing debate concerning whether high molecular weight Aß complexes that form amyloid plaques are protective through the sequestration of oligomeric species.

Additional Information

Biochimica et Biophysica Acta (BBA)
Language: English
Date: 2011
Amyloid Beta, Alzheimer’s Disease, GluR1, Aggregation, Synaptic Decline, Aß42

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