An enriched environment delays the progression from mild cognitive impairment to Alzheimer's disease in senescence‑accelerated mouse prone 8 mice

Abstract

A previous study demonstrated that middle-aged (5-6 months of age) senescence-accelerated mouse prone 8 (SAMP8) mice can be used as animal models of mild cognitive impairment (MCI). An enriched environment (EE) can mitigate cognitive decline and decrease the pathological changes associated with various neurodegenerative diseases. In the present study, the learning-memory abilities of SAMP8 mice during the MCI phase (5 months of age) was evaluated and neuropathological changes in the hippocampus were examined after the mice were exposed to an EE for 60 days. In the Morris water maze test, EE-exposed mice demonstrated significantly decreased escape latency and increased time spent in the target quadrant and number of platform crossings compared with control mice. Terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining showed that EE-exposed mice had reduced neuronal apoptosis and increased number of surviving neurons compared with control mice. Golgi staining, transmission electron microscopy, and immunohistochemical staining demonstrated that EE-exposed mice exhibited increased dendritic spine densities among secondary and tertiary apical dendrites; increases in synaptic numerical density, synaptic surface density, and expression of synaptophysin; and reduced deposition of amyloid-β (Aβ) and expression of amyloid-precursor protein (APP) in the hippocampal CA1 region compared with control mice. These results demonstrate that EE exposure effectively decreases neuronal loss and regulates neuronal synaptic plasticity by reducing the expression of APP and the deposition of Aβ in the hippocampal CA1 region, thereby mitigating cognitive decline in SAMP8 mice during the MCI phase and delaying the progression from MCI to Alzheimer's disease.

Restoring Age-Related Cognitive Decline through Environmental Enrichment: A Transcriptomic Approach

“…Its deficiency, as demonstrated here in old animals, is associated with neurodegenerative processes in PD [ 76 ] and autism [ 77 ]. Therefore, EE-induced reversed expression of Cttnbp2 and Esr2 is consistent with cognitive improvements and hippocampal spine-pool recovery as recently shown in senescent SAMP8 mice [ 78 ]. The GTPase Rras2 is essential for oligodendrocyte differentiation and survival and instrumental in the formation of myelin sheaths; experimental down-regulation leads to axonal degeneration in mice [ 79 , 80 ].…”

“…There is accumulating evidence that increased susceptibility to apoptosis contributes to aging of the brain [ 97 ] by reducing the number of stressed but functional cells [ 98 ]. Reduced apoptosis in association with EE was found in young [ 99 ], aged [ 100 ] and senescent SAMP8 mice [ 78 ]. In this context, Il4ra, a known mediator of IL-4-induced apoptosis in monocytes [ 101 ], mast cells [ 102 ], hepatocytes [ 103 ] and endothelial cells [ 104 ], was found to be up-regulated in our study in the hippocampus of aged mice.…”

Life Experience Matters: Enrichment and Stress Can Influence the Likelihood of Developing Alzheimer’s Disease via Gut Microbiome

“…EE typically involves providing subjects with a variety of items that can be interacted with, including toys, chews, hides, treats, and running wheels. In AD models, EE has been shown to improve recognition and spatial memory, reduce tau and Aβ pathology, improve neurogenesis, reverse effects of stress and high-fat or high-sucrose diets, reduce inflammation, increase synaptic plasticity, improve immune system activity, and reduce neuronal death seen in AD [58][59][60][61][62][63]66,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87]. These vast beneficial effects of EE are seen in both mouse and rat models, with enrichment protocols occurring over timelines beginning between 3 weeks of age to 18 months, and lasting between 1 month and 23 months.…”

The Molecular Effects of Environmental Enrichment on Alzheimer’s Disease

“…Recently, an increasing amount of evidence has hinted that EE can improve memory and delay age-related cognitive dysfunctions [ 205 , 206 ]. Early exposure of EE to AD transgenic rodents was previously found to delay the onset of memory deficits as well as improve neuropathological hallmarks [ 207 , 208 , 209 ]. Moreover, late-life EE was also found to be an effective strategy in improving learning and preserving memory in aged AD transgenic rodents [ 97 , 210 ].…”