Rapid amyloid‐β oligomer and protofibril accumulation in traumatic brain injury

Deposition of amyloid‐β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N‐terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life‐threatening brain swelling/hemorrhage within one week post‐injury. The TBI tissues were compared to post‐mortem AD brains (n = 5), to post‐mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N‐terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4‐negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short‐ and long‐term outcome in TBI.     

Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice

Transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid-β precursor protein (AβPP) develop amyloid-beta (Aβ) deposits in the brain that resemble Alzheimer's disease neuropathology. Earlier studies of this model have documented morphologic features in selected parts of the cerebral cortex and hippocampus, but the spatial distribution within the brain and variance of Aβ deposits within a group of tg-ArcSwe mice is unknown. Using immunohistochemistry and brainwide microscopic analysis of 12-month-old tg-ArcSwe mice, we show that Aβx-40 plaque deposits are consistently present in the cerebral cortex, hippocampus, and thalamus and variably present in other regions. Using quantitative image analysis, we demonstrated that the average Aβ burden in the cortex and hippocampus is similar across animals, with coefficients of variance of 22% and 25%, respectively. This indicates that interventional studies of tg-ArcSwe mice are feasible using region-of-interest comparisons and that interventional trials require larger group sizes than commonly used. We also present an online atlas providing access to images showing the detailed characteristics and spatial distribution patterns of Aβx-40 labeling.     

Effect of pitavastatin against expression of S100β protein in the gerbil hippocampus after transient cerebral ischaemia

Aim and methods: We investigated the immunohistochemical alterations of S100β‐, S100‐, glial fibrillary acidic protein (GFAP)‐ and isolectin B₄‐positive cells in the hippocampus after 5 min of transient cerebral ischaemia in gerbils. We also examined the effect of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor pitavastatin against neuronal damage in the hippocampal CA1 sector after ischaemia. Results: Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons from 5 days after ischaemia. GFAP‐positive cells increased gradually in the hippocampus from 5 days after ischaemia. Five and 14 days after ischaemia, significant increases in the number of GFAP‐positive cells and isolectin B₄‐positive cells were observed in the hippocampal CA1 and CA3 sector. Mild increases in the number of S100 and S100β‐positive cells were observed in the hippocampal CA1 sector from 1 h to 2 days after ischaemia. Thereafter, S100β‐positive cells increased in the hippocampal CA1 sector after ischaemia, whereas S100‐positive cells decreased in this region. In our double‐labelled immunostainings, S100 and S100β immunoreactivity was found in GFAP‐positive astrocytes, but not in isolectin B₄‐positive microglia. Pharmacological study showed that HMG‐CoA reductase inhibitor, pitavastatin, can protect against the hippocampal CA1 neuronal damage after ischaemia. This drug also prevented increases in the number of GFAP‐positive astrocytes, isolectin B₄‐positive microglia, S100‐positive astrocytes and S100β‐positive astrocytes after ischaemia. Conclusion: The present study demonstrates that pitavastatin can decrease the neuronal damage of hippocampal CA1 sector after ischaemia. This beneficial effect may be, at least in part, mediated by inhibiting the expression of astrocytic activation in the hippocampus at the acute phase after ischaemia. Thus the modulation of astrocytic activation may offer a novel therapeutic strategy of ischaemic brain damage.     

Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β‐amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. In recent years, Aβ‐immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single‐chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv‐h3D6 generated by our research group derives from this monoclonal antibody, which targets the N‐terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils. In this study, 3xTg‐AD mice were intraperitoneally and monthly treated with 100 μg of scFv‐h3D6 (a dose of ~3.3 mg/kg) or PBS, from 5 to 12 months of age (?mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non‐invasive manner and allowing to monitor its development across time. Compared with the genetic background, 3xTg‐AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ_1–42 at 12‐mo, and an inflammation process at this age, in both the hippocampus (IL‐6 and mIns) and cortex (IL‐6). In addition, treatment with scFv‐h3D6 partially recovered the values in brain volume, and Aβ, IL‐6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.     

Common Impact of Chronic Kidney Disease and Brain Microhemorrhages on Cerebral Aβ Pathology in SHRSP

While chronic kidney disease seems to be an independent risk factor for cognitive decline, its impact on cerebral amyloid‐β (Aβ) depositions, one hallmark of Alzheimer's Disease (AD) pathology, has not been investigated. Utilizing 80 male nontransgenic spontaneously hypertensive stroke prone rats (SHRSP) at various ages (12 to 44 weeks), tubulointerstitial renal damage, prevalence of cerebral microhemorrhages and Aβ accumulations were quantified. Using age‐adjusted general linear models we investigated the main and interaction effects of renal damage and cerebral microhemorrhages on cerebral Aβ load. In addition, using post mortem human brain tissue of 16 stroke patients we examined the co‐localization of perivascular Aβ deposits and small vessel wall damage. Statistical models revealed an age‐independent main effect of tubulointerstitial kidney damage on brain Aβ accumulations, which was reinforced by the consecutive presence of cerebral microhemorrhages. Moreover, cerebral microhemorrhages independently predicted brain Aβ burden in SHRSP. In up to 69% of all human cases perivascular Aβ deposits were detected in the direct vicinity of small vessel wall damage. Our results support the associations between vascular pathology and Aβ deposition, and demonstrate a relationship between chronic kidney disease and cerebral Aβ pathology. Hence, our data suggest that prevention of chronic renal damage may reduce cerebral Aβ pathology.     

Cerebral Amyloid β Protein Deposits and Other Alzheimer Lesions in Non-Demented Elderly East Africans

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid β (Aβ) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age-matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical Aβ deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound AS deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact Aβ deposits that were also predominantly reactive for the longer Aβ₄₂ species compared to Aβ₄₀. We also noted that Aβ plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed Aβ deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest Aβ deposition and some NFT in brains of non-demented East Africans are qualitatively and quantitatively similar to that in age-matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.     

Developmental trajectory of magnetic susceptibility in the healthy rhesus macaque brain

Quantitative susceptibility mapping (QSM) is used to quantify iron deposition in non-human primates in our study. Although QSM has many applications in detecting iron deposits in the human brain, including the distribution of iron deposits in specific brain regions, the change of iron deposition with aging, and the comparison of iron deposits between diseased groups and healthy controls, few studies have applied QSM to non-human primates, while most animal brain experiments focus on biochemical and anatomical results instead of non-invasive experiments. Additionally, brain imaging in children's research is difficult, but can be substituted using young rhesus monkeys, which are very similar to humans, as research animals. Therefore, understanding the relationship between iron deposition and age in rhesus macaques' brains can offer insights into both the developmental trajectory of magnetic susceptibility in the animal model and the correlated evidence in children's research. Twenty-three healthy rhesus macaque monkeys (23 ± 7.85 years, range 2–29 years) were included in this research. Seven regions of interest (ROIs—globus pallidus, substantia nigra, dentate nucleus, caudate nucleus, putamen, thalamus, red nucleus) have been analyzed in terms of QSM and R₂* (apparent relaxation rate). Susceptibility in most ROIs correlated significantly with the growth of age, similarly to the results for R₂*, but showed different trends in the thalamus and red nucleus, which may be caused by the different sensitivities of myelination and iron deposition in R₂* and QSM analysis. By assessing the correlation between iron content and age in healthy rhesus macaques' brains using QSM, we provide a piece of pilot information on normality for advanced animal disease models. Meanwhile, this study also could serve as the normative basis for further clinical studies using QSM for iron content quantification. Due to the comparison of the susceptibility on the same experimental objects, this research can also provide practical support for future research on characteristics for QSM and R₂*.     

Post‐ischaemic activation of kinases in the pre‐conditioning‐like cardioprotective effect of the platelet‐activating factor

Aim: Platelet‐activating factor (PAF) triggers cardiac pre‐conditioning against ischemia/reperfusion injury. The actual protection of ischaemic pre‐conditioning occurs in the reperfusion phase. Therefore, we studied in this phase the kinases involved in PAF‐induced pre‐conditioning. Methods: Langendorff‐perfused rat hearts underwent 30 min of ischaemia and 2 h of reperfusion (group 1, control). Before ischaemia, group 2 hearts were perfused for 19 min with PAF (2 × 10^?11 m ); groups 3–5 hearts were co‐infused during the initial 20 min of reperfusion, with the protein kinase C (PKC) inhibitor chelerythrine (5 × 10^?6 m ) or the phosphoinositide 3‐kinase (PI3K) inhibitor LY294002 (5 × 10^?5 m ) and atractyloside (2 × 10^?5 m ), a mitochondrial permeability transition pore (mPTP) opener respectively. Phosphorylation of PKCε, PKB/Aκt, GSK‐3β and ERK1/2 at the beginning of reperfusion was also checked. Left ventricular pressure and infarct size were determined. Results: PAF pre‐treatment reduced infarct size (33 ± 4% vs. 64 ± 5% of the area at risk of control hearts) and improved pressure recovery. PAF pre‐treatment enhanced the phosphorylation/activation of PKCε, PKB/Aκt and the phosphorylation/inactivation of GSK‐3β at reperfusion. Effects on ERK1/2 phosphorylation were not consistent. Infarct‐sparing effect and post‐ischaemic functional improvement induced by PAF pre‐treatment were abolished by post‐ischaemic infusion of either chelerythrine, LY294002 or atractyloside. Conclusions: The cardioprotective effect exerted by PAF pre‐treatment involves activation of PKC and PI3K in post‐ischaemic phases and might be mediated by the prevention of mPTP opening in reperfusion via GSK‐3β inactivation.     

Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds

Anti-amyloid beta (Aβ) immunotherapy provides potential benefits in Alzheimer's disease patients. Nevertheless, strategies based on Aβ_1–42 peptide induced encephalomyelitis and possible microhemorrhages. These outcomes were not expected from studies performed in rodents. It is critical to determine if other animal models better predict side effects of immunotherapies. Mouse lemur primates can develop amyloidosis with aging. Here we used old lemurs to study immunotherapy based on Aβ_1–42 or Aβ-derivative (K6Aβ_1–30). We followed anti-Aβ₄₀ immunoglobulin G and M responses and Aβ levels in plasma. In vivo magnetic resonance imaging and histology were used to evaluate amyloidosis, neuroinflammation, vasogenic edema, microhemorrhages, and brain iron deposits. The animals responded mainly to the Aβ_1–42 immunogen. This treatment induced immune response and increased Aβ levels in plasma and also microhemorrhages and iron deposits in the choroid plexus. A complementary study of untreated lemurs showed iron accumulation in the choroid plexus with normal aging. Worsening of iron accumulation is thus a potential side effect of Aβ-immunization at prodromal stages of Alzheimer's disease, and should be monitored in clinical trials.     

PIB binding in aged primate brain: Enrichment of high-affinity sites in humans with Alzheimer's disease

Aged nonhuman primates accumulate large amounts of human-sequence amyloid β (Aβ) in the brain, yet they do not manifest the full phenotype of Alzheimer's disease (AD). To assess the biophysical properties of Aβ that might govern its pathogenic potential in humans and nonhuman primates, we incubated the benzothiazole imaging agent Pittsburgh Compound B (PIB) with cortical tissue homogenates from normal aged humans, humans with AD, and from aged squirrel monkeys, rhesus monkeys, and chimpanzees with cerebral Aβ-amyloidosis. Relative to humans with AD, high-affinity PIB binding is markedly reduced in cortical extracts from aged nonhuman primates containing levels of insoluble Aβ similar to those in AD. The high-affinity binding of PIB may be selective for a pathologic, human-specific conformation of multimeric Aβ, and thus could be a useful experimental tool for clarifying the unique predisposition of humans to Alzheimer's disease.     

Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach

Vascular disorders can either be cause or consequence in the pathophysiology of Alzheimer’s disease (AD). To comprehensively characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APP_swe/PS1_dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBV_micro) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBV_micro changes. With this methodology the development of cerebral microvascular impairments can be described in vivo with 0.16 mm isotropic resolution for the whole mouse brain. At 8 months, impaired rCBV_micro appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. With a ROI-based approach, we further showed that hippocampal rCBV_micro in 13-month-old wild-type and APP_swe/PS1_dE9 mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBV_micro values showed no significant correlation with amyloid-β (Aβ) plaque deposition, Aβ at blood vessel walls and biochemically measured levels of Aβ_1-40, Aβ_1-42 oligomers and fibrillar forms. These results suggest that rCBV_micro reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Aβ deposition in parenchyma nor blood vessel walls.     

Detection of Aβ Plaques by a Novel Specific MRI Probe Precursor CR‐BSA‐(Gd‐DTPA)n in APP/PS1 Transgenic Mice

Amyloid plaques are one of the hallmarks of Alzheimer's disease (AD). The lack of specific probes that can detect individual senile plaques in AD has prompted the development of magnetic resonance imaging (MRI) probes. In this study, based on DTPA‐gadolinium (III) and congo red (CR), a novel specific MRI probe precursor CR‐BSA‐(Gd‐DTPA)n was successfully synthesized. Its ability to bind to amyloid plaques was evaluated by brain sections from APP/PS1 transgenic mice. Its specificity for Aβ plaques was further demonstrated by immunohistochemistry (IHC) staining with the monoclonal antibody to the Aβ protein. Meanwhile, the amyloid deposits detected by the CR‐BSA‐(Gd‐DTPA)n were matched to the amyloid deposits detected by Aβ specific antibody. We also found that a few amyloid‐like deposits which was not detected by IHC. The findings indicated that the probe perhaps could detect the neurofibrillary tangles (NFT) similar to the effect of CR itself, and this will be verified in future experiments. The works suggested that the Aβ protein‐specific magnetic resonance contrast agent precursor CR‐BSA‐(Gd‐DTPA)n can be used as a potential fluorescence and MR multi‐modal imaging probe precursor to display individual senile plaques in AD. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Extravascular fibrinogen in the white matter of Alzheimer’s disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer’s disease

The blood–brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood‐derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer’s disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid‐β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post‐mortem brains, parietal tissue from 20 AD and 22 non‐demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML‐ and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML‐ and NAWM fibrinogen burden (all P < 0.05) in controls only. In cases with minimal SVD NAWM fibrinogen burden was significantly higher in the AD cases (P < 0.05). BBB dysfunction was present in both non‐demented and AD brains and was not associated with the burden of AD‐associated cortical pathologies. BBB dysfunction was strongly associated with SVD but only in the non‐demented controls. In cases with minimal SVD, BBB dysfunction was significantly worse in AD cases possibly indicating the influence of CAA. In conclusion, extravascular fibrinogen is not associated with AD hallmark pathologies but indicates SVD, suggesting that the presence of fibrinogen in the CSF is not a surrogate marker for AD pathology.     

Intracerebroventricular injection of Aβ1-42 combined with two-vessel occlusion accelerate Alzheimer’s disease development in rats

Numerous experimental studies and clinical observations suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer’s disease (AD). Two-vessel occlusion caused cerebral ischemia model is often used in the study of vascular dementia (VaD). But how cerebral ischemia works on AD rat model which induced by intracerebroventricular injection of Aβ_1-42 remains unclear. In the following study, we investigated the characteristics of rat model caused by intracerebroventricular injection of Aβ_1-42 or two-vessel occlusion (2-VO) only and by both of the two operations. The animal cognitive functions were accessed by the Morris water maze. Regional cerebral blood flow was detected by Laser Doppler Blood Flowmeter. HE&Nissl staining, Congo red staining and immunohistochemistry were used to observe the status of neuronal loss, Aβ deposition and the phosphorylated tau expression in hippocampus, respectively. We also measured the contents of AchE and ChAT in serum and hippocampus by Enzyme Linked Immunosorbent Assay. The MWM results showed that rats of Aβ_1–42+2-VO group had a disorder in cognitive functions, at an early stage of one week after modeling, comparing with rats of sham group. The regional cerebral blood flow (rCBF) was significantly reduced in Aβ_1-42+2-VO and 2-VO group one week after modeling, and still maintained low perfusion levels four weeks after modeling. HE and Nissl staining showed that Aβ_1-42+2-VO rats’ hippocampal CA1 neurons were in disorder, degeneration and necrosis, severe neuronal loss from the first week to the fourth week, while this phenomenon only appeared in the fourth week after modeling in rats of Aβ_1-42 group and 2-VO group. Congo red staining showed that Aβ_1-42 + 2-VO group rats’ hippocampus CA1 had amyloid deposits from the first week to the fourth week, Aβ_1-42 group were not find amyloid deposition significantly until four weeks after modeling, however, 2-VO group had no significant amyloid deposition all the time. Notably, IHC showed that, two weeks after modeling, the p-tau positive total area and integrated optical density of hippocampal CA1 region were significantly increased in Aβ_1-42 + 2-VO group rats, while 2-VO group and Aβ_1-42 group rats had no significantly changes all the time. We also found that the content of AchE was increased both in serum and hippocampus of Aβ_1-42 + 2-VO group rats, and ChAT was decreased. However, there was no significantly change in cortex of content of AchE: acetylcholinesterase (AchE) and choline acetylase (ChAT) all three groups. Together, our study suggest that intracerebroventricular injection of Aβ_1-42 combined with two-vessel occlusion may accelerate Alzheimer’s disease development in rats. Also, this may serve as a less-time consuming new model to study the Alzheimer’s disease and especially AD accompanied by cerebral ischemia.     

A role for astrocyte‐derived amyloid β peptides in the degeneration of neurons in an animal model of temporal lobe epilepsy

Kainic acid, an analogue of the excitatory neurotransmitter glutamate, can trigger seizures and neurotoxicity in the hippocampus and other limbic structures in a manner that mirrors the neuropathology of human temporal lobe epilepsy (TLE). However, the underlying mechanisms associated with the neurotoxicity remain unclear. Since amyloid‐β (Aβ) peptides, which are critical in the development of Alzheimer's disease, can mediate toxicity by activating glutamatergic NMDA receptors, it is likely that the enhanced glutamatergic transmission that renders hippocampal neurons vulnerable to kainic acid treatment may involve Aβ peptides. Thus, we seek to establish what role Aβ plays in kainic acid‐induced toxicity using in vivo and in vitro paradigms. Our results show that systemic injection of kainic acid to adult rats triggers seizures, gliosis and loss of hippocampal neurons, along with increased levels/processing of amyloid precursor protein (APP), resulting in the enhanced production of Aβ‐related peptides. The changes in APP levels/processing were evident primarily in activated astrocytes, implying a role for astrocytic Aβ in kainic acid‐induced toxicity. Accordingly, we showed that treating rat primary cultured astrocytes with kainic acid can lead to increased Aβ production/secretion without any compromise in cell viability. Additionally, we revealed that kainic acid reduces neuronal viability more in neuronal/astrocyte co‐cultures than in pure neuronal culture, and this is attenuated by precluding Aβ production. Collectively, these results indicate that increased production/secretion of Aβ‐related peptides from activated astrocytes can contribute to neurotoxicity in kainic acid‐treated rats. Since kainic acid administration can lead to neuropathological changes resembling TLE, it is likely that APP/Aβ peptides derived from astrocytes may have a role in TLE pathogenesis.     

Sex differences in objective measures of sleep in post‐traumatic stress disorder and healthy control subjects

A growing literature shows prominent sex effects for risk for post‐traumatic stress disorder and associated medical comorbid burden. Previous research indicates that post‐traumatic stress disorder is associated with reduced slow wave sleep, which may have implications for overall health, and abnormalities in rapid eye movement sleep, which have been implicated in specific post‐traumatic stress disorder symptoms, but most research has been conducted in male subjects. We therefore sought to compare objective measures of sleep in male and female post‐traumatic stress disorder subjects with age‐ and sex‐matched control subjects. We used a cross‐sectional, 2 × 2 design (post‐traumatic stress disorder/control × female/male) involving83 medically healthy, non‐medicated adults aged 19–39 years in the inpatient sleep laboratory. Visual electroencephalographic analysis demonstrated that post‐traumatic stress disorder was associated with lower slow wave sleep duration (F_(3,82) = 7.63, P = 0.007) and slow wave sleep percentage (F_(3,82) = 6.11, P = 0.016). There was also a group × sex interaction effect for rapid eye movement sleep duration (F_(3,82) = 4.08, P = 0.047) and rapid eye movement sleep percentage (F_(3,82) = 4.30, P = 0.041), explained by greater rapid eye movement sleep in post‐traumatic stress disorder females compared to control females, a difference not seen in male subjects. Quantitative electroencephalography analysis demonstrated that post‐traumatic stress disorder was associated with lower energy in the delta spectrum (F_(3,82) = 6.79, P = 0.011) in non‐rapid eye movement sleep. Slow wave sleep and delta findings were more pronounced in males. Removal of post‐traumatic stress disorder subjects with comorbid major depressive disorder, who had greater post‐traumatic stress disorder severity, strengthened delta effects but reduced rapid eye movement effects to non‐significance. These findings support previous evidence that post‐traumatic stress disorder is associated with impairment in the homeostatic function of sleep, especially in men with the disorder. These findings suggest that group × sex interaction effects on rapid eye movement may occur with more severe post‐traumatic stress disorder or with post‐traumatic stress disorder comorbid with major depressive disorder.     

Aβ oligomers trigger and accelerate Aβ seeding

Aggregation of amyloid‐β (Aβ) that leads to the formation of plaques in Alzheimer's disease (AD) occurs through the stepwise formation of oligomers and fibrils. An earlier onset of aggregation is obtained upon intracerebral injection of Aβ‐containing brain homogenate into human APP transgenic mice that follows a prion‐like seeding mechanism. Immunoprecipitation of these brain extracts with anti‐Aβ oligomer antibodies or passive immunization of the recipient animals abrogated the observed seeding activity, although induced Aβ deposition was still evident. Here, we establish that, together with Aβ monomers, Aβ oligomers trigger the initial phase of Aβ seeding and that the depletion of oligomeric Aβ delays the aggregation process, leading to a transient reduction of seed‐induced Aβ deposits. This work extends the current knowledge about the role of Aβ oligomers beyond its cytotoxic nature by pointing to a role in the initiation of Aβ aggregation in vivo. We conclude that Aβ oligomers are important for the early initiation phase of the seeding process.     

Increased contribution of α1‐ vs. β‐adrenoceptor‐mediated inotropic response in rats with congestive heart failure

Aim: In failing myocardium the mechanical response to β‐adrenoceptor stimulation is attenuated. Alternative signalling systems might provide inotropic support when the β‐adrenoceptor system is dysfunctioning. Accordingly, the inotropic responses to α₁‐ and β‐adrenoceptor stimulation by the endogenous adrenoceptor agonist noradrenaline in non‐failing and failing rat hearts were compared. Methods: Chronic heart failure was induced in male Wistar rats by coronary artery ligation. Corresponding sham groups were prepared. After 6 weeks, papillary muscles from non‐failing and failing hearts were isolated. Receptor binding studies were performed in the corresponding myocardium. The α₁‐adrenoceptor‐mediated inotropic response was not changed while the β‐adrenoceptor‐mediated response was substantially reduced in failing compared with non‐failing myocardium. Results: No change in potency for the agonists was observed at the α₁‐adrenoceptors, while an increased potency for the agonists at the β‐adrenoceptors was found during heart failure. The lusitropic response to β‐adrenoceptor stimulation was intact during heart failure. No over all change in affinity or number of either adrenoceptor type was observed in receptor binding studies. The α₁‐adrenoceptor‐mediated inotropic response became dominating compared with the β‐adrenoceptor‐mediated one in failing rat myocardium in contrast to the dominating role of the latter in non‐failing myocardium. The attenuation of the β‐adrenoceptor‐mediated inotropic response in rat failing myocardium was not because of a reduced number of receptors. Conclusion: Increasing contractility through stimulation of α₁‐adrenoceptors in situ by the endogenous agonist may be an alternative way of inotropic support during heart failure and even more so during β‐adrenoceptor blockade.