Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

Round 1

Reviewer 1 Report

Manuscript ID: cells-1730150
Type of manuscript: Article
Title: Neuronal Rubicon represses extracellular APP/amyloid β deposition in Alzheimer's disease.

Rubicon is a well-studied inhibitor of autophagy in cells. Decreased autophagy during aging may contribute to brain dysfunction by accumulating potentially toxic substrates in neurons. However, Rubicon participates in different pathways depending on cell type, and there is little information on the role of neuronal Rubicon in AD. This well-written, interesting article, showed that neuronal Rubicon is a repressor of APP/amyloid β secretion, which may provide a new target for therapy of AD and other similar diseases. The methodology is not objectionable and is described accurately. Strength of the paper are the multitude of techniques used and very good quality of the images obtained to support their conclusion. The experiments were carried out on a wide variety of material to investigate the problem; on postmortem brain samples from AD patients, 5xFAD mice, AD transgenic mice lacking Rubicon, human induced pluripotent stem cells (hiPSCs) derived from early-to-moderate AD, and in postmortem samples from severe AD patients, and APP- expressing neuroblastoma cells.  Discussion on some of the contradictory results from other studies on the role of Rubicon is relevant and puts this evaluation in the correct context. Thus, this is a relevant and well-designed study, appropriate for this journal. In fact, I have no critical comments. Therefore I recommend this article to be published as it is.

Reviewer 2 Report

Autophagy attenuation was found in neurodegenerative diseases, aging and atherosclerosis. So, in experimental models of neurodegenerative disease the correction of autophagy in brain can reverse neuronal and behavioral deficit and seems to be a promising therapy for neuropathology. From other side, there is increasing interest to study effects of different inhibitors of autophagy (like Rubicon used by authors), which have not been studied enough until now.

In models of Alzheimer’s disease, (AD) using modern methods of investigation, authors have shown increased cell-specific expression of Rubicon in postmortem samples of brain of patients with Alzheimer’s disease, namely in neurons and in human-induced pluripotent stem cells (AD-hiPSCs). Significant changes were observed in hippocampus. These results open new approaches and perspectives to study mechanisms of development of neurodegeneration, first of all AD. It is necessary to support this interesting original work.