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Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities

Molecular Psychiatry volume 27, pages 3182–3191 (2022)Cite this article

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Abstract

The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer’s disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.

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Fig. 1: Summary of Aβ species-mediated effects on hippocampal long-term potentiation.
Fig. 2: Schematic diagram of Aβ oligomer-mediated effects on synaptic plasticity.
Fig. 3: N-terminal-specific antibodies, but not C-terminal-specific antibodies, prevent hippocampal LTP impairment induced by soluble AD brain extract.

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Acknowledgements

Supported by a grant (to SL) from the Massachusetts Alzheimer’s Disease Research Center (5P50 AG 005134).

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  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, 02115, United States

    Shaomin Li & Andrew M. Stern

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Li, S., Stern, A.M. Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities. Mol Psychiatry 27, 3182–3191 (2022). https://doi.org/10.1038/s41380-022-01589-5

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