Phosphorylation of a full length amyloid-β peptide modulates its amyloid aggregation, cell binding and neurotoxic properties

2017 ◽  
Vol 13 (8) ◽  
pp. 1545-1551 ◽  
Author(s):  
Elaheh Jamasbi ◽  
Frances Separovic ◽  
Mohammed Akhter Hossain ◽  
Giuseppe Donato Ciccotosto
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Amyloid Aggregation ◽  
Cell Binding ◽  
The Brain

Phosphorylation of Aβ42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in Alzheimer's disease.

scholarly journals Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra44-332ra44 ◽  
Author(s):  
Chia-Chen Liu ◽  
Na Zhao ◽  
Yu Yamaguchi ◽  
John R. Cirrito ◽  
Takahisa Kanekiyo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Interventions ◽  
Postmortem Human Brain ◽  
Aβ Clearance ◽  
Heparan Sulfates ◽  
The Brain

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

Pathways linking Aβ and tau pathologies

2010 ◽  
Vol 38 (4) ◽  
pp. 993-995 ◽  
Author(s):  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Amyloid ◽  
Cellular Compartments

Aβ (amyloid β-peptide) and tau are the main proteins that misfold and accumulate in amyloid plaques and NFTs (neurofibrillary tangles) of Alzheimer's disease and other neurological disorders. Historically, because plaques and NFTs accumulate in diverse cellular compartments, i.e. mainly extracellularly for plaques and intracellularly for NFTs, it was long presumed that the constituent proteins formed these lesions via unrelated pathways. Animal and cell studies over the last decade, however, have provided convincing evidence to show that Aβ can facilitate the development of tau pathology by altering several cell-dependent and -independent mechanisms. In the present article, results are reviewed from several laboratories that show that modulating Aβ pathology can directly affect the development of tau pathology, which has significant implications for the treatment of Alzheimer's disease.

scholarly journals Ameliorative effects of olibanum essential oil on learning and memory in Aβ1-42-induced Alzheimer’s disease mouse model

2020 ◽  
Vol 19 (8) ◽  
pp. 1643-1651
Author(s):  
Zhenzhen Zhang ◽  
Wenhua Chen ◽  
Jie Luan ◽  
Dagui Chen ◽  
Lina Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Essential Oil ◽  
Learning And Memory ◽  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Morris Water Maze Test ◽  
Amyloid Β Peptide ◽  
Brain Tissues

Purpose: To study the effect of olibanum essential oil (OEO) on learning and memory in Alzheimer’s disease (AD) mouse.Methods: Mice were administered the 42-amino acid form of amyloid β-peptide (Aβ1-42) to induce AD and then treated with OEO at 150, 300, and 600 mg/kg, p.o. for two weeks. Following treatment, the AD mice were assessed by step-down test (SDT), dark avoidance test (DAT), and Morris water maze test (MWM). Blood and brain tissues were collected for biochemical assessments. Gas chromatographymass spectroscopy was used to analyze the main constituents of OEO.Results: The main constituents of OEO were limonene, α-pinene, and 4-terpineol. Treatment with OEO prolonged t latency in SDT and DAT, but decreased error times. Escape latency decreased and crossing times were rose in the MWM following OEO treatment (p < 0.5). Treatment with OEO also enhanced the acetylcholine levels and decreased the acetylcholinesterase levels in serum and brain tissue (p < 0.5). Additionally, OEO reduced amyloid plaques in the hippocampus and protected hippocampal neurons from damage. Furthermore, OEO decreased c-fos expression in  hippocampus tissues from AD mice (p < 0.5).Conclusion: OEO has significant ameliorative effect AD-induced deterioration in learning and memory in AD mouse induced by Aβ1-42. The mechanisms of these effects are related to increased acetylcholine contents, reduction of amyloid plaques, protection of hippocampal neurons, and downregulation of c-fos in brain tissues. The results justify the need for further investigation of candidate drugs derived from OEO for the  management of AD. Keywords: Olibanum, Essential oil, Learning, Memory, AD

The contribution of astrocytes to Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1316-1320 ◽  
Author(s):  
Amy M. Birch
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Current Evidence ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Supporting Cells ◽  
Pathological Conditions ◽  
The Brain

Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets.

scholarly journals The Neurovascular Unit Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2022 ◽  
Author(s):  
Luis O. Soto-Rojas ◽  
Mar Pacheco-Herrero ◽  
Paola A. Martínez-Gómez ◽  
B. Berenice Campa-Córdoba ◽  
Ricardo Apátiga-Pérez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Vascular Risk ◽  
Therapeutic Approaches ◽  
The Brain

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

scholarly journals Longitudinal evaluation of the natural history of amyloid-β in plasma and brain

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Samantha C Burnham ◽  
Noelia Fandos ◽  
Christopher Fowler ◽  
Virginia Pérez-Grijalba ◽  
Vincent Dore ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural History ◽  
Total Protein ◽  
Surrogate Marker ◽  
Amyloid Β ◽  
Plaque Burden ◽  
Amyloid Β Peptide ◽  
The Brain ◽  
Pet Amyloid

Abstract Plasma amyloid-β peptide concentration has recently been shown to have high accuracy to predict amyloid-β plaque burden in the brain. These amyloid-β plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer’s disease. The aim of this study was to determine how longitudinal changes in blood amyloid-β track with changes in brain amyloid-β. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer’s disease). Amyloid-β burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-β 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-β 42/40 plasma ratios and PET amyloid-β. The natural history trajectory of total protein amyloid-β 42/40 plasma ratios appears to approximately mirror that of PET amyloid-β, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-β 42/40 plasma ratios and PET amyloid-β, respectively. The trajectory of plasma amyloid-β preceded that of brain amyloid-β by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-β, support the use of plasma total protein amyloid-β 42/40 plasma ratios as a surrogate marker of brain amyloid-β. Also, that plasma total protein amyloid-β 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure.

scholarly journals Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

2015 ◽  
Vol 212 (11) ◽  
pp. 1811-1818 ◽  
Author(s):  
Stefan Prokop ◽  
Kelly R. Miller ◽  
Natalia Drost ◽  
Susann Handrick ◽  
Vidhu Mathur ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Amyloid Plaques ◽  
Full Potential ◽  
Antibody Treatment ◽  
App Processing ◽  
The Brain

Although central nervous system–resident microglia are believed to be ineffective at phagocytosing and clearing amyloid-β (Aβ), a major pathological hallmark of Alzheimer’s disease (AD), it has been suggested that peripheral myeloid cells constitute a heterogeneous cell population with greater Aβ-clearing capabilities. Here, we demonstrate that the conditional ablation of resident microglia in CD11b-HSVTK (TK) mice is followed by a rapid repopulation of the brain by peripherally derived myeloid cells. We used this system to directly assess the ability of peripheral macrophages to reduce Aβ plaque pathology and therefore depleted and replaced the pool of resident microglia with peripherally derived myeloid cells in Aβ-carrying APPPS1 mice crossed to TK mice (APPPS1;TK). Despite a nearly complete exchange of resident microglia with peripheral myeloid cells, there was no significant change in Aβ burden or APP processing in APPPS1;TK mice. Importantly, however, newly recruited peripheral myeloid cells failed to cluster around Aβ deposits. Even additional anti-Aβ antibody treatment aimed at engaging myeloid cells with amyloid plaques neither directed peripherally derived myeloid cells to amyloid plaques nor altered Aβ burden. These data demonstrate that mere recruitment of peripheral myeloid cells to the brain is insufficient in substantially clearing Aβ burden and suggest that specific additional triggers appear to be required to exploit the full potential of myeloid cell–based therapies for AD.

scholarly journals Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Jesús Enrique García-Aviles ◽  
Rebeca Méndez-Hernández ◽  
Mara A. Guzmán-Ruiz ◽  
Miguel Cruz ◽  
Natalí N. Guerrero-Vargas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficit ◽  
Amyloid Β ◽  
Sleep Restriction ◽  
Amyloid Β Peptide ◽  
Metabolic Disturbances ◽  
The Brain ◽  
Chronic Sleep

Sleep has a major role in learning, memory consolidation, and metabolic function. Although it is known that sleep restriction increases the accumulation of amyloid β peptide (Aβ) and the risk to develop Alzheimer’s disease (AD), the mechanism behind these effects remains unknown. In this review, we discuss how chronic sleep restriction induces metabolic and cognitive impairments that could result in the development of AD in late life. Here, we integrate evidence regarding mechanisms whereby metabolic signaling becomes disturbed after short or chronic sleep restriction in the context of cognitive impairment, particularly in the accumulation of Aβ in the brain. We also discuss the role of the blood-brain barrier in sleep restriction with an emphasis on the transport of metabolic signals into the brain and Aβ clearance. This review presents the unexplored possibility that the alteration of peripheral metabolic signals induced by sleep restriction, especially insulin resistance, is responsible for cognitive deficit and, subsequently, implicated in AD development.

scholarly journals Intracellular ways of development of Alzheimer's disease against the background of herpes viral infections (literature review)

2021 ◽  
Vol 26 (1) ◽  
pp. 40-46
Author(s):  
S.S. Ostrovska ◽  
V.F. Shatorna ◽  
E.O. Liholetov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Body ◽  
Tau Proteins ◽  
Postmortem Brain ◽  
Amyloid Β Peptide ◽  
Protective Effects ◽  
Increased Risk ◽  
The Brain

The concept of the viral etiology of Alzheimer's disease (AD) was first proposed in 1982. Its author MJ Ball suggested that the herpes simplex virus (HSV1) may be involved in the pathogenesis of AD, finding that the areas of the brain damaged in acute herpetic encephalitis are the same as those that are affected in AD, and those who survived usually suffer from memory loss and other cognitive impairment typical of AD. Subsequently, in all postmortem brain samples (temporal, frontal, and hippocampal) viral sequences of the viral thymidinekinase gene were found in a high proportion (70-100%) both in AD and in elderly people without it, while in young people and children the virus was found in very low proportions, so it was suggested that HSV1 comes from the peripheral ganglia, where the virus can remain inactive for many years, then enters the brain at an older age due to a decrease in the activity of the immune system. The increased risk of AD is associated with the presence of HSV1 in the brain and the carriage of a specific genetic factor – allele-ε4 of the apolipoprotein E4 gene (APOE-ε4). By themselves, neither HSV1 nor the APOE-ɛ4 allele were found as risk factors for the development of AD but their combination increased the risk of AD development by 12 times and made up 60% in patients with AD. The phenomena involved in the pathophysiology of AD are neurodegenerative changes that occur as a result of fibrillation and deposition of amyloid-β-peptide (Aβ) and neurofibrillary tangles – accumulations of aggregated phosphorylated tau-proteins (P-tau), leading to brain atrophy due to neuronal death. Traditionally, Aβ has been characterized as a catabolic by-product. However, it has recently been shown that Aβ-peptide has antiviral activity and protective effects against HSV infections in the brain. А 16-year study in Thailand with more than 33,000 patients showed that long-term use of antiherpetic drugs reduces the risk of dementia, including AD patients infected with HSV1. Patients with HSV1 infection who received antiherpetic drugs showed a lower risk of all types of dementia compared with the group without these drugs. Their positive effect on stopping the accumulation of amyloid beta and tau protein in the body has been confirmed. In this regard, it is assumed that vaccination against HSV1 may be useful not only for treatment, but also for the prevention of AD.

The p3 Peptide, a Naturally Occurring Fragment of the Amyloid-β Peptide (Aβ)Found in Alzheimer's Disease, Has a Greater Aggregation Propensity In Vitro Than Full-Length Aβ, But Does Not Bind Cu2+.

2000 ◽  
Vol 53 (4) ◽  
pp. 321 ◽  
Author(s):  
Feda Ali ◽  
Andrew J. Thompson ◽  
Colin J. Barrow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down's Syndrome ◽  
Amyloid Β ◽  
Down’S Syndrome ◽  
Full Length ◽  
Amyloid Β Peptide ◽  
Sheet Structure ◽  
Β Sheet

Cerebellar preamyloid from both Down’s syndrome and Alzheimer’s disease contains the p3 fragment (Aβ 17–40/42) as a major amyloid-β peptide (Aβ) component. The p3 peptide was previously shown to form amyloid in vitro, but less readily than full-length Aβ. Here we show that the p3 peptide has a greater β-sheet-forming propensity than full-length Aβ. Using circular dichroism spectroscopy we determined that in aqueous solutions the p3 peptide forms β-sheet structure more readily than full-length Aβ. The p3 peptide also has a lower α-helical propensity than full-length Aβ in the structure-forming solvent trifluoroethanol. These results indicate that the lower amyloidogenicity of the p3 peptide is not related to an inability to form β-sheet structure. In this study we also show that, unlike full-length Aβ, the p3 peptide does not bind Cu2+ ions. This inability to bind copper ions may explain why the p3 peptide appears to play a lesser role in Down’s syndrome and Alzheimer’s disease related neurodegeneration than does full-length Aβ.

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