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A hallmark of Alzheimer’s disease (AD) is the aggregation of β-amyloid peptides (Aβ) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase produces Aβ of varying lengths, of which longer peptides such as Aβ42 are thought to be more harmful. Increased ratios of longer Aβs over shorter ones, exemplified by the ratio of Aβ42 over Aβ40, may lead to formation of amyloid plaques and consequent development of AD. In this study, we analyzed 138 reported mutations in human presenilin-1 (PS1) by individually reconstituting the mutant PS1 proteins into anterior-pharynx–defective protein 1 (APH-1)aL–containing γ-secretases and examining their abilities to produce Aβ42 and Aβ40 in vitro. About 90% of these mutations lead to reduced production of Aβ42 and Aβ40. Notably, 10% of these mutations result in decreased Aβ42/Aβ40 ratios. There is no statistically significant correlation between the Aβ42/Aβ40 ratio produced by a γ-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.

The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ 42 ), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau 181 ) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer’s Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ 42 to Aβ 40 (Aβ 42/40 Ratio) has been suggested to be superior to the concentration of Aβ 42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ 42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ 42/40 ratio, rather than the absolute value of CSF Aβ 42 , should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.

INTRODUCTION:Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ42 and Aβ40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.METHODS:One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included.RESULTS:Plasma Aβ1-42 and Aβ1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aβ1-42 and P = .04 for Aβ1-40). Globally, plasma Aβ1-42 correlated with age, Mini-Mental State Examination, and APOE ε4 allele. Plasma Aβ1-42 correlated with all CSF biomarkers in MCI but only with CSF Aβ42 in AD.DISCUSSION:Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aβ deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.

Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer disease (LOAD) by regulating several molecular processes such as cholesterol metabolism and amyloid processing and clearance. In this review we shed light on these new functions and their cross-talk, explaining its implication in brain functioning, and therefore in AD onset and development.

The electrochemical response of α/β‐peptides with (L‐Ala‐β‐Fpg)n sequence, where β‐Fpg refers to syn 3‐amino‐2‐(2‐fluorophenyl)‐3‐phenylpropanoic acid, has been investigated examining the effects of the peptide length (n = 1–3), the stereochemistry of the β2,3‐diaryl‐amino acid and their self‐assembly. α/β‐Peptides have been deposited by drop‐casting on a conducting polymer (CP) film, which is previously electropolymerized on a stainless steel conducting substrate. The current‐potential response of the CP coated by the different studied peptides suggests that, for α/β‐peptides, the role played by the electron transport through intermolecular stacking of aromatic side groups prevails over peptide length and stereochemistry. In order to prove such a hypothesis, the experimental conditions used to achieve an ordered self‐assembly are optimized for one of the α/β‐peptides. The achieved self‐assembled structures, which consist of well‐defined long microfibers, considerably improve the electrochemical response of the CP. Finally, the prepared α/β‐peptide‐based electrodes are used to electrochemically detect the oxidation of nicotinamide adenine dinucleotide (NADH). The analytical parameters are better for electrodes with well‐defined peptide microfibers than for uncoated CP, corroborating the importance of π‐π stacking interactions in the response of α/β‐peptides. The electrochemical response of α/β‐peptides with (L‐Ala‐β‐Fpg)n sequence, where β‐Fpg refers to syn 3‐amino‐2‐(2‐fluorophenyl)‐3‐phenylpropanoic acid, is investigated, analyzing the effects of the peptide length, the stereochemistry of the β2,3‐diaryl‐amino acid and the self‐assembly. Furthermore, the prepared α/β‐peptide‐based electrodes are used to electrochemically detect the oxidation of nicotinamide adenine dinucleotide (NADH).

MicroRNAs (miRNAs) are associated with amyloid‐β (Aβ) dysmetabolism, a pivotal factor in the pathogenesis of Alzheimer's disease (AD). This study unveiled a novel miRNA, microRNA‐32533 (miR‐32533), featuring a distinctive base sequence identified through RNA sequencing of the APPswe/PSEN1dE9 (APP/PS1) mouse brain. Its role and underlying mechanisms were subsequently explored. Bioinformatics and confirmatory experiments revealed that miR‐32533 had a novel 23‐base sequence with minimal coding potential, functioning within the Drosha ribonuclease III (Drosha)/Dicer 1, ribonuclease III (Dicer)‐dependent canonical pathway and identifiable via northern blot. miR‐32533 was abundantly brain‐distributed and downregulated in diverse AD‐related models, including APP/PS1 and five familial AD (5×FAD) mouse brains and AD patient plasma. Overexpression or inhibition of miR‐32533 led to improvements or exacerbations in cognitive dysfunction, respectively, by modulating Aβ production, apoptosis, oxidation, and neuroinflammation through targeting cAMP‐responsive element binding protein 5 (CREB5), which interacted with α disintegrin and metalloproteinase 10 (ADAM10), beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1), and presenilin 1 (PS1) promoters, thereby enhancing Aβ production through BACE1 and PS1 upregulation while suppressing non‐amyloidogenic amyloid precursor protein (APP) processing via ADAM10 downregulation. Furthermore, modulation of the miR‐32533/CREB5 axis ameliorated or worsened cognitive impairment by inhibiting or amplifying Aβ overproduction through the BACE1‐involved amyloidogenic and ADAM10‐involved non‐amyloidogenic pathways. Overall, the findings suggest miR‐32533 as a regulator of Aβ metabolism, oxidative stress, and neuroinflammation, establishing the miR‐32533/CREB5 signaling pathways as potential therapeutic targets for combating Aβ accumulation and cognitive deficits in AD. microRNA‐32533 (miR‐32533), a novel 23‐base sequence non‐coding RNA, improves Alzheimer's disease (AD)‐like cognitive impairment and inhibits amyloid‐β (Aβ) overload by regulating the beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1)‐involved amyloidogenic and α disintegrin and metalloproteinase 10 (ADAM10)‐involved non‐amyloidogenic pathways through its direct target cAMP‐responsive element binding protein 5 (CREB5) and downstream transcriptional machinery. The novel miR‐32533/CREB5 signaling cascade represents a promising therapeutic avenue to combat Aβ toxicity, oxidative stress, and neuroinflammation in AD.

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer’s disease (AD). Full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4–x peptides being particularly abundant. Aβ4–x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4–x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4–40 but unchanged levels of Aβ1–x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4–x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4−/− knockout background, Aβ4–40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4–40 peptides were absent in cultures derived from ADAMTS4−/− mice indicating that the enzyme was essential for Aβ4–x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4–x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.

Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8-dihydroguanine (8-oxoG) in mRNA, which can cause base mispairing during gene expression. Here we found that administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using secondgeneration sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid β peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions.

Alzheimer’s disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals’ accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.