ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease
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.
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TL;DR: The SARS-CoV-2 infection is likely from a zoonotic source and people with the infection may shed it while suggestive or asymptomatic, and clinical manifestations change generally.
Abstract: The SARS-CoV-2 infection is likely from a zoonotic source. Transmissibility between people happens principally
through beads and surface contacts. People with the infection may shed it while suggestive or asymptomatic. Despite
the fact that brooding period is as long as 12 days, middle term of viral shedding can be as long as 20 days. Clinical
manifestations change generally and might be mellow (80%), moderate (15%), or serious (5%).
183 citations
TL;DR: The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.
Abstract: The gateway for invasion by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human host cells is via the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor expressed in multiple immune and nonimmune cell types. SARS-CoV-2, that causes coronavirus disease 2019 (COVID-19; CoV-19) has the unusual capacity to attack many different types of human host cells simultaneously via novel clathrin- and caveolae-independent endocytic pathways, becoming injurious to diverse cells, tissues and organ systems and exploiting any immune weakness in the host. The elicitation of this multipronged attack explains in part the severity and extensive variety of signs and symptoms observed in CoV-19 patients. To further our understanding of the mechanism and pathways of SARS-CoV-2 infection and susceptibility of specific cell- and tissue-types and organ systems to SARS-CoV-2 attack in this communication we analyzed ACE2 expression in 85 human tissues including 21 different brain regions, 7 fetal tissues and 8 controls. Besides strong ACE2 expression in respiratory, digestive, renal-excretory and reproductive cells, high ACE2 expression was also found in the amygdala, cerebral cortex and brainstem. The highest ACE2 expression level was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers of the brain, and may in part explain the susceptibility of many CoV-19 patients to severe respiratory distress.
124 citations
TL;DR: In this article, the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons.
Abstract: COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence of central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It is unclear how much of the ischaemic damage is mediated by direct or inflammatory effects of virus on the CNS vasculature and how much is secondary to extracranial cardiorespiratory disease. Limited data suggest that the causative SARS-CoV-2 virus may enter the CNS via the nasal mucosa and olfactory fibres, or by haematogenous spread, and is capable of infecting endothelial cells, pericytes and probably neurons. Extracranially, SARS-CoV-2 targets endothelial cells and pericytes, causing endothelial cell dysfunction, vascular leakage and immune activation, sometimes leading to disseminated intravascular coagulation. It remains to be confirmed whether endothelial cells and pericytes in the cerebral vasculature are similarly targeted. Several aspects of COVID-19 are likely to impact on cognition. Cerebral white matter is particularly vulnerable to ischaemic damage in COVID-19 and is also critically important for cognitive function. There is accumulating evidence that cerebral hypoperfusion accelerates amyloid-β (Aβ) accumulation and is linked to tau and TDP-43 pathology, and by inducing phosphorylation of α-synuclein at serine-129, ischaemia may also increase the risk of development of Lewy body disease. Current therapies for COVID-19 are understandably focused on supporting respiratory function, preventing thrombosis and reducing immune activation. Since angiotensin-converting enzyme (ACE)-2 is a receptor for SARS-CoV-2, and ACE inhibitors and angiotensin receptor blockers are predicted to increase ACE-2 expression, it was initially feared that their use might exacerbate COVID-19. Recent meta-analyses have instead suggested that these medications are protective. This is perhaps because SARS-CoV-2 entry may deplete ACE-2, tipping the balance towards angiotensin II-ACE-1-mediated classical RAS activation: exacerbating hypoperfusion and promoting inflammation. It may be relevant that APOE e4 individuals, who seem to be at increased risk of COVID-19, also have lowest ACE-2 activity. COVID-19 is likely to leave an unexpected legacy of long-term neurological complications in a significant number of survivors. Cognitive follow-up of COVID-19 patients will be important, especially in patients who develop cerebrovascular and neurological complications during the acute illness.
120 citations
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: To confirm the neuro-invasive property of SARS-CoV-2 and the subsequent influence on patients will require further exploration by both virologist and neurologist.
Abstract: SARS-CoV-2 is a novel coronavirus leading to serious respiratory disease and is spreading around the world at a raging speed. Recently there is emerging speculations that the central nervous system (CNS) may be involved during SARS-CoV-2 infection, contributing to the respiratory failure. However, the existence of viral replication in CNS has not been confirmed due to the lack of evidence from autopsy specimens. Considering the tropism of SARS-CoV-2, ACE2, is prevailing in CNS, and the neuro-invasive property of human coronavirus was widely reported, there is a need to identified the possible complications during COVID-19 for CNS. In this review, we conduct a detailed summary for the potential of SARS-CoV-2 to infect central nervous system from latest biological fundamental of SARS-CoV-2 to the clinical experience of other human coronaviruses. To confirm the neuro-invasive property of SARS-CoV-2 and the subsequent influence on patients will require further exploration by both virologist and neurologist.
41 citations
Cites background from "ACE2 activation protects against co..."
...The latest research also revealed that the ACE2 in brain not only responsible for the body blood pressure regulation, but also present a protective profile for the brain itself in a series of neurologic pathologies, including aging-related neuroinflammation (45), focal cerebral ischemia (46), demyelinating disease (47), Alzheimer’s disease (48), and neuropsychiatric disorders (49)....
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References
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TL;DR: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory but showed impairment by 9 to 10 months of age.
Abstract: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
4,327 citations
"ACE2 activation protects against co..." refers methods in this paper
...Tg2576 mice expressing the human APP695Swe mutation were maintained on a hybrid C57Bl/6 × SJL background [42]....
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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
"ACE2 activation protects against co..." refers methods in this paper
...Object exploration was defined according to the methods described previously by Ennaceur and Delacour (1988)....
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TL;DR: Findings identify Mas as a functional receptor for Ang-(1–7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.
Abstract: The renin-angiotensin system plays a critical role in blood pressure control and body fluid and electrolyte homeostasis. Besides angiotensin (Ang) II, other Ang peptides, such as Ang III [Ang-(2-8)], Ang IV [Ang-(3-8)], and Ang-(1-7) may also have important biological activities. Ang-(1-7) has become an angiotensin of interest in the past few years, because its cardiovascular and baroreflex actions counteract those of Ang II. Unique angiotensin-binding sites specific for this heptapeptide and studies with a selective Ang-(1-7) antagonist indicated the existence of a distinct Ang-(1-7) receptor. We demonstrate that genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene abolishes the binding of Ang-(1-7) to mouse kidneys. Accordingly, Mas-deficient mice completely lack the antidiuretic action of Ang-(1-7) after an acute water load. Ang-(1-7) binds to Mas-transfected cells and elicits arachidonic acid release. Furthermore, Mas-deficient aortas lose their Ang-(1-7)-induced relaxation response. Collectively, these findings identify Mas as a functional receptor for Ang-(1-7) and provide a clear molecular basis for the physiological actions of this biologically active peptide.
1,639 citations
TL;DR: It is shown that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR), which uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity.
1,611 citations
TL;DR: The physiological role of ACE2 is elucidated, and its catalytic activity was characterized, and a consensus sequence of: Pro-X (1–3 residues)-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid is revealed.
1,316 citations
"ACE2 activation protects against co..." refers background in this paper
...N convert Ang-II (and Ang-III) into smaller bioactive fragments, most commonly Ang-1–7 and Ang-IV, reducing Ang-II associated cRAS signalling via AT1R....
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...Specifically, ACE2 activity, predominantly involved in the conversion of Ang-II to Ang-(1–7) [37, 38], was reduced by almost 50% in AD cases, which was significantly related to Aβ and Tau levels [35]....
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