Biology subjects

Salinas-Salinas, C.

Publications and source records attributed to Salinas-Salinas, C..

3 recordsLinked to original sources

bioRxiv2026

Amyloid precursor protein interacts with the mitochondrial phosphatase PGAM5 and regulates mitochondrial respiration

Amyloid Precursor Protein (APP) has been reported to partially localize to mitochondria, and mitochondrial dysfunction is a key feature of Alzheimers disease; however, the mechanisms linking APP to mitochondrial functions remain incompletely defined. In this study, we identified an interaction between APP and phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein phosphatase. We confirmed their endogenous interaction in mouse brain tissue and determined that APP and PGAM5 are both present at mitochondria-ER contact sites (MERCS) and. Using in vitro binding assays, we demonstrate a direct interaction between the linker region of APP and a region of PGAM5 that includes the Kelch-like ECH-associated protein 1 (Keap-1) binding domain. PGAM5 is known to anchor a portion of Nuclear factor erythroid 2 p45-related factor 2 (Nrf2) through Keap1 at the outer mitochondrial membrane and regulates mitochondrial respiration and stress responses. We found that the Nrf2-regulated genes Hmox1 (Heme oxygenase-1) and Nqo1 (NADH:quinone oxidoreductase 1), which are involved in mitochondrial respiration, are downregulated in APP KO astrocytes. Accordingly, mitochondria isolated from the brains of APP knockout (KO) mice have impaired substrate-specific respiration and electron transport chain (ETC) function. Together, these findings suggest that APP supports mitochondrial respiration by binding to PGAM5 and modulating Keap1-Nrf2 signaling.

neuroscience↗

bioRxiv2025

Oligodendrocytes show enriched expression of amyloid precursor protein and GABA B receptor isoform 1a

Amyloid precursor protein (APP) is a type I transmembrane protein that undergoes proteolytic processing to generate amyloid-{beta}, the main component of amyloid plaques found in brains with Alzheimers disease. The proteolytic processing of APP also generates soluble APP alpha (sAPP) which can modulate synaptic transmission and neurite outgrowth through the {gamma}-aminobutyric acid type B receptor (GABABR). Whether GABABR mediates functions of sAPP in other neural cell types such as glia remains unknown. sAPP binds the R1a subunit isoform of GABABR1 which contains two sushi domains absent in R1b. It is unclear whether both GABABR1 isoforms are expressed equally across brain cell types. We determined relative RNA levels of the GABABR1a and 1b isoforms in oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons in adult mice using two approaches. We developed a GABABR1 isoform-specific RNAseq analysis workflow to probe a publicly available dataset. We also isolated five cell types from a single mouse brain and performed RT-qPCR. We show that the GABABR1a and 1b isoforms are differentially expressed among cell types. GABABR1a expression was highest in oligodendrocytes and GABABR1b expression was highest in astrocytes, suggesting that sAPP-mediated GABABR signaling may be most prominent in oligodendrocytes. We also confirmed that APP is expressed in all five cell types and showed that APP RNA levels are highest in oligodendrocytes. Together, our findings uncover cell type-specific expression of GABABR isoforms and highlight oligodendrocytes as a principal cell type for GABABR1a-mediated APP signaling, providing a foundation for future mechanistic studies.

neuroscience↗

bioRxiv2025

sAPPalpha inhibits neurite outgrowth in primary mouse neurons via GABA B Receptor subunit 1a

Neurite outgrowth is essential for neural circuit formation and is tightly regulated by secreted factors and their receptors. The secreted extracellular domain of the amyloid precursor protein (sAPP) has been shown to modulate neurite outgrowth. Recently, the gamma amino butyric acid receptor type-B subunit 1a (GABABR1a) was identified as an sAPP binding partner that mediates its effects on synaptic transmission. Here, we investigated whether this interaction also regulates neurite outgrowth. In primary hippocampal neurons, the GABABR agonist baclofen reduced axon length; whereas, its antagonist CGP54626 increased axon length in primary hippocampal neurons. Moreover, GABABR1a knockout increased axon length and abolished the effect of baclofen. Application of sAPP reduced axon length, an effect that required the presence of both GABABR1a and the extension domain of sAPP, which mediates its binding to GABABR1a. Similarly, the APP 17mer peptide, which is sufficient to bind GABABR1a and mimic the effects of sAPP on synaptic transmission, reduced axon outgrowth in wildtype but not in GABABR1a-deficient neurons. Together, these findings indicate that the 1a isoform contributes to GABABR-dependent suppression of neurite outgrowth and mediates the inhibitory effect of sAPP on neurite outgrowth. Statement of SignificanceAmyloid precursor protein (APP) plays a central role in Alzheimers disease, yet its normal functions are not fully understood. In this study, we uncover a previously unrecognized role of the GABA B Receptor in mediating the inhibitory effects of sAPP on neurite outgrowth. These findings provide mechanistic insight into how disruptions in APP signaling could influence both normal brain development and pathological processes in neurodevelopmental disorders and Alzheimers disease.

neuroscience↗