Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions.</p> <p>Results</p> <p>In apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts.</p> <p>Conclusion</p> <p>The identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.</p

Abnormal connectivity between the default mode and the visual system underlies the manifestation of visual hallucinations in Parkinson’s disease:A task-based fMRI study

Background: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. Aims: To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease. Methods: In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease. Results: Correct performance of the task was associated with increased activity in primary visual regions; however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. Conclusions: Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations

Terra incognita—cerebellar contributions to neuropsychiatric and cognitive dysfunction in behavioral variant frontotemporal dementia

Although converging evidence has positioned the human cerebellum as an important relay for intact cognitive and neuropsychiatric processing, changes in this large structure remain mostly overlooked in behavioral variant frontotemporal dementia (bvFTD), a disease which is characterized by cognitive and neuropsychiatric deficits. The present study assessed whether degeneration in specific cerebellar subregions associate with indices of cognition and neuropsychiatric performance in bvFTD. Our results demonstrate a relationship between cognitive and neuropsychiatric decline across various domains of memory, language, emotion, executive, visuospatial function, and motivation and the degree of gray matter degeneration in cerebellar lobules V–VII. Most notably, bilateral cerebellar lobule VII and the posterior vermis emerged as distinct for memory processes, the right cerebellar hemisphere underpinned emotion, and the posterior vermis was highlighted in language dysfunction in bvFTD. Based on cortico-cerebellar connectivity maps, these findings in the cerebellum are consistent with the neural connections with the cortices involved in these domains in patients with bvFTD. Overall, the present study underscores the significance of cortical-cerebellar networks associated with cognition and neuropsychiatric dysfunction in bvFTD

Macroautophagy in sporadic and the genetic form of Parkinson’s disease with the A53T a-synuclein mutation

The A53T mutation in the a-synuclein gene causes autosomal-dominant Lewy body Parkinson’s disease (PD). Cultured cell models have linked this mutation to increased cell macroautophagy, although evidence of enhanced macroautophagy in patients with this mutation has not been assessed. Objective: To determine whether macroautophagy is increased by the A53T a-synuclein gene mutation in PD patients and cell models. Methods: Formalin-fixed paraffin-embedded 10 μm-thick tissue sections from the substantia nigra and anterior cingulate cortex of two PD patients with the A53T a-synuclein gene mutation were compared with four sporadic PD cases and four controls obtained from the Sydney Brain Bank. Lewy bodies were isolated from frontal cortex of a case with late stage PD (recruited from South Australian Brain Bank). Immunohistochemistry was performed for a-synuclein and the macroautophagy markers autophagy-specific gene (ATG) 5, ATG6/Beclin1 and ATG8/LC3. SHSY5Y cells were transfected with wild type or A53T mutant a-synuclein plasmids and observable changes in macroautophagy marker protein levels assessed using Western blotting. Results: a-Synuclein immunoreactive neurites and dots were more numerous in patients with A53T mutations compared with late stage sporadic PD patients, and perinuclear cytoplasmic a-synuclein aggregates were observed in the a-synuclein A53T gene transfected SH-SY5Y cells compared to wild type transfections. All PD patients (with or without A53T mutations) had increased immunohistochemical evidence for macroautophagy compared with controls, and the levels of the ATG5 complex were equally increased in wild type and A53T a-synuclein gene transfected cells compared to controls. Conclusion: Despite increased a-synuclein accumulation with A53T mutations, macroautophagy is not increased above that observed in sporadic patients with PD or in cells transfected with wild type a-synuclein, suggesting that mutated a-synuclein protein is not removed by macroautophagy

Is Seladin-1 really a selective Alzheimer\u27s disease indicator?

Selective Alzheimer\u27s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer\u27s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD

Содержание труда фармацевтического персонала в процессе аптечного изготовления лекарственных средств

ТЕХНОЛОГИЯ ФАРМАЦЕВТИЧЕСКАЯЛЕКАРСТВ ПРИГОТОВЛЕНИЕ ПО РЕЦЕПТУ ВРАЧАФАРМАЦЕВТЫФАРМАЦЕВТОВ ПОМОЩНИК

Cerebellar atrophy in Parkinson's disease and its implication for network connectivity.

Pathophysiological and atrophic changes in the cerebellum are documented in Parkinson's disease. Without compensatory activity, such abnormalities could potentially have more widespread effects on both motor and non-motor symptoms. We examined how atrophic change in the cerebellum impacts functional connectivity patterns within the cerebellum and between cerebellar-cortical networks in 42 patients with Parkinson's disease and 29 control subjects. Voxel-based morphometry confirmed grey matter loss across the motor and cognitive cerebellar territories in the patient cohort. The extent of cerebellar atrophy correlated with decreased resting-state connectivity between the cerebellum and large-scale cortical networks, including the sensorimotor, dorsal attention and default networks, but with increased connectivity between the cerebellum and frontoparietal networks. The severity of patients' motor impairment was predicted by a combination of cerebellar atrophy and decreased cerebellar-sensorimotor connectivity. These findings demonstrate that cerebellar atrophy is related to both increases and decreases in cerebellar-cortical connectivity in Parkinson's disease, identifying potential cerebellar driven functional changes associated with sensorimotor deficits. A post hoc analysis exploring the effect of atrophy in the subthalamic nucleus, a cerebellar input source, confirmed that a significant negative relationship between grey matter volume and intrinsic cerebellar connectivity seen in controls was absent in the patients. This suggests that the modulatory relationship of the subthalamic nucleus on intracerebellar connectivity is lost in Parkinson's disease, which may contribute to pathological activation within the cerebellum. The results confirm significant changes in cerebellar network activity in Parkinson's disease and reveal that such changes occur in association with atrophy of the cerebellum

The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimer’s disease

BACKGROUND: Early atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. The total number of neurons in this region, rather than the density of neurons, is associated with mood disturbance in other dementias, although there are no data on the extent and magnitude of neuronal loss in patients with bvFTD. While the density of small populations of neurons in this region has been assessed, it is unlikely that the degree of atrophy of the cingulate cortex seen in bvFTD can be explained by the loss of these subpopulations. This suggests that there is more generalized degeneration of neurons in this region in bvFTD. The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N = 11) and AD (N = 9) patients compared with age-matched controls (N = 14). The bvFTD cohort comprised 5 cases with tau pathology (Pick’s disease), and 6 with TDP-43 pathology. RESULTS: At postmortem, atrophy was detected in the anterior and posterior cingulate cortices of bvFTD cases, but only in the posterior cingulate cortex of AD cases. As predicted, there was a significant reduction in both the density and total number of neurons in the anterior but not the posterior cingulate cortex of bvFTD cases with the opposite observed for the AD cases. Importantly, neuronal loss in the anterior cingulate cortex was only observed in cases with tau pathology. CONCLUSIONS: This study confirms significant neuronal loss in the posterior but not anterior cingulate cortex in AD, and demonstrates that significant neuron loss in bvFTD occurs only in the anterior cingulate cortex but only in cases with tau pathology compared with cases with TDP pathology. We propose that significant neurodegeneration in the anterior cingulate cortex may be useful in differentiating the pathological subtypes in vivo

Expanding the phenotypic associations of globular glial tau subtypes

AbstractIntroductionClinicopathologic correlation in non-Alzheimer's tauopathies is variable, despite refinement of pathologic diagnostic criteria. In the present study, the clinical and neuroimaging characteristics of globular glial tauopathy (GGT) were examined to determine whether subtyping according to consensus guidelines improves clinicopathologic correlation.MethodsConfirmed GGT cases (n = 11) were identified from 181 frontotemporal tauopathy cases. Clinical and neuroimaging details were collected, and cases sub-typed according to the consensus criteria for GGT diagnosis. Relationships between clinical syndrome and GGT subtype were investigated.ResultsIn total, 11 patients (seven males, four females, mean age = 67.3 +/− 10.6 years) with GGT were included. Most, but not all, presented with behavioral variant frontotemporal dementia, but none had amyotrophic lateral sclerosis. Subtyping of GGT proved to be difficult and did not improve clinicopathologic correlation.DiscussionSub-classification of GGT pathology may be difficult and did not improve clinicopathologic correlation. Better biomarkers of tau pathology are needed