Environmental Enrichment Improves Cognitive Deficits, AD Hallmarks and Epigenetic Alterations Presented in 5xFAD Mouse Model
Open accessAbstract
Cumulative evidence shows that modifications in lifestyle factors constitute an effective strategy to modulate molecular events related to neurodegenerative diseases, confirming the relevant role of epigenetics. Accordingly, Environmental Enrichment (EE) represents an approach to ameliorate cognitive decline and neuroprotection in Alzheimer´s disease (AD). AD is characterized by specific neuropathological hallmarks, such as β-amyloid plaques and neurofibrillary tangles, which severely affect the areas of the brain responsible for learning and memory. We evaluated EE neuroprotective influence on 5xFAD mice. We found a better cognitive performance on EE versus Control (Ct) 5xFAD mice, until being similar to Wild-Type (Wt) mice group. Neurodegenerative markers as β-CTF and tau hyperphosphorylation, reduced protein levels whiles APPα, postsynaptic density 95 (PSD95) and synaptophysin (SYN) protein levels increased protein levels in the hippocampus of 5xFAD-EE mice group. Furthermore, a reduction in gene expression of Il-6, Gfap, Hmox1, and Aox1 was determined. However, no changes were found in the gene expression of neurotrophins, such as Bdnf, Ngf, Tgf, and Vgf in mice with EE. Specifically, we found a reduced DNA-methylation level (5-mC) and an increased hydroxymethylation level (5-hmC), as well as an increased histone H3 and H4 acetylation level. Likewise, we found changes in the hippocampal gene expression of some chromatin-modifying enzyme, such as Dnmt3a/b, Hdac1, and Tet2. Extensive molecular analysis revealed a correlation between neuronal function and changes in epigenetic marks after EE that explain the cognitive improvement in 5xFAD.
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In 5XFAD pathology, spine loss (4-9 months) occurs subsequent to cognitive dysfunction (3-6 months) and Aβ plaque formation (two months).
“An interesting observation in the progression of 5XFAD pathology is that spine loss (4–9 months) [62] occurs subsequent to cognitive dysfunction (3–6 months) [35,63,64,65,66] and Aβ plaque formation (two months) [67].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [63]
A consistent decrease in synaptophysin or PSD95 has not been observed prior to nine months of age.
“a consistent decrease in synaptophysin or PSD95 has not been observed prior to nine months of age [35,63,74,75,76].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [63]
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- Authors
- Griñán-Ferré, C., Izquierdo, V., Otero, E., Puigoriol-Illamola, D., Corpas, R., Sanfeliu, C., Ortuño-Sahagún, D., & Pallàs, M.
- Affiliations
- Universitat de Barcelona (ES)
- Institut d'Investigacions Biomèdiques de Barcelona (ES)
- Corresponding author
- Pallàs, Mercè
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2018-08-15
- Volume
- 12
- Pages
- 224-224
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC6104164
- OpenAlex
- W2884538590
- Cited by
- 94
- References
- 93
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 14 · 2022: 15 · 2021: 19 · 2020: 13 · 2019: 11 · 2018: 1
- FWCI
- 7.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministerio de Economàa y Competitividad (SAF2016-33307)
- Agencia de Gestió d’Ajuts Universitaris i de Recerca (2017SGR106)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- environmental enrichment, Alzheimer's disease, 5xFAD mice, cognitive impairment, epigenetics, DNA methylation, hydroxymethylation, histone acetylation, tau hyperphosphorylation, amyloid-beta, neuroprotection, hippocampus, chromatin-modifying enzymes, neurotrophins, neuroinflammation, lifestyle intervention
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