Monomeric amyloid-ß reduced amyloid-ß oligomer-induced synapse damage in neuronal cultures

Bate, C; Williams, A

Abstract

Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-? (A?) in the brain. A? oligomers are believed to cause synapse damage resulting in the memory deficits that are characteristic of this disease. Since the loss of synaptic proteins in the brain correlates closely with the degree of dementia in Alzheimer's disease, the process of A?-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble A? oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes A? oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A2 (cPLA2). In contrast, A? monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA2, nor did they damage synapses. The A? oligomer-induced aggregation of cellular prion proteins (PrPC) at synapses triggered the activation of cPLA2 that leads to synapse degeneration. Critically, A? monomer preparations did not cause the aggregation of PrPC; rather they reduced the A? oligomer-induced aggregation of PrPC. The presence of A? monomer preparations also inhibited the A? oligomer-induced increase in cholesterol concentrations and activation of cPLA2 in synaptosomes and protected neurons against the A? oligomer-induced synapse damage. These results support the hypothesis that A? monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological A? monomer:oligomer ratio rather than the total concentrations of A? within the brain.

Citation

Bate, C., & Williams, A. (2018). Monomeric amyloid-ß reduced amyloid-ß oligomer-induced synapse damage in neuronal cultures. Neurobiology of Disease, 111, 48-58. https://doi.org/10.1016/j.nbd.2017.12.007

• Journal Article Type: Article
• Acceptance Date: Dec 12, 2017
• Publication Date: Mar 1, 2018
• Deposit Date: Jan 27, 2018
• Publicly Available Date: Mar 2, 2019
• Journal: NEUROBIOLOGY OF DISEASE
• Print ISSN: 0969-9961
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 111
• Pages: 48-58
• DOI: https://doi.org/10.1016/j.nbd.2017.12.007
• Public URL: https://rvc-repository.worktribe.com/output/1388306