Environmental Enrichment Improves Cognitive Deficits, AD Hallmarks and Epigenetic Alterations Presented in 5xFAD Mouse Model

Abstract

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 vs. 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 Brain-derived neurotrophic factor (Bdnf), Nerve growth factor (Ngf), Tumor growth factor (Tgf) and Nerve growth factor inducible (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.

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

“…are consistent with previous studies of nine month old 5XFAD mice [35]. Furthermore, a consistent decrease in synaptophysin or PSD95 has not been observed prior to nine months of age [35,63,[74][75][76]. Future experiments with mice over nine months of age might exacerbate this difference (AD pathology due to Aβ toxicity is age-dependent), potentially leading to more robust synaptic pathology, allowing for a more effective evaluation of CAW's impact on synaptic density.…”

“…We found a statistically significant CAW treatment-dependent increase in these synaptic markers in the cortex, while there was a significant increase in synaptophysin in the hippocampus and an increasing trend in Psd95 (p=0.026) with CAW treatment. 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]. This is different from the progression in Tg2576, which manifests synaptic damage at an early stage of pathological development (4.5 months) [68,69] with a corresponding decrease in synaptic density markers [70] prior to Aβ plaque development (10 months) [71] and cognitive deficiencies (one year) [72,73].…”

Trigonelline recovers memory function in Alzheimer’s disease model mice: evidence of brain penetration and target molecule

“…3). Decrease in synaptophysin level in 5XFAD mice was not clearly detected at least by western blotting as other reports showing 23,24 . More fine detection of synaptophysin at limited presynaptic areas might be needed in future.…”

Suan-Zao-Ren Decoction Ameliorate Synaptic Plasticity Through the Inhibition of JAK2/STAT3 Signaling Pathway in APP/PS1 Transgenic Mice

“…Both SNY and PSD95 play an essential role in synaptic plasticity [39]. With this respect, several studies have demonstrated that the protein expressions of SYN and PSD95 in the AD's hippocampus were enhanced signi cantly, and decreases in these protein expressions can restrain cognitive decline [40,41]. In this study, using Golgi-Cox staining, we found that the dendritic spines in hippocampal CA3 and DG subsets in APP/PS1 mice were markedly reduced, and the protein levels of SYN and PSD95 in the hippocampus were decreased as well.…”