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The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model.<\/jats:p>","DOI":"10.3390\/cells11162603","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T21:05:51Z","timestamp":1661115951000},"page":"2603","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Foteini","family":"Vasilopoulou","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-753X","authenticated-orcid":false,"given":"Aina","family":"Bellver-Sanchis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7102-7700","authenticated-orcid":false,"given":"J\u00falia","family":"Companys-Alemany","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"Jarne-Ferrer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5850-5058","authenticated-orcid":false,"given":"Alba","family":"Irisarri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ver\u00f3nica","family":"Palomera-\u00c1valos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. Joan XXIII, 27, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Gonzalez-Castillo","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 64710, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-2514","authenticated-orcid":false,"given":"Daniel","family":"Ortu\u00f1o-Sahag\u00fan","sequence":"additional","affiliation":[{"name":"Laboratorio de Neuroinmunolog\u00eda Molecular, Instituto de Investigaci\u00f3n de Ciencias Biom\u00e9dicas (IICB) CUCS, Universidad de Guadalajara, Guadalajara 44340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9004-1206","authenticated-orcid":false,"given":"Coral","family":"Sanfeliu","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC and Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-4254","authenticated-orcid":false,"given":"Merc\u00e8","family":"Pall\u00e0s","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Avda. 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