Radhika Vaishnav

The systemic iron-regulatory proteins hepcidin and ferroportin are reduced in the brain in Alzheimer’s disease

BackgroundThe pathological features of the common neurodegenerative conditions, Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis are all known to be associated with iron dysregulation in regions of the brain where the specific pathology is most highly expressed. Iron accumulates in cortical plaques and neurofibrillary tangles in AD where it participates in redox cycling and causes oxidative damage to neurons. To understand these abnormalities in the distribution of iron the expression of proteins that maintain systemic iron balance was investigated in human AD brains and in the APP-transgenic (APP-tg) mouse.ResultsProtein levels of hepcidin, the iron-homeostatic peptide, and ferroportin, the iron exporter, were significantly reduced in hippocampal lysates from AD brains. By histochemistry, hepcidin and ferroportin were widely distributed in the normal human brain and co-localised in neurons and astrocytes suggesting a role in regulating iron release. In AD brains, hepcidin expression was reduced and restricted to the neuropil, blood vessels and damaged neurons. In the APP-tg mouse immunoreactivity for ferritin light-chain, the iron storage isoform, was initially distributed throughout the brain and as the disease progressed accumulated in the core of amyloid plaques. In human and mouse tissues, extensive AD pathology with amyloid plaques and severe vascular damage with loss of pericytes and endothelial disruption was seen. In AD brains, hepcidin and ferroportin were associated with haem-positive granular deposits in the region of damaged blood vessels.ConclusionOur results suggest that the reduction in ferroportin levels are likely associated with cerebral ischaemia, inflammation, the loss of neurons due to the well-characterised protein misfolding, senile plaque formation and possibly the ageing process itself. The reasons for the reduction in hepcidin levels are less clear but future investigation could examine circulating levels of the peptide in AD and a possible reduction in the passage of hepcidin across damaged vascular endothelium. Imbalance in the levels and distribution of ferritin light-chain further indicate a failure to utilize and release iron by damaged and degenerating neurons.

Humans Have Antibodies against a Plant Virus: Evidence from Tobacco Mosaic Virus

Tobacco mosaic virus (TMV), a widespread plant pathogen, is found in tobacco (including cigarettes and smokeless tobacco) as well as in many other plants. Plant viruses do not replicate or cause infection in humans or other mammals. This study was done to determine whether exposure to tobacco products induces an immune response to TMV in humans. Using a sandwich ELISA assay, we detected serum anti-TMV antibodies (IgG, IgG1, IgG3, IgG4, IgA, and IgM) in all subjects enrolled in the study (20 healthy smokers, 20 smokeless-tobacco users, and 20 non-smokers). Smokers had a higher level of serum anti-TMV IgG antibodies than non-smokers, while the serum level of anti-TMV IgA from smokeless tobacco users was lower than smokers and non-smokers. Using bioinformatics, we also found that the human protein TOMM40L (an outer mitochondrial membrane 40 homolog – like translocase) contains a strong homology of six contiguous amino acids to the TMV coat protein, and TOMM40L peptide exhibited cross-reactivity with anti-TMV antibodies. People who smoke cigarettes or other tobacco products experience a lower risk of developing Parkinson’s disease, but the mechanism by which this occurs is unclear. Our results showing molecular mimicry between TMV and human TOMM40L raise the question as to whether TMV has a potential role in smokers against Parkinson’s disease development. The potential mechanisms of molecular mimicry between plant viruses and human disease should be further explored.

Aquaporin 4 molecular mimicry and implications for neuromyelitis optica

Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207-232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207-232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology.

Cross-kingdom sequence similarities between human micro-RNAs and plant viruses

Micro-RNAs regulate the expression of cellular and tissue phenotypes at a post-transcriptional level through a complex process involving complementary interactions between micro-RNAs and messenger-RNAs. Similar nucleotide interactions have been shown to occur as cross-kingdom events; for example, between plant viruses and plant micro-RNAs and also between animal viruses and animal micro-RNAs. In this study, this view is expanded to look for cross-kingdom similarities between plant virus and human micro-RNA sequences. A method to identify significant nucleotoide sequence similarities between plant viruses and hsa micro-RNAs was created. Initial analyses demonstrate that plant viruses contain nucleotide sequences which exactly match the seed sequences of human micro-RNAs in both parallel and anti-parallel directions. For example, the bean common mosaic virus strain NL4 from Colombia contains sequences that match exactly the seed sequence for micro-RNA of the hsa-mir-1226 in the parallel direction, which suggests a cross-kingdom conservation. Similarly, the rice yellow stunt viral cRNA contains a sequence that is an exact match in the anti-parallel direction to the seed sequence of hsa-micro-RNA let-7b. The functional implications of these results need to be explored. The finding of these cross-kingdom sequence similarities is a useful starting point in support of bench level investigations.

Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer's disease.

Vascular dysfunction and decreased cerebral blood flow are linked to Alzheimers disease (AD). Loss of endothelial nitric oxide (NO) and oxidative stress in human cerebrovascular endothelium increase expression of amyloid precursor protein (APP) and enhance production of the Aβ peptide, suggesting that loss of endothelial NO contributes to AD pathology. We hypothesize that decreased systemic NO bioavailability in AD may also impact lung microcirculation and induce pulmonary endothelial dysfunction. The acute effect of NO synthase (NOS) inhibition on pulmonary arteriolar tone was assessed in a transgenic mouse model (TgAD) of AD (C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax) and age‐matched wild‐type controls (C57BL/6J). Arteriolar diameters were measured before and after the administration of the NOS inhibitor, L‐NAME. Lung superoxide formation (DHE) and formation of nitrotyrosine (3‐NT) were assessed as indicators of oxidative stress, inducible NOS (iNOS) and tumor necrosis factor alpha (TNF‐α) expression as indicators of inflammation. Administration of L‐NAME caused either significant pulmonary arteriolar constriction or no change from baseline tone in wild‐type (WT) mice, and significant arteriolar dilation in TgAD mice. DHE, 3‐NT, TNF‐α, and iNOS expression were higher in TgAD lung tissue, compared to WT mice. These data suggest L‐NAME could induce increased pulmonary arteriolar tone in WT mice from loss of bioavailable NO. In contrast, NOS inhibition with L‐NAME had a vasodilator effect in TgAD mice, potentially caused by decreased reactive nitrogen species formation, while significant oxidative stress and inflammation were present. We conclude that AD may increase pulmonary microvascular tone as a result of loss of bioavailable NO and increased oxidative stress. Our findings suggest that AD may have systemic microvascular implications beyond central neural control mechanisms.

Parkinson disease, edible Solanaceae, and tobacco mosaic virus.

Potential Conflicts of Interest D.S.: None. T.S.: travel expenses to a scientific meeting have been covered by Boehringer Ingelheim. M.K.: has received honoraria and his travel expenses have been covered for participating in the Steering Committee meetings of the ECASS, ECASS II, ECASS III, DIAS, DIAS-2, and DIAS-4 trials, and for serving as a consultant for Boehringer-Ingelheim, PAION AG, Forest Research Laboratories, Inc., and Lundbeck A/S. P.J.L.: None.

Symptomatic Intracranial Atherosclerosis: Natural History of Medical Management Beyond the Hyperacute Stage of Ischemic Stroke in the Post-SAMMPRIS Era

Abstract Background: A major cause of ischemic stroke (IS) worldwide, especially in Asia, is intracranial atherosclerotic stenosis (ICAS), which is also associated with the high risk of recurrent stroke. Objective: The aim of our study was to determine the natural history of symptomatic ICAS ischemic stroke (ICAS IS) patients. Materials and Methods: We collected data on acute ICAS IS patients beyond the hyperacute IS phase to determine stroke recurrence and mortality at a tertiary care neurology hospital. Data were collected on basic demographics and traditional risk factors such as hypertension, coronary artery disease, diabetes mellitus, tobacco abuse, and hyperlipidemia, and statistical analysis was done. The primary endpoint was to measure the unfavorable outcome as defined by recurrent stroke or death from any cause. Results: The mean follow-up time for the total 87 patients was 24.5 months. Nine patients (10.3%) had an unfavorable outcome in the follow-up period; 2 (2.3%) of them had recurrent IS. Age was a predictor of the unfavorable outcome (P = .0025), whereas hyperlipidemia was present more in patients with the favorable outcome (P = .033). There was a tendency for patients with poor outcomes to have a higher National Institutes of Health Stroke Scale at their onset of stroke. Conclusions: Aggressive medical treatment was associated with a relatively low risk of recurrent stroke in our ICAS IS population. This study provides groundwork for larger studies that can take into account clinical and newer imaging techniques to improve secondary prevention in ICAS IS patients.