Mechanisms of synaptotoxicity in Alzheimer's disease : Pre- and postsynaptic differences to amyloid beta-induced injury
The mechanisms by which amyloid beta (Aβ) causes synaptic dysfunction in Alzheimer’s disease (AD) remain elusive. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) and released from neurons, but to date, it is not possible to determine whether Aβ-induced synaptic injury is...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2017 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/664238 |
| Acceso en línea: | http://hdl.handle.net/10803/664238 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer's disease Aging Amyloid-beta peptide Synaptic loss Hippocampus Malaltia d'Alzheimer Envelliment Pèptid beta-amiloide Sinapsis Hipocamp 616.8 |
| Sumario: | The mechanisms by which amyloid beta (Aβ) causes synaptic dysfunction in Alzheimer’s disease (AD) remain elusive. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) and released from neurons, but to date, it is not possible to determine whether Aβ-induced synaptic injury is initiated by the pre- or postsynaptic neurons and how injury propagates. To address this, we generated transgenic mice with targeted expression of APP in CA1 or CA3 neurons of the hippocampus, a region of the brain crucial for memory formation and mainly affected in AD. We focused on identifying patterns of synaptic injury in the neuronal populations situated pre- and postsynaptically to the site of APP expression by studying synaptic functionality namely long-term potentiation (LTP), a process crucial for memory formation, as well as synaptic numbers. LTP was impaired only in synapses where APP was expressed in pre- but not postsynaptic neurons. Similarly, synapse loss was detected in synapses located postsynaptic to APP-expressing neurons, both by immunostaining and electron microscopy. In addition, the presence of Aβ deposits in regions where axons terminate is consistent with a release of Aβ from presynaptic terminals. Turning off APP expression, or treatment with a γ-secretase inhibitor to inhibit Aβ production, reversed the synaptic deficits, pointing to Aβ as the major toxic species. Taken together, our findings show that Aβ-induced synaptic injury is preferentially mediated by the presynaptic release of Aβ. |
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