Background: Reactive microglia are associated with β-amyloid (Aβ) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear Aβ deposits although they mainly exist in an "activated" state. Oligomeric Aβ (oAβ), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar Aβ (fAβ). However, the role of the different Aβ forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear. Results: We demonstrated that Aβ(1-42) fibrils, not Aβ(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oAβ(1-42) not only attenuated fAβ(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fAβ(1-42). Compared with the fAβ(1-42) treatment, the oAβ(1-42) treatment resulted in a rapid and transient increase in interleukin 1β (IL-1β) level and produced higher levels of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E₂ (PGE₂) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fAβ(1-42)-induced microglia was decreased by IL-1β, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-κB (NF-κB) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oAβ-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oAβ(1-42) stimulation reduced the mRNA expression of CD36, integrin β1 (Itgb1), and Ig receptor FcγRIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oAβ(1-42) or the inflammatory and oxidative milieu (IL-1β, LPS or t-BHP) significantly downregulated the fAβ(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells. Conclusion: These results imply that Aβ oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of Aβ fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

The diagnosis of PD might be in difficulty, especially in the early stages. Therefore, the identification of novel biomarkers is imperative for the diagnosis and monitoring disease progression in PD. DJ-1 and α-synuclein, are two proteins that are critically involved in the pathogenesis of PD, and they have been examined as disease biomarkers in studies. However, no study exists regarding DJ-1 in plasma neural-derived exosomes. In the present study, the levels of DJ-1 and α-synuclein in plasma neural-derived exosomes were studied together in order to investigate novel biomarkers for PD. DJ-1 and α-synuclein in plasma and plasma neural-derived exosomes of the patients with PD and controls were quantified by ELISAs. The data revealed that the levels of DJ-1 and α-synuclein in plasma neural-derived exosomes and the ratio of plasma neural-derived exosomal DJ-1 to total DJ-1 were significantly higher in patients with PD, compared with controls, while levels of the two proteins in plasma exhibited no difference between the patients with PD and controls. However, no relationship was identified between biomarkers and disease progression. In addition, significant positive correlations between DJ-1 and α-synuclein in plasma neural-derived exosomes were found in the patients with PD and in healthy individuals. We hypothesize that DJ-1 in plasma neural-derived exosomes may be used as a potential biomarker as α-synuclein in PD and they might participate in the mechanism of PD together.

Parkinson’s disease is a high incidence neurodegenerative disease in elderly people, and oxidative stress plays an important role in the pathogenesis. Oxygen metabolism in the brain is high, which lacks an antioxidative protection mechanism. Recently, it has been found that polyphenols play an important role in antioxidation. (−)-epigallocatechin-3-gallate (EGCG) is an important component of tea polyphenols and its biological effects, such as strong antioxidation, scavenging of free radicals and anti-apoptosis, can pass through the blood brain barrier. The SIRT1/PGC-1α signaling pathway has not been reported in PC12 cells. Therefore, research of the protective mechanism of EGCG in PC12 cells damaged by -methyl-4-phenyl-pyridine (MMP+) may provide a new insight into protect against and treatment of Parkinson’s disease.

Background: Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer’s disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. Methods: We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice. Results: We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner. Conclusion: ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Graphical Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.

Background: Although the etiology of PD remains unclear, increasing evidence has shown that oxidative stress plays an important role in its pathogenesis and that of other neurodegenerative disorders. NOX2, a cytochrome subunit of NOX, transports electrons across the plasma membrane to generate ROS, leading to physiological and pathological processes. Heme oxygenase-1 (HO-1) can be rapidly induced by oxidative stress and other noxious stimuli in the brain or other tissues. Astaxanthin (ATX), a carotenoid with antioxidant properties, is 100–1000 times more effective than vitamin E. The present study investigated the neuroprotective effects of ATX on MPP⁺-induced oxidative stress in PC12 cells. Results: MPP⁺ significantly decreased MTT levels in a concentration-dependent manner. Hemin, SnPPIX and ATX didn’t exhibit any cytotoxic effects on PC12 cells. Pretreatment with ATX (5, 10, 20 μM), caused intracellular ROS production in the MPP⁺ group to decrease by 13.06%, 22.13%, and 27.86%, respectively. MPP⁺ increased NOX2, NRF2 and HO-1 protein expression compared with control (p < 0.05). Co-treatment with hemin or ATX suppressed NOX2 expression (p < 0.01), and greatly increased NRF2 and HO-1 expression (p < 0.01). MPP⁺ treatment up-regulated both NOX2 (p < 0.01) and HO-1 (p < 0.01) mRNA levels. Co-treatment with hemin or ATX significantly increased HO-1 mRNA levels (p < 0.01), and decreased NOX2 mRNA levels (p < 0.01). MPP⁺ increased NOX2 and HO-1 expression with considerable fluorescence extending out from the perinuclear region toward the periphery; this was attenuated by DPI. Co-treatment with hemin or ATX significantly up-regulated HO-1 expression and decreased NOX2 expression with considerable fluorescence intensity (stronger than the control and MPP⁺ groups). Conclusions: ATX suppresses MPP⁺-induced oxidative stress in PC12 cells via the HO-1/NOX2 axis. ATX should be strongly considered as a potential neuroprotectant and adjuvant therapy for patients with Parkinson’s disease.

Background: Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored the association between pro-inflammatory diets and dementia using the dietary inflammatory index (DII). Additionally, the relationship between DII and different subtypes of dementia, such as Alzheimer's dementia and vascular dementia, remains largely unexplored. Given the changes in brain structure already observed in patients with dementia, we also investigated the association between DII and magnetic resonance imaging (MRI) measures of brain structure to provide some hints to elucidate the potential mechanisms between pro-inflammatory diet and cognitive decline. Methods: A total of 166,377 UK Biobank participants without dementia at baseline were analyzed. DII calculations were based on the information collected by the 24-h recall questionnaire. Brain structural anatomy and tissue-specific volumes were measured using brain MRI. Cox proportional hazards models, competing risk models, and restricted cubic spline were applied to assess the longitudinal associations. The generalized linear model was used to assess the association between DII and MRI measurements. Results: During a median follow-up time of 9.46 years, a total of 1372 participants developed dementia. The incidence of all-cause dementia increased by 4.6% for each additional unit of DII [hazard ratio (HR): 1.046]. Besides, DII displayed a “J-shaped” non-linear association with Alzheimer’s dementia (P_nonlinear = 0.003). When DII was above 1.30, an increase in DII was significantly associated with an increased risk of Alzheimer’s dementia (HR: 1.391, 95%CI: 1.085–1.784, P = 0.009). For brain MRI, the total volume of white matter hyperintensities increased with an increase in DII, whereas the volume of gray matter in the hippocampus decreased. Conclusions: In this cohort study, higher DII was associated with a higher risk of all-cause dementia and Alzheimer’s dementia. However, our findings suggested that the association with DII and vascular and frontotemporal dementia was not significant.