Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer's Disease

Alzheimer's type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1-42 (A beta), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low A beta in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by A beta and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with A beta and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, A beta and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low A beta and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders

Performances and nutritional values of a new hooded barley (cv. Mochona) and a high yield triticale (cv. Titania) as hay or silage for sheep under Mediterranean conditions

Altres ajuts: acords transformatius de la UABThe hooded barley phenotype produces an extra sterile flower in spikelets instead of awns. Hence, it might improve the nutritive value of the whole plant. The aim of this work was to evaluate a new variety of hooded barley (cv. Mochona) and a high yield triticale (cv. Titania) harvested and processed as hay and silage during 2 consecutive years for sheep. Digestibility was determined using 32 ewes which were distributed in 2 balanced groups by treatment, and fed with hay and silage sequentially. Results showed differences in the chemical composition of hay and silage according to harvesting year, but no differences were found on voluntary intake by year, species, or their interaction. Both forages showed high sheep fill values (sFV) either as hay or as silage (2.65 ± 0.030 and 3.09 ± 0.042 sFV/kg DM, on average, respectively). Impact on apparent nutrient digestibility coefficients varied according to preservation method, the digestibility of hays being mainly affected by the harvesting year, and that of silages by species. Digestible undegradable protein values were greater in hooded barley than in triticale for silages. In conclusion, marked compositional differences between years, but slight differences between species, were observed. Consequently, intake was similar, although triticale revealed slightly greater nutritive values than hooded barley. The obtained values for hooded barley as forage were greater than those reported in the literature for common fodder barley

Grey and white matter correlates of recent and remote autobiographical memory retrieval:Insights from the dementias

The capacity to remember self-referential past events relies on the integrity of a distributed neural network. Controversy exists, however, regarding the involvement of specific brain structures for the retrieval of recently experienced versus more distant events. Here, we explored how characteristic patterns of atrophy in neurodegenerative disorders differentially disrupt remote versus recent autobiographical memory. Eleven behavioural-variant frontotemporal dementia, 10 semantic dementia, 15 Alzheimer's disease patients and 14 healthy older Controls completed the Autobiographical Interview. All patient groups displayed significant remote memory impairments relative to Controls. Similarly, recent period retrieval was significantly compromised in behavioural-variant frontotemporal dementia and Alzheimer's disease, yet semantic dementia patients scored in line with Controls. Voxel-based morphometry and diffusion tensor imaging analyses, for all participants combined, were conducted to investigate grey and white matter correlates of remote and recent autobiographical memory retrieval. Neural correlates common to both recent and remote time periods were identified, including the hippocampus, medial prefrontal, and frontopolar cortices, and the forceps minor and left hippocampal portion of the cingulum bundle. Regions exclusively implicated in each time period were also identified. The integrity of the anterior temporal cortices was related to the retrieval of remote memories, whereas the posterior cingulate cortex emerged as a structure significantly associated with recent autobiographical memory retrieval. This study represents the first investigation of the grey and white matter correlates of remote and recent autobiographical memory retrieval in neurodegenerative disorders. Our findings demonstrate the importance of core brain structures, including the medial prefrontal cortex and hippocampus, irrespective of time period, and point towards the contribution of discrete regions in mediating successful retrieval of distant versus recently experienced events

Olfactory Receptor OR2K2 Expression in Human Choroid Plexus as a Potential Marker in Early Sporadic Alzheimer’s Disease

Epithelial cells comprising the choroid plexus (CP) form a crucial barrier between the blood and the cerebrospinal fluid, thereby assuming a central position in brain homeostasis and signaling. Mounting evidence suggests that the impairment of CP function may be a significant contributor to Alzheimer's disease (AD) pathogenesis. CP function relies on the expression of specific receptors, and the potential involvement of olfactory receptors (ORs) and taste receptors (TASRs) in chemical surveillance within the CP is being investigated. Previous studies have implicated ORs and TASRs in neurodegenerative disorders like AD, although the direct evidence of their expression in the human CP remains to be established. In this study, we conducted a transcriptomic analysis encompassing eleven ORs and TASRs in the CP, comparing samples from healthy age-matched controls to those from patients with AD spanning Braak stages I to VI. Among these receptors, a striking finding emerged-OR2K2 exhibited robust expression, with a statistically significant upregulation noted at Braak stage I. Surprisingly, at the protein level, OR2K2 showed a significant decrease in both Braak stage I and VI. Additionally, we identified CP epithelial cells as the source of OR2K2 expression, where it colocalized with autophagy markers LC3 and p62. We postulate that OR2K2 could be subjected to degradation by autophagy in the early stages of AD, triggering a compensatory mechanism that leads to increased OR2K2 mRNA transcription. This study uncovers a potential role for OR2K2 in AD pathogenesis, offering a novel perspective on the intricate dynamics at play in this neurodegenerative disorder

Glycogen synthase kinase 3 activity mediates neuronal pentraxin 1 expression and cell death induced by potassium deprivation in cerebellar granule cells

ABSTRACT Expression of neuronal pentraxin 1 (NP1) is part of the apoptotic cell death program activated in mature cerebellar granule neurons when potassium concentrations drop below depolarizing levels. NP1 is a glycoprotein homologous to the pentraxins of the acute phase immune response, and it is involved in both synaptogenesis and synaptic remodeling. However, how it participates in the process of apoptotic neuronal death remains unclear. We have studied whether the signaling pathways known to control neuronal cell death and survival influence NP1 expression. Both activation of the phosphatidylinositol 3-kinase/Akt (PI-3-K/AKT) pathway by insulin-like growth factor I and pharmacological blockage of the stress activated c-Jun NH 2 -terminal kinase (JNK) offer transitory neuroprotection from the cell death evoked by nondepolarizing concentrations of potassium. However, neither of these neuroprotective treatments prevents the overexpression of NP1 upon potassium depletion, indicating that nondepolarizing conditions activate additional cell death signaling pathways. Inhibiting the phosphorylation of the p38 mitogen-activated protein kinase without modifying JNK, neither diminishes cell death nor inhibits NP1 overexpression in nondepolarizing conditions. In contrast, impairing the activity of glycogen synthase kinase 3 (GSK3) completely blocks NP1 overexpression induced by potassium depletion and provides transient protection against cell death. Moreover, simultaneous pharmacological blockage of both JNK and GSK3 activities provides long-term protection against the cell death evoked by potassium depletion. These results show that both the JNK and GSK3 signaling pathways are the main routes by which potassium deprivation activates apoptotic cell death, and that NP1 overexpression is regulated by GSK3 activity independently of the PI-3-K/AKT or JNK pathway

Performance of dairy ewes fed diets with a fibrolytic enzyme product included in the concentrate during the suckling period

Seventy-two multiparous ewes from two dairy breeds (Manchega, n = 36 and Lacaune, n = 36) were used in a replicated 2 x 2 factorial design to evaluate the effects of diet supplementation with an exogenous fibrolytic enzyme product on lactation performance and feed intake during the suckling period (weeks 1 to 4) according to breed. Ewes were blocked in groups of nine and fed ad libitum after lambing a diet based on 70% forage and 30% concentrate to which the enzyme was added after pelleting. Experimental concentrates were: control (without enzyme) and enzyme (fibrolytic enzyme complex, included at 0.47% volume to weight of concentrate). Twenty-four dry and open ewes (Manchega, n = 12 and Lacaune, n = 12) were also grouped by breed and used to measure the fill value of the ration used. During the suckling period, milk yield, milk composition, dry matter intake, lamb growth, as well as body weight change and body condition score change were not affected by enzyme supplementation. Breed effect was significant for milk yield, the Manchega ewes yielding less milk with a higher content of milk components than the Lacaune ewes. The opposite was observed for dry matter intake. Enzyme supplementation reduced intake by 9% in the dry ewes, resulting in a greater fill value of the diet. In conclusion, no lactational effects were detected when the fibrolytic enzyme product was added to the concentrate fed to dairy ewes