  Citation: Alvarez, J.; Alvarez-Illera, P.; Santo-Domingo, J.; Fonteriz, R.I.; Montero, M. Modeling Alzheimer’s Disease in Caenorhabditis elegans. Biomedicines 2022, 10, 288. https://doi.org/10.3390/ biomedicines10020288 Academic Editors: Susana Cardoso, Cristina Carvalho and Sónia Catarina Correia Received: 21 December 2021 Accepted: 24 January 2022 Published: 26 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biomedicines Review Modeling Alzheimer’s Disease in Caenorhabditis elegans Javier Alvarez * , Pilar Alvarez-Illera , Jaime Santo-Domingo , Rosalba I. Fonteriz and Mayte Montero Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and CSIC, Ramón y Cajal, 7, E-47005 Valladolid, Spain; pilar_alvill@hotmail.com (P.A.-I.); jaime.santo-domingo@uva.es (J.S.-D.); rfonteri@ibgm.uva.es (R.I.F.); mmontero@ibgm.uva.es (M.M.) * Correspondence: jalvarez@ibgm.uva.es Abstract: Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase. Keywords: Alzheimer’s; C. elegans; β-amyloid; amyloid precursor protein; tau protein; presenilin; new therapies 1. Introduction Alzheimer’s disease is a chronic and irreversible neurodegenerative disease that constitutes approximately 80% of dementia cases and mainly affects the population over 65 years of age. It is characterized by a progressive loss of cognitive function with severe memory impairment and impaired thinking and social skills, which together make daily living activities considerably more difficult or even impossible and lead to dependence [1,2]. From a neuropathological point of view, Alzheimer’s disease is characterized by the presence of neurofibrillary tangles (NFTs) and extracellular insoluble amyloid plaques, ac- companied by neuronal damage and death mainly in the cerebral cortex and hippocampus, brain regions critical for learning and memory. The main constituent of NFTs is a hyper- phosphorylated form of tau protein, a phosphoprotein that promotes tubulin assembly on microtubules and helps stabilize their structure. On the other hand, extracellular amyloid plaques are composed mainly of amyloid (Aβ) peptide. Aβ accumulates in extracellular plaques and then there is uptake by endocytosis of these neurotoxic oligomers. This process induces tau phosphorylation and its aggregation into NFTs, as well as other toxicity phe- nomena, including ER stress, alterations of Ca 2+ homeostasis, mitochondrial dysfunction, neuroinflammation and neuronal death [1,2]. The accumulation of the Aβ peptide is the result of sequential enzymatic process- ing of the human amyloid precursor protein (APP) by enzymes called secretases, which are proteases responsible for cleaving this protein. APP is a glycoprotein with a single transmembrane segment that can undergo sequential proteolytic processing through two Biomedicines 2022, 10, 288. https://doi.org/10.3390/biomedicines10020288 https://www.mdpi.com/journal/biomedicines