| First Author | Rolland M | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 27 | Pages | 5161-5176 |
| PubMed ID | 32444385 | Mgi Jnum | J:297385 |
| Mgi Id | MGI:6438318 | Doi | 10.1523/JNEUROSCI.2501-19.2020 |
| Citation | Rolland M, et al. (2020) Effect of Abeta Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons. J Neurosci 40(27):5161-5176 |
| abstractText | Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-beta oligomers (Abetaos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Abetaos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Abetaos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Abetaos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Abetaos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Abetaos. Intracellular Abetaos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Abetaos. Furthermore, we provide evidence that following APP processing, extracellular release of Abetaos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Abetaos in AD, while intracellular Abetaos alter synaptic function, extracellular Abetaos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.SIGNIFICANCE STATEMENT Here we provide the proof that a vicious cycle between extracellular and intracellular pools of Abeta oligomers (Abetaos) is required for the spreading of Alzheimer's disease (AD) pathology. We showed that extracellular Abetaos propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequent to APP cleavage two pools of Abetaos are produced. One pool accumulates inside the cytosol, inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extracellular and intracellular Abeta, providing a therapeutic approach for the disease. |
