Biomolecular Markers of Brain Aging.

Characterized by the gradual loss of physiological integrity, impaired function, and increased susceptibility to death, aging is considered the primary risk factor for major human diseases, such as cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. The time-dependent accumulation of cellular damage is widely considered the general cause of aging. While the mechanism of normal aging is still unresolved, researchers have identified different markers of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Theories of aging can be divided into two categories: (1) aging is a genetically programmed process, and (2) aging is a random process caused by gradual damage to the organism over time as a result of its vital activities. Aging affects the entire human body, and aging of the brain is undoubtedly different from all other organs, as neurons are highly differentiated postmitotic cells, and the lifespan of most neurons in the postnatal period is equal to the lifespan of the brain. In this chapter, we discuss the conserved mechanisms of aging that may underlie the changes observed in the aging brain, with a focus on mitochondrial function and oxidative stress, autophagy and protein turnover, insulin/IGF signaling, target of rapamycin (TOR) signaling, and sirtuin function.

Neurobiological Mechanisms of Cognitive Decline Correlated with Brain Aging.

Cognitive decline has emerged as one of the greatest health threats of old age. Meanwhile, aging is the primary risk factor for Alzheimer's disease (AD) and other prevalent neurodegenerative disorders. Developing therapeutic interventions for such conditions demands a greater understanding of the processes underlying normal and pathological brain aging. Despite playing an important role in the pathogenesis and incidence of disease, brain aging has not been well understood at a molecular level. Recent advances in the biology of aging in model organisms, together with molecular- and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline. This chapter seeks to integrate the knowledge about the neurological mechanisms of age-related cognitive changes that underlie aging.

Scutellarin Modulates the Microbiota-Gut-Brain Axis and Improves Cognitive Impairment in APP/PS1 Mice.

BACKGROUND: Scutellarin, a flavonoid purified from the Chinese herb Erigeron breviscapus, has been reported to prevent Alzheimer's disease (AD) by affecting Aß assembly. Given the low brain uptake rate of scutellarin, we hypothesize that the microbiota-gut-brain axis may be a potential route by which scutellarin prevents AD. OBJECTIVE: This study aimed to explore the microbiota-gut-brain mechanism by which scutellarin prevented AD. METHODS: Scutellarin was administrated to APP/PS1 mouse model of AD for two months, and the behaviors, pathological changes as well as gut microbial changes in APP/PS1 mice were evaluated after scutellarin treatment. RESULTS: This study found that scutellarin improved Aß pathology, neuroinflammation, and cognitive deficits in APP/PS1 mice. It elucidated the effects of scutellarin on the diversity and activity of gut microbiota in APP/PS1 mice and these findings promoted us to focus on inflammation-related bacteria and short-chain fatty acids (SCFAs). Cognitive behaviors were significantly associated with inflammatory cytokines and inflammation-related bacteria, suggesting that microbiota-gut-brain axis was involved in this model and that inflammatory pathway played a crucial role in this axis. Moreover, we observed that cAMP-PKA-CREB-HDAC3 pathway downstream of SCFAs was activated in microglia of AD and inactivated by scutellarin. Furthermore, by chromatin immunoprecipitation (ChIP) assays, we found that the increased association between acetylated histone 3 and interleukin-1ß (IL-1ß) promoter in AD mice was reversed by scutellarin, leading to a decreased level of IL-1ß in scutellarin-treated AD mice. CONCLUSION: Scutellarin reverses neuroinflammation and cognitive impairment in APP/PS1 mice via beneficial regulation of gut microbiota and cAMP-PKA-CREB-HDAC3 signaling in microglia.

Dengzhanxixin Injection Ameliorates Cognitive Impairment Through a Neuroprotective Mechanism Based on Mitochondrial Preservation in Patients With Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is a global health burden and cognitive impairment is one of its most serious complication. Adequate interventions for AIS may have the potential to improve cognitive outcomes. In the present study, we selected Erigeron breviscapus (Vaniot) Hand.-Mazz. injection (Dengzhanxixin injection, DZXI), a widely used Chinese herbal injection, in contrast to edaravone as the positive control drug to test its potential to ameliorates neurological and cognitive impairments caused by AIS. We performed a 2-week randomized trial with these two drugs in AIS patients presenting mild to moderate cognitive impairments. Neuropsychological tests and MRI examinations showed that DZXI attenuated the neurological and cognitive impairments of patients and protected the grey matter in specific regions from ischemic damage. Notably, DZXI exerted better effects than edaravone in some neuropsychological tests, probably due to the protective effect of DZXI on grey matter. To explore the therapeutic mechanisms, we carried out an experiment with a middle cerebral artery occlusion rat model. We found that DZXI decreased the infarct volume and increased the survival of neuronal cells in the ischemic penumbra; furthermore, DZXI modulated the mitochondrial respiratory chain process and preserved the mitochondrial structure in the brain tissue. Overall, our data suggested that the administration of DZXI is effective at ameliorating neurological and cognitive impairments in AIS, and the underlying mechanisms are related to the protective effects of DZXI on cerebral neurons and neuronal mitochondria.

Shenqi Yizhi granules protect hippocampus of AD transgenic mice by modulating on multiple pathological processes.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese herbal medicine (CHM) draws more attention to explore effective therapeutic strategy for Alzheimer's disease (AD). CHM usually uses combinations of herbs or herbal ingredients to treat diseases, with the components targeting different disease processes. CHM might improve cognition in AD and MCI patients by optimizing network activity, promoting neural plasticity and repairing damaged neurons. Shenqi Yizhi granules (SQYG), a CHM prescription, are mainly consists of Panax ginseng C.A.Mey, Astragalus membranaceus (Fisch.) Bunge, and Scutellaria baicalensis Georgi and have been used to ameliorate cognitive impairment in mild-to-moderate dementia patients. AIM OF THE STUDY: To investigate the neuroprotection effect and pharmacological mechanism of SQYG in the hippocampus of 5XFAD transgenic mice. MATERIALS AND METHODS: The immunofluorescence detection, 2DE-gels, mass spectrum identification, biological information analysis and Western blot were performed after SQYG treatment. RESULTS: SQYG treatment significantly decreased the fluorescence intensities of anti-GFAP and anti-Iba1 in the hippocampus of 5XFAD mice. The expression levels of 31 proteins in the hippocampus were significantly influenced by SQYG, approximately 65% of these proteins are related to energy metabolism, stress response and cytoskeleton, whereas others are related to synaptic transmission, signal transduction, antioxidation, amino acid metabolism, and DNA repair. The expression of these proteins were increased. The changes in the expression levels of malate dehydrogenase (cytoplasmic) and pyruvate kinase M were confirmed by Western blot. CONCLUSIONS: The pharmacological mechanism of SQYG on the hippocampus may be related to modulation of multiple pathological processes, including energy metabolism, stress response, cytoskeleton, synaptic transmission, signal transduction, and amino acid metabolism in 5XFAD mice.

Dengzhan Shengmai capsules and their active component scutellarin prevent cognitive decline in APP/PS1 mice by accelerating Aß aggregation and reducing oligomers formation.

There is currently no effective treatment to prevent the progress of Alzheimer's disease (AD). The traditional Chinese herbs Dengzhan Shengmai (DZSM) capsules and their active component scutellarin possess multiple effects and are clinically used for the treatment of cerebrovascular diseases. Scutellarin has been reported to affect Aß aggregation. However, the effects of DZSM capsules on AD remain unknown. Through in vivo experiments, our study proved that the alleviating effects of DZSM capsules on cognitive deficits of AD mice were due to the role of scutellarin, which up-regulated low toxic amyloid plaques and down-regulated highly toxic soluble Aß42 and Aß40 levels in cortex. In vitro, we confirmed scutellarin's role in accelerating transforming Aß42 monomers into high-molecular-mass aggregates by biochemical assays, which supported the results observed in drug-treated APP/PS1 mice. In detail, the 1:10 ratio of scutellarin/Aß42 mixtures promoted production of large ß-sheet-rich fibrils whereas the 1:1 ratio promoted production of protofibrils. In addition, the binding between scutellarin and Aß monomers was quantified by microscale thermophoresis test and the apparent dissociation constant (Kd) was 1284.4 ±â€¯238.8 µM. What's more, binding regions between scutellarin and Aß fibrils were predicted by computational docking models and scutellarin might bind parallel to the long axis of Aß42 fibrils targeting hydrophobic grooves at residues 35-36 or 39. In conclusion, DZSM capsules protected against cognitive defects of AD through scutellarin-mediated acceleration of Aß aggregation into fibrils or protofibrils and reduction of soluble Aß oligomers, thus suggesting potential clinical applications of DZSM capsules and scutellarin in the treatment of AD.

SQYZ granules, a traditional Chinese herbal, attenuate cognitive deficits in AD transgenic mice by modulating on multiple pathogenesis processes.

The pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid ß (Aß) peptide aggregation, inflammation, oxidative stress, and others. Effective therapeutic drugs for treating AD are urgently needed. SQYZ granules (SQYZ), a Chinese herbal preparation, are mainly composed of the ginsenoside Rg1, astragaloside A and baicalin, and have been widely used to treat dementias for decades in China. In this study, we found the therapeutic effects of SQYZ on the cognitive impairments in an AD mouse model, the ß-amyloid precursor protein (APP) and presenilin-1 (PS1) double-transgenic mouse, which co-expresses five familial AD mutations (5XFAD); next, we further explored the underlying mechanism and observed that after SQYZ treatment, the Aß burden and inflammatory reactions in the brain were significantly attenuated. Through a proteomic approach, we found that SQYZ regulated the expression of 27 proteins, mainly those related to neuroinflammation, stress responses and energy metabolism. These results suggested that SQYZ has the ability to improve the cognitive impairment and ameliorate the neural pathological changes in AD, and the therapeutic mechanism may be related to the modulation of multiple processes related to AD pathogenesis, especially anti-neuroinflammation, promotion of stress recovery and improvement of energy metabolism.

Gamma rhythm low field magnetic stimulation alleviates neuropathologic changes and rescues memory and cognitive impairments in a mouse model of Alzheimer's disease.

INTRODUCTION: The abnormal amyloid ß (Aß) accumulation and Aß-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress-related cognitive impairments. METHODS: Amyloid precursor protein/presenilin-1 transgenic mice (5XFAD) were treated with DMS, and cognitive behavior and AD-like pathologic changes in the neurochemical and electrophysiological properties in 5XFAD mice were assessed. RESULTS: We demonstrate that DMS treatment enhances cognitive performances, attenuates Aß load, upregulates postsynaptic density protein 95 level, and promotes hippocampal long-term potentiation in 5XFAD mouse brain. Intriguingly, the gamma burst magnetic stimulation reverses the aberrant gamma oscillations in the transgenic hippocampal network. DISCUSSION: This work establishes a solid foundation for the effectiveness of DMS in treating AD and proposes a future study of gamma rhythm stimulation on reorganizing rhythmic neural activity in AD brain.

Deep Brain Magnetic Stimulation Promotes Neurogenesis and Restores Cholinergic Activity in a Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive decline of memory and cognitive functions. Deep magnetic stimulation (DMS), a noninvasive and nonpharmacological brain stimulation, has been reported to alleviate stress-related cognitive impairment in neuropsychiatric disorders. Our previous study also discovered the preventive effect of DMS on cognitive decline in an AD mouse model. However, the underlying mechanism must be explored further. In this study, we investigated the effect of DMS on spatial learning and memory functions, neurogenesis in the dentate gyrus (DG), as well as expression and activity of the cholinergic system in a transgenic mouse model of AD (5XFAD). Administration of DMS effectively improved performance in spatial learning and memory of 5XFAD mice. Furthermore, neurogenesis in the hippocampal DG of DMS-treated 5XFAD mice was clearly enhanced. In addition, DMS significantly raised the level of acetylcholine and prevented the increase in acetylcholinesterase activity as well as the decrease in acetyltransferase activity in the hippocampus of 5XFAD mice. These findings indicate that DMS may be a promising noninvasive tool for treatment and prevention of AD cognitive impairment by promoting neurogenesis and enhancing cholinergic system function.

The E3 Ubiquitin Ligase c-Cbl Inhibits Microglia-Mediated CNS Inflammation by Regulating PI3K/Akt/NF-κB Pathway.

BACKGROUND: Microglia-mediated inflammation may play an important role in the pathophysiology progression of neurodegenerative diseases, such as Parkinson's disease (PD), but the molecular mechanisms are poorly understood. AIMS: This study sought to determine whether E3 ubiquitin ligase c-Cbl plays a role in the brain inflammation and to explore the relevant molecular mechanism. METHODS: After BV2 microglial cells and c-Cbl-deficient mice were treated with lipopolysaccharide (LPS), neuroinflammation and microglial activation were evaluated by immunohistochemistry, ELISA and Western blot. We further investigated the possible mechanism of c-Cbl in regulating microglial activation. RESULTS: Here, we showed that the E3 ubiquitin ligase c-Cbl had high expression in brain tissues including substantia nigra pars compacta (SNc), striatum and hippocampus, and it was abundantly expressed in microglia. Systemic LPS administration resulted in more severe microglial activation in CNS and increased expression of brain proinflammatory factors (TNF-α, IL-6, IL-1ß and MCP-1) in c-Cbl knockout mice than wild type mice (WT). Downregulation of c-Cbl expression with c-Cbl siRNA in BV-2 microglial cells demonstrated a more robust increase in the proinflammatory factors release and NF-κB p65 nuclear translocation than that in control siRNA. Interestingly, Akt phosphorylation induced by LPS was also significantly augmented after c-Cbl knockdown. Moreover, blockade of PI3K/Akt activation by LY294002 significantly reduced inflammation response and NF-κB p65 nuclear translocation. CONCLUSION: In sum, c-Cbl inhibits expression of LPS-stimulated proinflammatory cytokines and chemokines in microglia. We demonstrate an unprecedented role for c-Cbl in microglia-mediated neuroinflammation involving PI3K/Akt/NF-κB pathway.

Triptolide treatment reduces Alzheimer's disease (AD)-like pathology through inhibition of BACE1 in a transgenic mouse model of AD.

The complex pathogenesis of Alzheimer's disease (AD) involves multiple contributing factors, including amyloid ß (Aß) peptide accumulation, inflammation and oxidative stress. Effective therapeutic strategies for AD are still urgently needed. Triptolide is the major active compound extracted from Tripterygium wilfordii Hook.f., a traditional Chinese medicinal herb that is commonly used to treat inflammatory diseases. The 5-month-old 5XFAD mice, which carry five familial AD mutations in the ß-amyloid precursor protein (APP) and presenilin-1 (PS1) genes, were treated with triptolide for 8 weeks. We observed enhanced spatial learning performances, and attenuated Aß production and deposition in the brain. Triptolide also inhibited the processing of amyloidogenic APP, as well as the expression of ßAPP-cleaving enzyme-1 (BACE1) both in vivo and in vitro. In addition, triptolide exerted anti-inflammatory and anti-oxidative effects on the transgenic mouse brain. Triptolide therefore confers protection against the effects of AD in our mouse model and is emerging as a promising therapeutic candidate drug for AD.

Therapeutic effects of fucoidan in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: Role of NADPH oxidase-1.

AIMS: To explore the effect of fucoidan treatment on oxidative stress-mediated dopaminergic neuronal damage and its potential mechanisms. METHODS: The effect of fucoidan was investigated in a 6-hydroxydopamine (6-OHDA) rat model of PD, an animal model considered appropriate for preclinical studies of PD therapy. The effects of fucoidan treatment on animal behavior and the survival ratio of dopaminergic neurons were investigated. We further observed the effect of fucoidan on microglia and the NADPH oxidases-1 (Nox1), a family of enzymes generating reactive oxygen species (ROS). RESULTS: We found that chronic fucoidan administration mitigated the motor dysfunction induced by 6-OHDA. Similarly, fucoidan reduced the loss of DA neurons in the SNc and DA fibers in the striatum in 6-OHDA-lesioned rats. Moreover, we found that fucoidan inhibited the 6-OHDA-stimulating expression of Nox1 in both tyrosine hydroxylase (TH)-positive neurons and non-TH-positive neurons, prevented Nox1-sensitive oxidative stress and cell damage in SNc neurons. Fucoidan also effectively inhibited nigral microglial activation. CONCLUSION: These results support the beneficial effect of fucoidan in 6-OHDA-lesioned rat model of PD. Fucoidan may suppress the Nox1-triggered oxidative stress in the SNc to protect DA neurons from 6-OHDA-induced toxicity and achieve its beneficial effect.