Oxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer's disease (AD). It has been assumed that oxidative stress contributes to the ...ß-amyloid deposition in cerebral blood vessels.
In order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice. Following exposure of EC by 1 μM hydrogen peroxide for up to 48 hours, formation and secretion of APP cleavage products sAPPα and sAPPß into the culture medium as well as the expression of endothelial APP were assessed.
Oxidative stress resulted in enhanced secretion of sAPPß into the culture medium as compared to controls (absence of hydrogen peroxide), which was accompanied by an increased APP expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression.
The data suggest that oxidative stress may represent a major risk factor in causing Aß deposition in the brain vascular system by initiating the amyloidogenic route of endothelial APP processing. The enhanced β-secretase activity following oxidative stress exposure, possibly promoted by phosphorylation of p42/44 MAPK.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The majority of patients suffering from Alzheimer's disease (AD) demonstrate cerebral vascular changes and impaired regulation of cerebral blood flow, which has been assumed to play an important role ...in AD pathogenesis (vascular hypothesis of AD). There is strong evidence that both β-amyloid (Aβ) oligomers and plaques contribute to vascular injuries and functional impairments of the neurovascular unit. Vice versa, Aβ lesions can be triggered by hypertension and ischemic brain injury, while Aβ aggregates appear to have anti-angiogenic properties. Cholinergic dysfunction may result in impaired cerebral blood flow with consequences on normal function of the neurovascular unit including processing of the amyloid precursor protein (APP). To characterize in vivo the developmental relationship between Aβ formation and deposition, cortical cholinergic innervation and cerebrovascular abnormalities, transgenic Tg2576 mice that overexpress the Swedish double mutation of human APP, and demonstrate significant cerebral cortical deposition of Aβ plaques at ages from 9 months onwards, were considered as an appropriate animal model. Using the somatosensory cortex as a representative region, serial cryocut sections, were obtained from mice at ages ranging from 4 up to 18 months. These were subjected to immunohistochemistry to label vascular endothelial cells (anti-glucose transporter 1 (GluT1) immunostaining), cholinergic nerve terminals (anti-vesicular acetylcholine transporter (VAChT) immunostaining) and β-amyloid plaques (thioflavin S, and/or Solanum tuberosum lectin staining). This was followed by a thorough quantitative evaluation of the age-related spatial relationship between cerebral cortical capillaries, Aβ plaques and cholinergic terminals, using computer-assisted image analysis. The density of cholinergic terminals estimated by evaluation of VAChT immunohistochemistry in somatosensory cortical sections of wild type mice did not change with aging regardless of the cortical layer examined, while in cortical layers II/III and IV of somatosensory cortex of transgenic Tg2576 mice age-related decreases in cholinergic fiber densities were assessed. However, quantitative morphometric analysis demonstrated an age-related reduction in the number of varicosities on cholinergic fibers, particularly in layer IV, in both transgenic Tg2576 mice and non-transgenic littermates. Cholinergic innervation of microvessels in the somatosensory cortex decreased with aging in both Tg2576 mice and non-transgenic littermates, as revealed by estimating the ratio of the number of cholinergic vascular contacts and total length of blood vessel. There was no significant difference in the perivascular cholinergic innervation in areas that demonstrated significant plaque load and those with no plaque deposits regardless of the cortical layer examined. The density of blood vessels estimated in the somatosensory cortex of transgenic mice by anti-GluT-1 immunohistochemistry did not differ to that obtained in wild type mice before the onset of plaque deposition (younger than 10 months). However, in aged, 18-month-old Tg2576 mice, demonstrating high plaque loads, decreased blood vessel densities, particularly in layer IV of the somatosensory cortex, were observed. The data obtained in this study strongly support the idea of an age-related interplay between Aβ accumulation, cholinergic dysfunction, and vascular impairments. However, it remains to be elucidated as to which processes play a causative role and which events are secondary. A potential mechanism is provided by the vascular hypothesis of AD. Aging-, and life-style-associated damage of the brain microvasculature may affect Aβ clearance and perivascular drainage, promoting cerebrovascular Aβ deposition, inducing partial loss of cholinergic vascular innervation and changes in vascular function, angiogenesis and upregulation of the vesicular endothelial growth factor (VEGF) with consequences on APP processing and Aβ accumulation.
▶ Aging-related cognitive impairments are due to loss of cholinergic function. ▶ In inherited and late AD basal forebrain cholinergic cells degenerate. ▶ Mild cognitive impairment characterized by ...loss of cholinergic function – a step to AD. ▶ Intervention in cholinergic and neurotrophic signaling a useful therapeutic strategy. ▶ β-Amyloid and tau patholgy may trigger cholinergic dysfunction.
The basal forebrain cholinergic complex comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert provides the mayor cholinergic projections to the cerebral cortex and hippocampus. The cholinergic neurons of this complex have been assumed to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging.
However, the previous view of significant cholinergic cell loss during aging has been challenged. Neuronal cell loss was found predominantly in pathological aging, such as Alzheimer's disease, while normal aging is accompanied by a gradual loss of cholinergic function caused by dendritic, synaptic, and axonal degeneration as well as a decrease in trophic support. As a consequence, decrements in gene expression, impairments in intracellular signaling, and cytoskeletal transport may mediate cholinergic cell atrophy finally leading to the known age-related functional decline in the brain including aging-associated cognitive impairments.
However, in pathological situations associated with cognitive deficits, such as Parkinsons's disease, Down-syndrome, progressive supranuclear palsy, Jakob–Creutzfeld disease, Korsakoff's syndrome, traumatic brain injury, significant degenerations of basal forebrain cholinergic cells have been observed. In presenile (early onset), and in the advanced stages of late-onset Alzheimer's disease (AD), a severe loss of cortical cholinergic innervation has extensively been documented. In contrast, in patients with mild cognitive impairment (MCI, a prodromal stage of AD), and early forms of AD, apparently no cholinergic neurodegeneration but a loss of cholinergic function occurs. In particular imbalances in the expression of NGF, its precursor proNGF, the high and low NGF receptors, trkA and p75NTR, respectively, changes in acetylcholine release, high-affinity choline uptake, as well as alterations in muscarinic and nicotinic acetylcholine receptor expression may contribute to the cholinergic dysfunction. These observations support the suggestion of a key role of the cholinergic system in the functional processes that lead to AD. Malfunction of the cholinergic system may be tackled pharmacologically by intervening in cholinergic as well as neurotrophic signaling cascades that have been shown to ameliorate the cholinergic deficit at early stages of the disease, and slow-down the progression. However, in contrast to many other, dementing disorders, in AD the cholinergic dysfunctions are accompanied by the occurrence of two major histopathological hallmarks such as β-amyloid plaques and neurofibrillary tangles, provoking the question whether they play a particular role in inducing or mediating cholinergic dysfunction in AD. Indeed, there is abundant evidence that β-amyloid may trigger cholinergic dysfunction through action on α7 nicotinic acetylcholine receptors, affecting NGF signaling, mediating tau phosphorylation, interacting with acetylcholinesterase, and specifically affecting the proteome in cholinergic neurons. Therefore, an early onset of an anti β-amyloid strategy may additionally be potential in preventing aging-associated cholinergic deficits and cognitive impairments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
...this special issue aims to shed light on the physiological and pathological processes affected by epigenetic mechanisms that are involved in the regulation of neural plasticity, highlighting the ...potential diagnostic and therapeutic strategies that may become commonplace in the future. ...diet, exercise, environmental conditions, stressors or drugs can alter pathological events to benefit the patient, driving epigenetic processes that co-ordinate a number of translational processes. ...the individual's physical and social surroundings are clearly important in providing the brain with some arms to resist neurodegenerative processes, increasing resilience of paramount importance in aging processes. ...Cui et al. present a detailed genomic analysis of the differentiation of neuronal stem cells (NSCs) in outer space flights.
Abstract The main pathological hallmarks of Alzheimer's disease (AD) consist of amyloid plaques and neurofibrillary tangles. Hippocampal cell loss, atrophy and cholinergic dysfunction are also ...features of AD. The present work is aimed at studying the interactions between cholinergic denervation, APP processing and hippocampal integrity. The cholinergic immunotoxin mu p-75-saporin was injected into the 3rd ventricle of 6‐ to 8‐month-old Tg2576 mice to induce a cholinergic denervation. Four weeks after cholinergic immunolesion, a significant 14-fold increase of soluble Aβ1–42 was observed. Cholinergically lesioned Tg2576 mice showed hippocampal atrophy together with degenerating FluoroJade-B-stained neurons and reduction of synaptophysin expression in CA1–3 pyramidal layers. We also found that cholinergic denervation led to reduced levels of ADAM17 in hippocampus of Tg2576 mice. Inhibition of ADAM17 with TAPI-2 (5 μM) decreased viability of hippocampal primary neurons from Tg2576 brains and decreased phosphorylation of downstream effectors of trophic signalling (ERK and Akt). The cholinergic agonist carbachol (100 μM) rescued these effects, suggesting that cholinergic deficits might render hippocampus more vulnerable to neurotoxicity upon certain toxic environments. The present work proposes a novel model of AD that worsens the patent amyloid pathology of Tg2576 mice together with hippocampal synaptic pathology and neurodegeneration. Drugs aimed at favoring cholinergic transmission should still be considered as potential treatments of AD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Alzheimer's disease, the most common neurodegenerative disorder of senile dementia, is characterized by two major morpho-pathological hallmarks. Deposition of extracellular neuritic, beta-amyloid ...peptide-containing plaques (senile plaques) in cerebral cortical regions of Alzheimer patients is accompanied by the presence of intracellular neurofibrillary tangles in cerebral pyramidal neurons. Basal forebrain cholinergic dysfunction is also a consistent feature of Alzheimer's disease, which has been suggested to cause, at least partly, the cognitive deficits observed in patients with Alzheimer's disease. Impaired cortical cholinergic neurotransmission may also contribute to beta-amyloid plaque pathology in Alzheimer's disease by affecting expression and processing of the beta-amyloid precursor protein (APP). Vice versa, low level of soluble beta-amyloid has been observed to inhibit cholinergic synaptic function. Deposition of beta-amyloid plaques in Alzheimer's disease is also accompanied by a significant plaque-associated glial up-regulation of interleukin-1, which has been attributed to affect expression and metabolism of APP and to interfere with cholinergic transmission. Understanding the molecular mechanisms underlying the interrelationship between cortical cholinergic dysfunction, beta-amyloid formation and deposition, as well as local inflammatory upregulation, would allow to derive potential treatment strategies to pharmacologically intervene in the disease-causing signaling cascade.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The transgenic Tg2576 mouse is a widely used animal model that develops some of the cognitive and neuropathological deteriorations observed in patients suffering Alzheimer's disease. The authors ...investigated 9-month-old Tg2576 mice with respect to behavioral and endocrinological (hypothalamic-pituitary-adrenal HPA axis activity) parameters. The locomotor activity test revealed that Tg2576 mice moved almost twice as much as controls. Tg2576 mice spent significantly more time visiting the open arms and performed more entries into these open arms than did controls. However, the amount of time that Tg2576 mice remained in each entry to the open arm was similar to that of controls, and the number of arm entries correlated positively to locomotor activity. In the forced swimming test, Tg2576 mice showed a significant decrease in immobility time, which correlated negatively to locomotor activity. Parameters of the HPA axis, such as plasma level of corticosterone, adrenal gland weight, and noradrenaline or adrenaline release, did not differ between controls and Tg2576 mice. These data suggest that the disinhibitory behavior of Tg2576 mice seems to be related to increased locomotor activity but not to any disturbance of the HPA axis.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore ...the impact of NEP deficiency on the initial development of dementia-like symptoms in mice.
We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice.
Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Interleukin-1beta (IL-1β) has been implicated in various neuropathologies, while IL-1 receptor antagonist (IL-1ra) has been shown to reduce neuronal injury. We investigated the pattern of ...expression of both cytokines in murine hippocampus after trimethyltin (TMT) intoxication. Using a ribonuclease protection assay, we demonstrated induction of transcription of IL-1β and IL-1ra 3 days following TMT treatment which correlated with the peak of neuronal apoptosis. At this time, immunocytochemical staining revealed enhanced expression of both cytokines in NG2 proteoglycan expressing ameboid cells located at the site of neurotoxic insult, some of which bound also the microglial marker, lectin. There was some overlap between NG2 and lectin staining. Our results suggest that the two cytokines are involved in apoptotic processes in dentate granule cells and indicate that the pro-apoptotic effect of IL-1β prevails over the presumed protective action of IL-1ra. The novel finding of expression of both cytokines in NG2(+) cells of ameboid phenotype indicates that these cells, through the regulatory roles of pro- and anti-inflammatory cytokines, may be involved in control of neuronal death or survival after injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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