TY - JOUR T1 - APOE4 Affects Basal and NMDAR-Mediated Protein Synthesis in Neurons by Perturbing Calcium Homeostasis. JF - J Neurosci Y1 - 2021 A1 - Ramakrishna, Sarayu A1 - Jhaveri, Vishwaja A1 - Konings, Sabine C A1 - Nawalpuri, Bharti A1 - Chakraborty, Sumita A1 - Holst, Bjørn A1 - Schmid, Benjamin A1 - Gouras, Gunnar K A1 - Freude, Kristine K A1 - Muddashetty, Ravi S AB -

Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans, APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the predisposition for Alzheimer's disease (AD). The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4-induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague Dawley (SD) rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male SD rats. APOE4 treatment also abrogates the NMDA-mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDA receptors (NMDARs) leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-type voltage-gated calcium channels (L-VGCCs), thereby causing sustained translation inhibition through eukaryotic translation elongation factor 2 (eEF2) phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity-mediated protein synthesis responses in neurons by affecting calcium homeostasis. Defective protein synthesis has been shown as an early defect in familial Alzheimer's disease (AD). However, this has not been studied in the context of sporadic AD, which constitutes the majority of cases. In our study, we show that Apolipoprotein E4 (APOE4), the predominant risk factor for AD, inhibits global protein synthesis in neurons. APOE4 also affects NMDA activity-mediated protein synthesis response, thus inhibiting synaptic translation. We also show that the defective protein synthesis mediated by APOE4 is closely linked to the perturbation of calcium homeostasis caused by APOE4 in neurons. Thus, we propose the dysregulation of protein synthesis as one of the possible molecular mechanisms to explain APOE4-mediated synaptic and cognitive defects. Hence, the study not only suggests an explanation for the APOE4-mediated predisposition to AD, it also bridges the gap in understanding APOE4-mediated pathology.

VL - 41 IS - 42 ER - TY - JOUR T1 - Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3. JF - Stem Cell Reports Y1 - 2021 A1 - Chandrasekaran, Abinaya A1 - Dittlau, Katarina Stoklund A1 - Corsi, Giulia I A1 - Haukedal, Henriette A1 - Doncheva, Nadezhda T A1 - Ramakrishna, Sarayu A1 - Ambardar, Sheetal A1 - Salcedo, Claudia A1 - Schmidt, Sissel I A1 - Zhang, Yu A1 - Cirera, Susanna A1 - Pihl, Maria A1 - Schmid, Benjamin A1 - Nielsen, Troels Tolstrup A1 - Nielsen, Jørgen E A1 - Kolko, Miriam A1 - Kobolák, Julianna A1 - Dinnyés, András A1 - Hyttel, Poul A1 - Palakodeti, Dasaradhi A1 - Gorodkin, Jan A1 - Muddashetty, Ravi S A1 - Meyer, Morten A1 - Aldana, Blanca I A1 - Freude, Kristine K AB -

Frontotemporal dementia type 3 (FTD3), caused by a point mutation in the charged multivesicular body protein 2B (CHMP2B), affects mitochondrial ultrastructure and the endolysosomal pathway in neurons. To dissect the astrocyte-specific impact of mutant CHMP2B expression, we generated astrocytes from human induced pluripotent stem cells (hiPSCs) and confirmed our findings in CHMP2B mutant mice. Our data provide mechanistic insights into how defective autophagy causes perturbed mitochondrial dynamics with impaired glycolysis, increased reactive oxygen species, and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This shift in astrocyte homeostasis triggers a reactive astrocyte phenotype and increased release of toxic cytokines, which accumulate in nuclear factor kappa b (NF-κB) pathway activation with increased production of CHF, LCN2, and C3 causing neurodegeneration.

VL - 16 IS - 11 ER -