Mechanisms of synaptotoxicity in Alzheimer's disease : Pre- and postsynaptic differences to amyloid beta-induced injury

Vicario Orri, Elena

Mechanisms of synaptotoxicity in Alzheimer's disease : Pre- and postsynaptic differences to amyloid beta-induced injury

Document Type

Doctoral thesis
Published Version

Author

Vicario Orri, Elena

Director

Koo, Edward H
Muñoz López, Francisco José

Publication Date

2017-10-03

Pages

186 p.

Citation

Vicario Orri, E. Mechanisms of synaptotoxicity in Alzheimer's disease : Pre- and postsynaptic differences to amyloid beta-induced injury. Universitat Pompeu Fabra; 2017. handle: http://hdl.handle.net/10803/664238

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

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.
Els mecanismes pels quals la beta-amiloide (Aβ) afecta les sinapsis en l’Alzheimer es desconeixen. L’Aβ és derivat del precursor de la proteïna d’amiloide (APP) i és alliberat per les neurones. Avui dia no és possible determinar si el dany sinàptic ocasionat per Aβ és iniciat per la neurona presinàptica o postsinàptica, ni com el dany es propaga. Per tal d’adreçar això, hem generat uns ratolins transgènics que expressen APP només a les neurones CA3 o CA1 de l’hipocamp, una zona del cervell crucial per la memòria i que degenera en la malaltia d’Alzheimer. Ens hem centrat en analitzar els patrons de dany sinàptic en poblacions neuronals situades pre- o postsinàpticament a l’expressió d’APP tot estudiant la funcionalitat, és a dir, la potenciació a llarg termini, un procés clau en la formació de la memòria, i examinant el nombre de sinapsis. Els nostres resultats mostren que els dèficits de plasticitat sinàptica i la pèrdua de sinapsis ocorren en les sinapsis situades postsinàpticament a les neurones que expressen APP. També, la presència de dipòsits d’Aβ en les regions on els axons acaben és consistent amb un alliberament d’Aβ des dels terminals presinàptics. A més, aquests dèficits són reversibles en suprimir l’expressió d’APP o tractar els ratolins amb un inhibidor de la γ-secretasa, apuntant a Aβ com la principal espècie tòxica. En definitiva, els nostres resultats mostren que el dany sinàptic induït per Aβ és preferencialment mediat per l’alliberament presinàptic d’Aβ.

Keywords

Alzheimer's disease, Aging, Amyloid-beta peptide, Synaptic loss, Hippocampus, Malaltia d'Alzheimer, Envelliment, Pèptid beta-amiloide, Sinapsis, Hipocamp