Selective reduction of APP-BACE1 activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PDAPP mice.
TL;DR: An antibody, 2B3, is used that binds to APP at the BACE cleavage site, inhibiting Aβ production and improves memory for object-in-place associations and working memory in a foraging task in PDAPP mice and WT mice.
About: This article is published in Neurobiology of Aging.The article was published on 2019-03-01 and is currently open access. It has received 11 citations till now.
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TL;DR: In this article, diminazene aceturate (DIZE), an established activator of ACE2, was shown to reduce hippocampal Aβ and restore cognition in mid-aged (13-14-month-old) symptomatic Tg2576 mice.
Abstract: Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer’s disease (AD). The classical renin–angiotensin system (cRAS), a physiological regulator of blood pressure, functions independently within the brain and is overactive in AD. cRAS-targeting anti-hypertensive drugs are associated with reduced incidence of AD, delayed onset of cognitive decline, and reduced levels of Aβ and tau in both animal models and human pathological studies. cRAS activity is moderated by a downstream regulatory RAS pathway (rRAS), which is underactive in AD and is strongly associated with pathological hallmarks in human AD, and cognitive decline in animal models of CNS disease. We now show that enhancement of brain ACE2 activity, a major effector of rRAS, by intraperitoneal administration of diminazene aceturate (DIZE), an established activator of ACE2, lowered hippocampal Aβ and restored cognition in mid-aged (13–14-month-old) symptomatic Tg2576 mice. We confirmed that the protective effects of DIZE were directly mediated through ACE2 and were associated with reduced hippocampal soluble Aβ42 and IL1-β levels. DIZE restored hippocampal MasR levels in conjunction with increased NMDA NR2B and downstream ERK signalling expression in hippocampal synaptosomes from Tg2576 mice. Chronic (10 weeks) administration of DIZE to pre-symptomatic 9–10-month-old Tg2576 mice, and acute (10 days) treatment in cognitively impaired 12–13-month-old mice, prevented the development of cognitive impairment. Together these data demonstrate that ACE2 enhancement protects against and reverses amyloid-related hippocampal pathology and cognitive impairment in a preclinical model of AD.
86 citations
Cites background or methods from "Selective reduction of APP-BACE1 ac..."
...We have previously shown that changes in the ratio of total:phosphorylated ERK, specifically within synaptosomes, is associated with OiP performance in PDAPP mice [51]....
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...In Experiments 1, 2 and 4, both hemispheres were dissected into cortex, hippocampus and frontal cortex and snap frozen at − 80 °C until protein extraction as previously described [51]....
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...We also found evidence of increased hippocampal expression of a subset of glutamate receptors and signalling pathways, specifically NR2B receptor and ERK, which influence performance on the OiP task performance in normal mice [51, 73]....
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...1 3 Western blotting was performed using standard methods as described previously [51]....
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TL;DR: The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington’s disease, and amyotrophic lateral sclerosis, as well as prionic diseases.
Abstract: The signaling pathway of the microtubule-associated protein kinase or extracellular regulated kinase (MAPK/ERK) is a common mechanism of extracellular information transduction from extracellular stimuli to the intracellular space The transduction of information leads to changes in the ongoing metabolic pathways and the modification of gene expression patterns In the central nervous system, ERK is expressed ubiquitously, both temporally and spatially As for the temporal ubiquity, this signaling system participates in three key moments: (i) Embryonic development; (ii) the early postnatal period; and iii) adulthood During embryonic development, the system is partly responsible for the patterning of segmentation in the encephalic vesicle through the FGF8-ERK pathway In addition, during this period, ERK directs neurogenesis migration and the final fate of neural progenitors During the early postnatal period, ERK participates in the maturation process of dendritic trees and synaptogenesis During adulthood, ERK participates in social and emotional behavior and memory processes, including long-term potentiation Alterations in mechanisms related to ERK are associated with different pathological outcomes Genetic alterations in any component of the ERK pathway result in pathologies associated with neural crest derivatives and mental dysfunctions associated with autism spectrum disorders The MAP-ERK pathway is a key element of the neuroinflammatory pathway triggered by glial cells during the development of neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, as well as prionic diseases The process triggered by MAPK/ERK activation depends on the stage of development (mature or senescence), the type of cellular element in which the pathway is activated, and the anatomic neural structure However, extensive gaps exist with regards to the targets of the phosphorylated ERK in many of these processes
68 citations
TL;DR: In this article, the authors investigated the mechanisms behind anti-AD effects of SkQ1 in OXYS rats and focused on hippocampal extracellular regulated kinases' (ERK1 and -2) activity alterations.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide, with no cure. There is growing interest in mitogen-activated protein kinases (MAPKs) as possible pathogenesis-related therapeutic targets in AD. Previously, using senescence-accelerated OXYS rats, which simulate key characteristics of the sporadic AD type, we have shown that prolonged treatment with mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) during active progression of AD-like pathology improves the activity of many signaling pathways (SPs) including the p38 MAPK SP. In this study, we continued to investigate the mechanisms behind anti-AD effects of SkQ1 in OXYS rats and focused on hippocampal extracellular regulated kinases' (ERK1 and -2) activity alterations. According to high-throughput RNA sequencing results, SkQ1 eliminated differences in the expression of eight out of nine genes involved in the ERK1/2 SP, compared to untreated control (Wistar) rats. Western blotting and immunofluorescent staining revealed that SkQ1 suppressed ERK1/2 activity via reductions in the phosphorylation of kinases ERK1/2, MEK1, and MEK2. SkQ1 decreased hyperphosphorylation of tau protein, which is present in pathological aggregates in AD. Thus, SkQ1 alleviates AD pathology by suppressing MEK1/2-ERK1/2 SP activity in the OXYS rat hippocampus and may be a promising candidate drug for human AD.
10 citations
TL;DR: The results demonstrated that ICT reduced BACE-1 levels, the contents of Aβ1-42, and the Bax/Bcl-2 ratio, suggesting that I CT might have potential therapeutic benefits by delaying or modifying the progression of AD.
Abstract: Icaritin (ICT) is the main component in the traditional Chinese herb Epimedium, and it has been shown to have anti-Alzheimer's disease (AD) effects, but its neuroprotective effects and the pharmacological mechanisms are unclear. In the present study, senescence-accelerated mouse prone 8 (SAMP8) mice were randomly divided into a model group and an ICT-treated group. Learning and memory abilities were detected by the Morris water maze assay, and the expression of amyloid beta protein (Aβ) and β-site APP cleavage enzyme 1 (BACE1) was determined by Western blotting and polymerase chain reaction (PCR). Histological changes in CA1 and CA3 were detected by hematoxylin-eosin staining (H&E staining), and the immunohistochemical analysis was used to detect the expression and localization of Bax and Bcl-2. The results showed that compared with the SAMP8 mice, the ICT-treated SAMP8 mice showed improvements in spatial learning and memory retention. In addition, the number of necrotic cells and the morphological changes in CA1 and CA3 areas were significantly alleviated in the group of ICT-treated SAMP8 mice, and the expression of BACE1, Aβ 1-42 levels, and the Bax/Bcl-2 ratio in the hippocampus was obviously decreased in the ICT-treated group compared with the control group. The results demonstrated that ICT reduced BACE-1 levels, the contents of Aβ 1-42, and the Bax/Bcl-2 ratio, suggesting that ICT might have potential therapeutic benefits by delaying or modifying the progression of AD.
10 citations
TL;DR: TA-III targets BACE1 to reduce A β aggregation through down-regulating the NMDAR/ERK pathway for treating AD and has pharmacological effects through improving memory impairment, reducing Aβ aggregation via the amyloidogenic pathway and preventing neuronal impairment through downregulatingThe NMDar/ERk signaling pathway.
6 citations
References
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TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.
12,652 citations
"Selective reduction of APP-BACE1 ac..." refers background in this paper
...The excess accumulation of b-amyloid (Ab) in the brainwith age is considered an important factor in the cascade of cellular, neural network, and cognitive changes that characterize the early stages of Alzheimer’s disease (AD) (Hardy and Selkoe, 2002; Selkoe, 2001)....
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TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Abstract: Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...
5,890 citations
"Selective reduction of APP-BACE1 ac..." refers background or result in this paper
...The excess accumulation of b-amyloid (Ab) in the brainwith age is considered an important factor in the cascade of cellular, neural network, and cognitive changes that characterize the early stages of Alzheimer’s disease (AD) (Hardy and Selkoe, 2002; Selkoe, 2001)....
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...Similar to previous studies, the age-dependent decline in associative recognition memory coincided with a rise in hippocampal Ab levels (Barker and Warburton, 2013; Good and Hale, 2007; Hale and Good, 2005; Selkoe, 2001)....
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4,479 citations
TL;DR: A new memory test in rats, based on the differential exploration of familiar and new objects, which is comparable to memory tests currently used in man and allows interspecies comparisons.
2,970 citations
TL;DR: Transgenic mice that express high levels of human mutant APP support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.
Abstract: Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.
2,669 citations
"Selective reduction of APP-BACE1 ac..." refers methods in this paper
...Male PDAPP mice (Games et al., 1995), and their WT littermates, were bred and maintained on a C57Bl/6 genetic background as previously described (Evans et al....
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