Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L-Tg mouse model of Alzheimer's disease through modulation of oxidative stress.

Oxidative stress refers to an imbalance between oxidative and antioxidative systems due to environmental factors. Although oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD), its precise role is not yet understood. We aimed to investigate the pathogenic mechanisms of the oxidative stress by using in vitro cultured neurons and in vivo AD models of PS1V97L-transgenic (Tg) mice. Our results showed that when oxidative stress became increasingly evident, the endogenous protective pathway of nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) decreased in 10-month-old PS1V97L-Tg mice. Activating the Nrf2/ARE pathway suppressed oxidative stress, decreased amyloid-ß (Aß), and improved the cognitive function of the PS1V97L-Tg mice. In contrast, blocking the Nrf2/ARE pathway augmented oxidative injury and decreased the cell viability of PS1V97L-Tg neurons. Our results highlight the role of the Nrf2/ARE pathway in regulating oxidative stress of the PS1V97L-Tg mice and may indicate a potential therapeutic avenue for AD treatment.

A systematic topographical relationship between mouse lateral posterior thalamic neurons and their visual cortical projection targets.

Higher-order visual thalamus communicates broadly and bi-directionally with primary and extrastriate cortical areas in various mammals. In primates, the pulvinar is a topographically and functionally organized thalamic nucleus that is largely dedicated to visual processing. Still, a more granular connectivity map is needed to understand the role of thalamocortical loops in visually guided behavior. Similarly, the secondary visual thalamic nucleus in mice (the lateral posterior nucleus, LP) has extensive connections with cortex. To resolve the precise connectivity of these circuits, we first mapped mouse visual cortical areas using intrinsic signal optical imaging and then injected fluorescently tagged retrograde tracers (cholera toxin subunit B) into retinotopically-matched locations in various combinations of seven different visual areas. We find that LP neurons representing matched regions in visual space but projecting to different extrastriate areas are found in different topographically organized zones, with few double-labeled cells (~4-6%). In addition, V1 and extrastriate visual areas received input from the ventrolateral part of the laterodorsal nucleus of the thalamus (LDVL). These observations indicate that the thalamus provides topographically organized circuits to each mouse visual area and raise new questions about the contributions from LP and LDVL to cortical activity.

The impact of miR-183/182/96 gene regulation on the maturation, survival, and function of photoreceptor cells in the retina.

MicroRNAs (MiRNAs) play important roles in posttranscriptional processes to regulate gene expression. MiRNAs control various biological processes, such as growth, development, and differentiation. The continuous physiological function of photoreceptors and retinal pigment epithelium requires precise regulation to maintain their homeostasis and function; hence, these cells are highly susceptible to premature death in retinal degenerative disorders. MiRNAs are essential for the retinal cell maturation and function; the miR-183 cluster represents one of the most important regulatory factors for the photoreceptor cells. Various studies together with bioinformatics analyses have shown that many genes contributing to the differentiation pathway of photoreceptors are targets of the miR-183 cluster, and the miR-183 cluster dysregulation causes certain defects in the differentiation of the photoreceptors and other retinal neurons by influencing the expression of target genes. Misexpression of miR-183 cluster in the human retinal epithelial cells leads to the reprogramming and transformation of these cells to neuron- and photoreceptor-like cells, which are associated with the expression of neuron- and photoreceptor-specific markers in human retinal pigment epitheliums cells. The knockout of this cluster causes the destruction of the outer segment of the photoreceptors, which subsequently causes the cells to exhibit severe susceptibility to light and eventually degenerate. Hundreds of target genes in this family are likely to affect the development and maintenance of the retina. Identifying the genes that are regulated by the miRNA-183 cluster provides researchers with important insights into the complex development and regeneration mechanism of the retina and may offer a new way for maintaining and regenerating photoreceptor cells in neurodegenerative diseases.