Modulation of Alzheimer's Disease Pathology and Neuroplasticity by Environmental Factors

Alzheimer’s disease (AD) is an aging-linked neurodegenerative disease characterized by memory impairments and cognitive deterioration, and it is associated with a massive loss of neurons in specific brain areas, such as in the hippocampal formation and in the cortex. The pathological hallmarks of the disease include amyloid deposition and neurofibrillary tangles. The familial form of the disease (FAD) is caused by mutations in amyloid precursor protein (APP), presenilin-1 (PS1) or presenilin-2 (PS2). This work suggests that in addition to genetics, environmental factors play an important role in the development and/or progression of the disease. Modulation of environmental factors can promote hippocampal neurogenesis and synaptic plasticity, as well as ameliorates AD pathology. Specifically, we showed that experience of transgenic mice harboring FAD-linked APPswe/PS1ΔE9 in an enriched environment dramatically reduced the levels of oligomeric Aβ and the extent of amyloid deposition in the brains. We also observed a significant reduction in the level of hyperphosphorylated tau concomitantly with the upregulation of the main anterograde motor protein, kinesin-1, in several brain regions of these mice. The molecular pathways underlying the effects of EE on AD pathology and neuroplasticity are not fully understood. In this study, we aimed at investigating the molecular pathways by which environmental enrichment regulates neuroplasticity and tau phosphorylation. We showed that the levels of BDNF and BDNF-associated molecular targets were significantly elevated in the hippocampus following EE, suggesting an increased of BDNF-dependent signaling transductions following EE. In addition, we showed that EE modulated PI3K/Akt/GSK3β signaling pathway in the nontransgenic mice, suggesting that EE induces a reduction in GSK3β activity in an Akt-dependent manner. However, this signaling pathway was not affected in APPswe/PS1ΔE9 mice following EE, suggesting an alternative signaling regulation by EE in FAD mice. Taken together, this work strongly suggests that despite the severe neuropathology, EE can attenuate AD pathology and enhance neuroplasticity in the brains of FAD-linked APPswe/PS1ΔE9 mice. This study further provides several mechanistic explanations for the effects of EE on the AD brains

Molecular Mechanisms of Environmental Enrichment: Impairments in Akt/GSK3β, Neurotrophin-3 and CREB Signaling

<div><p>Experience of mice in a complex environment enhances neurogenesis and synaptic plasticity in the hippocampus of wild type and transgenic mice harboring familial Alzheimer's disease (FAD)-linked APPswe/PS1ΔE9. In FAD mice, this experience also reduces levels of tau hyperphosphorylation and oligomeric β-amyloid. Although environmental enrichment has significant effects on brain plasticity and neuropathology, the molecular mechanisms underlying these effects are unknown. Here we show that environmental enrichment upregulates the Akt pathway, leading to the downregulation of glycogen synthase kinase 3β (GSK3β), in wild type but not FAD mice. Several neurotrophic signaling pathways are activated in the hippocampus of both wild type and FAD mice, including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and this increase is accompanied by the upregulation of the BDNF receptor, tyrosine kinase B (TrkB). Interestingly, neurotrophin-3 (NT-3) is upregulated in the brains of wild type mice but not FAD mice, while insulin growth factor-1 (IGF-1) is upregulated exclusively in the brains of FAD mice. Upregulation of neurotrophins is accompanied by the increase of N-Methyl-D-aspartic acid (NMDA) receptors in the hippocampus following environmental enrichment. Most importantly, we observed a significant increase in levels of cAMP response element- binding (CREB) transcripts in the hippocampus of wild type and FAD mice following environmental enrichment. However, CREB phosphorylation, a critical step for the initiation of learning and memory-required gene transcription, takes place in the hippocampus of wild type but not of FAD mice. These results suggest that experience of wild type mice in a complex environmental upregulates critical signaling that play a major role in learning and memory in the hippocampus. However, in FAD mice, some of these pathways are impaired and cannot be rescued by environmental enrichment.</p></div