Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment

Article type: Research Article

Authors: Sierra-Fonseca, Jorge A.^a | Rodriguez, Minerva^a | Themann, Anapaula^a | Lira, Omar^a | Flores-Ramirez, Francisco J.^a | Vargas-Medrano, Javier^b | Gadad, Bharathi S.^b | Iñiguez, Sergio D.^{a; *}

Affiliations: [a] Department of Psychology, The University of Texas at El Paso, El Paso, TX, USA | [b] Department of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Science Center, El Paso, TX, USA

Correspondence: [*] Correspondence to: Sergio D. Iñiguez, PhD, Department of Psychology, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968, USA. Tel.: +1 915 747 5769; Fax: +1 915 747 6553; E-mail: [email protected].

Abstract: Background: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Objective: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. Methods: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. Results: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortex Conclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.

Keywords: Abnormal protein accumulation, Alzheimer’s disease, antidepressant, drug safety, juvenile, LC3-II, long-term effects, p62, proteostasis, SSRI

DOI: 10.3233/JAD-210475

Journal: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1691-1702, 2021