Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures
Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) in the brain. Aβ 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117302851 |
| _version_ | 1818724414507712512 |
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| author | Clive Bate Alun Williams |
| author_facet | Clive Bate Alun Williams |
| author_sort | Clive Bate |
| collection | DOAJ |
| description | Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) in the brain. Aβ 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 Aβ-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble Aβ oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes Aβ oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A2 (cPLA2). In contrast, Aβ monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA2, nor did they damage synapses. The Aβ oligomer-induced aggregation of cellular prion proteins (PrPC) at synapses triggered the activation of cPLA2 that leads to synapse degeneration. Critically, Aβ monomer preparations did not cause the aggregation of PrPC; rather they reduced the Aβ oligomer-induced aggregation of PrPC. The presence of Aβ monomer preparations also inhibited the Aβ oligomer-induced increase in cholesterol concentrations and activation of cPLA2 in synaptosomes and protected neurons against the Aβ oligomer-induced synapse damage. These results support the hypothesis that Aβ monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological Aβ monomer:oligomer ratio rather than the total concentrations of Aβ within the brain. |
| first_indexed | 2024-12-17T21:26:02Z |
| format | Article |
| id | doaj.art-670068fb83a044e6be9fdd20f62af072 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:26:02Z |
| publishDate | 2018-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-670068fb83a044e6be9fdd20f62af0722022-12-21T21:32:02ZengElsevierNeurobiology of Disease1095-953X2018-03-011114858Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal culturesClive Bate0Alun Williams1Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts AL9 7TA, UK; Corresponding author.Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UKAlzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) in the brain. Aβ 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 Aβ-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble Aβ oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes Aβ oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A2 (cPLA2). In contrast, Aβ monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA2, nor did they damage synapses. The Aβ oligomer-induced aggregation of cellular prion proteins (PrPC) at synapses triggered the activation of cPLA2 that leads to synapse degeneration. Critically, Aβ monomer preparations did not cause the aggregation of PrPC; rather they reduced the Aβ oligomer-induced aggregation of PrPC. The presence of Aβ monomer preparations also inhibited the Aβ oligomer-induced increase in cholesterol concentrations and activation of cPLA2 in synaptosomes and protected neurons against the Aβ oligomer-induced synapse damage. These results support the hypothesis that Aβ monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological Aβ monomer:oligomer ratio rather than the total concentrations of Aβ within the brain.http://www.sciencedirect.com/science/article/pii/S0969996117302851Amyloid-βCholesterolMonomersOligomersPhospholipase A2Synapses |
| spellingShingle | Clive Bate Alun Williams Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures Neurobiology of Disease Amyloid-β Cholesterol Monomers Oligomers Phospholipase A2 Synapses |
| title | Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures |
| title_full | Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures |
| title_fullStr | Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures |
| title_full_unstemmed | Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures |
| title_short | Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures |
| title_sort | monomeric amyloid β reduced amyloid β oligomer induced synapse damage in neuronal cultures |
| topic | Amyloid-β Cholesterol Monomers Oligomers Phospholipase A2 Synapses |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117302851 |
| work_keys_str_mv | AT clivebate monomericamyloidbreducedamyloidboligomerinducedsynapsedamageinneuronalcultures AT alunwilliams monomericamyloidbreducedamyloidboligomerinducedsynapsedamageinneuronalcultures |