Shelley Jane Allen

The use of Next Generation Sequencing (NGS) techniques has generated a wide variety of blood microbiome data. Due to the large variation in bacterial DNA profiles between studies and the likely high concentrations of cell-free bacterial DNA in the blood, it is still not clear how such microbiome data relates to viable microbiota. For these reasons much remains to be understood about the true nature of any possible healthy blood microbiota and of bacteraemic events associated with disease. The gut, reproductive tracts, skin, and oral cavity are all likely sources of blood-borne bacteria. Oral bacteria, especially those associated with periodontal diseases, are also commonly associated with cardiovascular diseases such as infective endocarditis, and also have been linked to rheumatoid arthritis and Alzheimer’s disease. Periodontal treatment, dental probing, and toothbrushing have been shown to cause transient bacteraemia and oral bacteria from the phyla Firmicutes (e.g. Streptococci) and Bacteroidetes (e.g. Porphyromonas) are found in cardiovascular lesions (CVD). Many studies of blood bacterial DNA content however, find Proteobacteria DNA to be the dominant microbiome component, suggesting a gut origin. Most studies of this type use total DNA extracted from either whole blood or blood fractions, such as buffy coat. Here, using a method that purifies DNA from intact bacterial cells only, we examined blood donated by those with active, severe periodontitis and periodontally healthy controls and show that 43–52% of bacterial species in blood are classified as oral. Firmicutes, consisting largely of members of the Streptococcus mitis group and Staphylococcus epidermidis, were predominant at 63.5% of all bacterial sequences detected in periodontal health and, little changed at 66.7% in periodontitis. Compared to studies using total DNA Proteobacteria were found here at relatively low levels in blood at 13.3% in periodontitis and 17.6% in health. This study reveals significant phylogenetic differences in blood bacterial population profiles when comparing periodontal health to periodontal disease cohorts.

This minireview is a brief overview examining the roles of insulin-like growth factors (IGFs) and the PI3K/Akt pathway in two apparently unconnected diseases: Alzheimer's dementia and cancer. For both, increased age is a major risk factor, and, in accord with the global rise in average life expectancy, their prevalence is also increasing. Cancer, however, involves excessive cell proliferation and metastasis, whereas Alzheimer's disease (AD) involves cell death and tissue destruction. The apparent “inverse” nature of these disease states is examined here, but also some important commonalities in terms of the PI3K/Akt pathway, glucose utilization and cell deregulation/death. The focus here is on four key molecules associated with this pathway; notably, the insulin receptor substrate 1 (IRS-1), cellular tumor antigen p53 (p53), peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) and low-density lipoprotein receptor–related protein-1 (LRP1), all previously identified as potential therapeutic targets for both diseases. The insulin-resistant state, commonly reported in AD brain, results in neuronal glucose deprivation, due to a dampening down of the PI3K/Akt pathway, including overactivity of the mammalian target of rapamycin 1 (mTORC1) complex, hyperphosphorylation of p53 and neuronal death. This contrasts with cancer, where there is overstimulation of the PI3K/Akt pathway and the suppression of mTORC1 and p53, enabling abundant energy and unrestrained cell proliferation. Although these disease states appear to be diametrically opposed, the same key molecules are controlling pathology and, with differential targeting of therapeutics, may yet provide a beneficial outcome for both.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer’s disease (AD), probably in response to amyloid-β , vasoconstriction, and tissue hypoxia, there is no consequent increase

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression with important roles in cancer, cardiovascular and neurological disorders. Present in the brain, they play numerous regulatory roles shaping the proteome in an orchestrated manner with other non-coding RNAs. An independent brain-specific renin-angiotensin system (RAS) exists that is subject to miRNA remodelling. The brain RAS regulates cerebral blood flow and electrolytic balance and is involved in neurotransmitter signalling and cognitive processes. Circulating microRNAs allow interaction between systemic and local RAS in the heart and the brain. Their screening and manipulation may be valuable towards understanding pathophysiology and development of treatments for various systemic and central nervous system diseases.

The neurological deterioration associated with Alzheimer’s disease, involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next Generation Sequencing of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal.

Neurogenic detrusor overactivity (NDO) is a well known consequence of spinal cord injury (SCI), recognizable after spinal shock, during which the bladder is areflexic. NDO emergence and maintenance depend on profound plastic changes of the spinal neuronal pathways regulating bladder function. It is well known that neurotrophins (NTs) are major regulators of such changes. NGF is the best-studied NT in the bladder and its role in NDO has already been established. Another very abundant neurotrophin is BDNF. Despite being shown that, acting at the spinal cord level, BDNF is a key mediator of bladder dysfunction and pain during cystitis, it is presently unclear if it is also important for NDO. This study aimed to clarify this issue.Results obtained pinpoint BDNF as an important regulator of NDO appearance and maintenance. Spinal BDNF expression increased in a time-dependent manner together with NDO emergence. In chronic SCI rats, BDNF sequestration improved bladder function, indicating that, at later stages, BDNF contributes NDO maintenance. During spinal shock, BDNF sequestration resulted in early development of bladder hyperactivity, accompanied by increased axonal growth of calcitonin gene-related peptide-labeled fibers in the dorsal horn. Chronic BDNF administration inhibited the emergence of NDO, together with reduction of axonal growth, suggesting that BDNF may have a crucial role in bladder function after SCI via inhibition of neuronal sprouting. These findings highlight the role of BDNF in NDO and may provide a significant contribution to create more efficient therapies to manage SCI patients.

The tyrosine kinase A (TrkA) receptor is a validated therapeutic intervention point for a wide range of conditions. TrkA activation by nerve growth factor (NGF) binding the second extracellular immunoglobulin (TrkAIg2) domain triggers intracellular signaling cascades. In the periphery, this promotes the pain phenotype and, in the brain, cell survival or differentiation. Reproducible structural information and detailed validation of protein–ligand interactions aid drug discovery. However, the isolated TrkAIg2 domain crystallizes as a β-strand-swapped dimer in the absence of NGF, occluding the binding surface. Here we report the design and structural validation by nuclear magnetic resonance spectroscopy of the first stable, biologically active construct of the TrkAIg2 domain for binding site confirmation. Our structure closely mimics the wild-type fold of TrkAIg2 in complex with NGF (1WWW.pdb), and the ¹H–¹⁵N correlation spectra confirm that both NGF and a competing small molecule interact at the known binding interface in solution.

This review, gathered from diverse sources, shows how our microbiome influences health and ultimately how well we age. Evidence linking oral bacteria to Alzheimer's disease (AD) is discussed in the context of aging, drawing together data from epidemi