New Insights into the Spontaneous Human Alzheimer’s Disease-Like Model Octodon degus: Unraveling Amyloid-β Peptide Aggregation and Age-Related Amyloid Pathology

Article type: Research Article

Authors: Cisternas, Pedro^{a; 1} | Zolezzi, Juan M.^{a; 1} | Lindsay, Carolina^a | Rivera, Daniela S.^{a; b} | Martinez, Alexis^a | Bozinovic, Francisco^{b; d} | Inestrosa, Nibaldo C.^{a; c; e; *}

Affiliations: [a] Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile | [b] Centro de Ecología Aplicada y Sustentabilidad (CAPES), Departamento de Ecología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile | [c] Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia | [d] Centro UC-Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile | [e] Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

Correspondence: [*] Correspondence to: Dr. Nibaldo C. Inestrosa at CARE UC, Pontificia Universidad Católica de Chile, Av. Bernardo ÓHiggins 340, Santiago, Chile. Tel.: +56 2 6862724; Fax: +56 2 6862959; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.

Keywords: Alzheimer’s disease, Aβ peptide, natural model, Octodon degus, senile plaques

DOI: 10.3233/JAD-180729

Journal: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1145-1163, 2018