Stress and Alzheimer's disease: A senescence link?

Alzheimer's disease (AD) is a neurodegenerative disease in which autophagy plays a crucial role. Amentoflavone is a flavonoid obtained from various plants and has been shown to have AD-resistant neuroprotective effects. This study investigated the role of amentoflavone on memory impairment and abnormal autophagy in amyloid-β25-35 (Aβ25-35)-induced mice to elucidate the mechanisms by which it exerts neuroprotective effects. In this experiment, the AD mouse model was established by intracerebroventricular (ICV) injection of Aβ25-35 peptides, and amentoflavone was administered orally for 4 weeks. Behavioral changes in mice and pathological changes in the hippocampus were observed, and levels of inflammation, oxidative stress, and autophagy in the brain were detected and analyzed. PC-12 and APPswe-N2a cells were used in vitro to further investigate the effect of amentoflavone on the level of intracellular autophagy. Molecular docking was used to determine the action sites of amentoflavone. The results showed that amentoflavone improved memory function, eased anxiety symptoms in Aβ25-35-induced mice, and reduced atrophic degeneration of neurons in the hippocampus. Moreover, amentoflavone lessened the oxidative stress and inflammation in the brains of mice. Through in vivo and in vitro experiments, we found that amentoflavone may enhance autophagy, by way of binding to the ATP site of the mTOR protein kinase domain. Amentoflavone not only interacted with mTOR, but also improved Aβ25-35-induced cognitive dysfunction in mice by enhancing autophagy, attenuating levels of inflammation and oxidative stress, and reducing apoptosis in brain cells.

Amentoflavone Ameliorates Memory Deficits and Abnormal Autophagy in Aβ25-35-Induced Mice by mTOR Signaling.

The role of microRNA-34 family in Alzheimer’s disease: A potential molecular link between neurodegeneration and metabolic disorders

The advent of nanotechnologies such as nanocarriers and nanotherapeutics has changed the treatment strategy and developed a more efficacious novel drug delivery system. Various drug delivery systems are focused on drug-targeting of brain cells. However, the manifestation of the brain barrier is the main hurdle for the effective delivery of chemotherapeutics, ultimately causing treatment failure of various drugs. To solve this problem, various nanocarrier-based drug delivery system has been developed for brain targeting. This review outlines nanocarrier-based composites for different brain diseases and highlights nanocarriers for drug targeting towards brain cells. It also summarizes the latest developments in nanocarrier-based delivery systems containing liposomal systems, dendrimers, polymeric micelles, polymeric nanocarriers, quantum dots (QDs), and gold nanoparticles. Besides, the optimal properties of nanocarriers and therapeutic implications for brain targeting have been extensively studied. Finally, the potential applications and research opportunities for nanocarriers in brain targeting are discussed.

/pdf/potential-of-nanocarrier-based-drug-delivery-systems-for-3qbquj9pvg.pdf

Potential of Nanocarrier-Based Drug Delivery Systems for Brain Targeting: A Current Review of Literature

Aging is a major risk factor for a number of chronic diseases, including neurodegenerative and cerebrovascular disorders. Aging processes have therefore been discussed as potential targets for the development of novel and broadly effective preventatives or therapeutics for age-related diseases, including those affecting the brain. Mechanisms thought to contribute to aging have been summarized under the term the "hallmarks of aging" and include a loss of proteostasis, mitochondrial dysfunction, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, stem cell exhaustion, epigenetic alterations and altered intercellular communication. We here examine key claims about the "hallmarks of aging". Our analysis reveals important weaknesses that preclude strong and definitive conclusions concerning a possible role of these processes in shaping organismal aging rate. Significant ambiguity arises from the overreliance on lifespan as a proxy marker for aging, the use of models with unclear relevance for organismal aging, and the use of study designs that do not allow to properly estimate intervention effects on aging rate. We also discuss future research directions that should be taken to clarify if and to what extent putative aging regulators do in fact interact with aging. These include multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate. 

/pdf/targeting-the-hallmarks-of-aging-to-slow-aging-and-treat-age-2lo76wfi.pdf

Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?

Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

/pdf/integrated-analysis-of-the-aging-brain-transcriptome-and-322tay2x1z.pdf

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Background 
Tau neurofibrillary tangle pathology characterizes Alzheimer disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. 

Methods 
Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutation causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy.

Results 
TauWT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes.

Conclusions
Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

https://www.biorxiv.org/content/biorxiv/early/2020/02/20/2020.02.19.954578.full.pdf

Timothy Wu

Papers

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Integrated analysis of the aging brain transcriptome and proteome in tauopathy