The Association between Cardiovascular Risk Factors and Carotid Intima-Media Thickness in 42,726 Adults in UK Biobank: A Cross-Sectional Study.

BACKGROUND: Traditional modifiable cardiovascular risk factors, such as high blood pressure, have long been positively correlated with high carotid intima-media thickness (cIMT). However, traditional cardiovascular risk factors made a minor contribution to cIMT variance, meaning that other markers may be regarded as independent markers for increasing cIMT. AIMS: To investigate the simple demographic patterns of carotid intima-media thickness (cIMT) in the UK Biobank and to identify which upstream cardiovascular disease (CVD) risk factors are independently associated with cIMT. METHODS AND RESULTS: A cross-sectional-based study of healthy middle-aged people recruited in the UK between 2006 and 2010 (n = 42,726). RESULTS: This study showed that the cardiovascular risk profile generally worsened across the cIMT quantiles from lowest to highest. The lowest cIMT quartile was defined as having a mean cIMT < 588 µm, while the highest cIMT quartile was defined as having a mean cIMT > 748 µm. Specifically, the highest cIMT quantile group had a worse CVD risk factors profile compared to the lowest cIMT quantile group. It was found that, for every one SD increase in age and systolic blood pressure, the mean cIMT increased by 0.357 SD and 0.115 SD, respectively. CONCLUSION: Systolic blood pressure and age were the strongest independent risk factors for a high cIMT value compared to other risk factors.

Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.

Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aß1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aß25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD.

Fractalkine signaling and Tau hyper-phosphorylation are associated with autophagic alterations in lentiviral Tau and Aß1-42 gene transfer models.

Tau hyper-phosphorylation (p-Tau) and neuro-inflammation are hallmarks of neurodegeneration. Previous findings suggest that microglial activation via CX3CL1 promotes p-Tau. We examined inflammation and autophagic p-Tau clearance in lentiviral Tau and mutant P301L expressing rats and used lentiviral Aß1-42 to induce p-Tau. Lentiviral Tau or P301L expression significantly increased caspase-3 activity and TNF-α, but CX3CL1 was significantly higher in animals expressing Tau compared to P301L. Lentiviral Aß1-42 induced p-Tau 4 weeks post-injection, and increased caspase-3 activation (8-fold) and TNF-α levels. Increased levels of ADAM-10/17 were also detected with p-Tau. IL-6 levels were increased but CX3CL1 did not change in the absence of p-Tau (2 weeks); however, p-Tau reversed these effects, which were associated with increased microglial activity. We observed changes in autophagic markers, including accumulation of autophagic vacuoles (AVs) and p-Tau accumulation in autophagosomes but not lysosomes, suggesting alteration of autophagy. Taken together, microglial activation may promote p-Tau independent of total Tau levels via CX3CL1 signaling, which seems to depend on interaction with inflammatory markers, mainly IL-6. The simultaneous change in autophagy and CX3CL1 signaling suggests communication between microglia and neurons, raising the possibility that accumulation of intraneuronal amyloid, due to lack of autophagic clearance, may lead microglia activation to promote p-Tau as a tag for phagocytic degradation.

Parkin ubiquitinates Tar-DNA binding protein-43 (TDP-43) and promotes its cytosolic accumulation via interaction with histone deacetylase 6 (HDAC6).

The importance of E3 ubiquitin ligases, involved in the degradation of misfolded proteins or promotion of protein-protein interaction, is increasingly recognized in neurodegeneration. TDP-43 is a predominantly nuclear protein, which regulates the transcription of thousands of genes and binds to mRNA of the E3 ubiquitin ligase Parkin to regulate its expression. Wild type and mutated TDP-43 are detected in ubiquitinated forms within the cytosol in several neurodegenerative diseases. We elucidated the mechanisms of TDP-43 interaction with Parkin using transgenic A315T mutant TDP-43 (TDP43-Tg) mice, lentiviral wild type TDP-43, and Parkin gene transfer rat models. TDP-43 expression increased Parkin mRNA and protein levels. Lentiviral TDP-43 increased the levels of nuclear and cytosolic protein, whereas Parkin co-expression mediated Lys-48 and Lys-63-linked ubiquitin to TDP-43 and led to cytosolic co-localization of Parkin with ubiquitinated TDP-43. Parkin and TDP-43 formed a multiprotein complex with HDAC6, perhaps to mediate TDP-43 translocation. In conclusion, Parkin ubiquitinates TDP-43 and facilitates its cytosolic accumulation through a multiprotein complex with HDAC6.

Diminished parkin solubility and co-localization with intraneuronal amyloid-ß are associated with autophagic defects in Alzheimer's disease.

Alzheimer's disease (AD) is an aging disorder characterized by amyloid-ß (Aß) accumulation in extracellular plaques and formation of intracellular tangles containing hyperphosphorylated tau (p-Tau). Autophagic defects, leading to accumulation of autophagosomes, are recognized in AD. Parkin is an E3 ubiquitin ligase involved in degradation of proteins via autophagy and the proteasome. We investigated the role of parkin in postmortem brain tissues from 21 AD patients and 15 control subjects. We detected decreased parkin solubility in AD cortex and parkin co-localization with intraneuronal Aß(1-42) in the hippocampus and cortex of AD patients. Parkin accumulation with intraneuronal Aß and p-Tau was detected in autophagosomes in AD brains. To determine the role of parkin in Aß clearance, we generated gene transfer animals expressing lentiviral Aß(1-42)with and without parkin and examined autophagic mechanisms. Lentiviral expression of Aß(1-42) led to p-Tau accumulation and induced autophagic defects, leading to accumulation of autophagic vacuoles. However, co-expression of wild type parkin facilitated autophagic clearance and promoted deposition of Aß(1-42) and p-Tau into the lysosome. Taken together, these data suggest that Aß(1-42) alters normal autophagy and parkin enhances autophagic clearance. In conclusion, decreased parkin solubility may lead to co-localization with intraneuronal Aß(1-42) and compromise the cell autophagic clearance ability. Parkin may clear autophagic defects via autophagosome degradation.

Fractalkine Mediates Communication between Pathogenic Proteins and Microglia: Implications of Anti-Inflammatory Treatments in Different Stages of Neurodegenerative Diseases.

The role of inflammation in neurodegenerative diseases has been widely demonstrated. Intraneuronal protein accumulation may regulate microglial activity via the fractalkine (CX3CL1) signaling pathway that provides a mechanism through which neurons communicate with microglia. CX3CL1 levels fluctuate in different stages of neurodegenerative diseases and in various animal models, warranting further investigation of the mechanisms underlying microglial response to pathogenic proteins, including Tau, ß-amyloid (Aß), and α-synuclein. The temporal relationship between microglial activity and localization of pathogenic proteins (intra- versus extracellular) likely determines whether neuroinflammation mitigates or exacerbates disease progression. Evidence in transgenic models suggests a beneficial effect of microglial activity on clearance of proteins like Aß and a detrimental effect on Tau modification, but the role of CX3CL1 signaling in α-synucleinopathies is less clear. Here we review the nature of fractalkine-mediated neuronmicroglia interaction, which has significant implications for the efficacy of anti-inflammatory treatments during different stages of neurodegenerative pathology. Specifically, it is likely that anti-inflammatory treatment in early stages of disease during intraneuronal accumulation of proteins could be beneficial, while anti-inflammatory treatment in later stages when proteins are secreted to the extracellular space could exacerbate disease progression.