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.

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.

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 α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

2019 ◽  
Vol 116 (18) ◽  
pp. 8895-8900 ◽  
Author(s):  
Dylan Shea ◽  
Cheng-Chieh Hsu ◽  
Timothy M. Bi ◽  
Natasha Paranjapye ◽  
Matthew Carter Childers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Secondary Structure ◽  
De Novo ◽  
Specific Binding ◽  
Amyloid Β ◽  
Plaque Burden ◽  
Lag Phase ◽  
Amyloid Β Peptide ◽  
Β Sheet

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

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.

scholarly journals Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

2021 ◽  
Vol 22 (7) ◽  
pp. 3654
Author(s):  
Luis O. Soto-Rojas ◽  
B. Berenice Campa-Córdoba ◽  
Charles R. Harrington ◽  
Andrés Salas-Casas ◽  
Mario Hernandes-Alejandro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Amyloid Β Peptide ◽  
Cerebral Blood Vessels ◽  
Amyloid Deposits ◽  
Cellular Components ◽  
The Brain

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD.

scholarly journals Cerebral autoregulation in Alzheimer's disease

2011 ◽  
Vol 31 (7) ◽  
pp. 1572-1577 ◽  
Author(s):  
Jurgen AHR Claassen ◽  
Rong Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Autoregulation ◽  
Perfusion Pressure ◽  
Amyloid Β ◽  
Systemic Blood Pressure ◽  
Amyloid Β Peptide ◽  
Systemic Blood ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Cerebral autoregulation aims to stabilize blood flow to the brain during variations in perfusion pressure, thus protecting the brain against the risks of low or high systemic blood pressure. This vital mechanism is severely impaired in the transgenic mouse model of Alzheimer's disease (AD) that abundantly produces amyloid-β peptide β1-42. These observations have been extrapolated to human AD, wherein impairment of autoregulation could have important implications for the clinical management and prevention of AD. Research on cerebral autoregulation in human AD, however, has only recently become available. Contrary to the animal models, preliminary studies suggest that cerebral autoregulation is preserved in patients with AD. Further research is urgently needed to elucidate this discrepancy in the current literature, given the accumulating evidence that implicates cerebrovascular pathology in AD.

scholarly journals Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

2021 ◽  
Author(s):  
Hiroki Sasaguri ◽  
Risa Takamura ◽  
Naoto Watamura ◽  
Naomasa Kakiya ◽  
Toshio Ohshima ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Association Studies ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Genome Wide Association Studies ◽  
Insulin Degrading Enzyme ◽  
Preclinical Ad ◽  
Apolipoprotein E Genotypes ◽  
The Brain

AbstractNeprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid β peptide (Aβ), the primary cause of Alzheimer’s disease (AD). However, their roles in Aβ metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and Aβ pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble Aβ whereas IDE affects soluble Aβ. A deficiency of NEP, but not of IDE, augmented the formation of Aβ plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades Aβ in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of Aβ, and of Aβ 42 and Aβ 43 in particular, the anabolism of Aβ appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic Aβ likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.

scholarly journals Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models.

2021 ◽  
Author(s):  
Aarti Patel ◽  
Ryoichi Kimura ◽  
Wen Fu ◽  
Rania Soudy ◽  
David MacTavish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Plaque Burden ◽  
Amyloid Precursor Protein Gene ◽  
Amyloid Β Peptide ◽  
Class B

Abstract Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a Class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris Water Maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

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