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Abstract: Neurotoxicity of amyloid β (Aβ) plays an important role in Alzheimer's disease (AD) pathogenesis. In this study, we researched the potential protective effects of resistin against Aβ neurotoxicity in mouse Neuro2a (N2a) cells transfected with the Swedish amyloid precursor protein (Sw-APP) mutant and Presenilin exon 9 deletion mutant (N2a/D9), which overproduced Aβ with abnormal intracellular Aβ accumulation. The results show increased levels of ROS, NO, protein carbonyls, and 4HNE in N2a/D9 cells, which were attenuated by resistin treatment in a dose dependent manner. We also found that resistin could improve mitochondrial function in N2a/D9 cells through increasing the level of ATP and mitochondrial membrane potential. MTT and LDH assay indicated that N2a/D9 cells show increased vulnerability to H2O2-induced insult, which could be ameliorated by resistin. Mechanically, we found that resistin prevented apoptosis signals through reducing the ratio of Bax/Bcl2, the level of cleaved caspase-3, and attenuating cytochrome C release. Finally, the results demonstrated that resistin did not change the production of Aβ1–40 and Aβ1–42 in N2a/D9 cells, which suggests that the protective effects of resistin are independent of APP metabolism. This raises the possibility of novel AD therapies using resistin. [Copyright &y& Elsevier]

Abstract: We have investigated the effect of IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one), a coumarin derivative, on the amyloid beta (Aβ)-induced neurotoxicity in primary culture cortical neurons and pheochromocytoma (PC12) cells. Our results showed that treatment with IMM-H004 markedly reduced the number of apoptotic cells after exposure to Aβ25–35 or Aβ1–42, determined by MTT, TUNEL staining and Flow cytometry. Further study indicated that IMM-H004 significantly inhibited Aβ-induced cytotoxicity and apoptosis by reversing Aβ-induced mitochondrial dysfunction, including MMP (mitochondrial membrane potential) decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. IMM-H004 can regulate the interaction between Bax and Bcl-2, decreased levels of p53 and active caspase-3 protein induced by Aβ25–35. Furthermore, IMM-H004 also reduced translocation of AIF (apoptosis-inducing factor) induced by Aβ25–35. These results demonstrated that IMM-H004 was capable of protecting neuronal cells from Aβ-induced degeneration through a mitochondrial-dependent apoptotic pathway. The results of this study lend further credence to the notion that IMM-H004 is a ‘multipotent therapeutic agrent’ that reduces toxic levels of brain Aβ, and holds the potential to protect neuronal mitochondrial function in Alzheimer’s disease. [Copyright &y& Elsevier]

Abstract: Amyloid precursor protein (APP) derived amyloid beta (Aβ) peptides have been extensively investigated in Alzheimer's disease pathology of the brain. However, the function of full length APP in the central nervous system remains unclear. Even less is known about the function of this ubiquitously expressed protein and its metabolites outside of the central nervous system. This review summarizes key aspects of the current understanding of the expression and function of APP and its proteolytic fragments in specific non-neuronal tissues. [Copyright &y& Elsevier]

Highlights: [•] We develop a multiple reaction monitoring (MRM) assay for possible Alzheimer's disease biomarkers. [•] MRM assay offers good linearity for peptide analytes of interest. [•] MRM assay results are similar to results from ELISA assays. [Copyright &y& Elsevier]

Highlights: [•] Phenolic compounds in wild plants and in vitro cultures of L. viridis extracts. [•] In vitro cultures accumulate high amounts of rosmarinic acid. [•] L. viridis metabolites have antioxidant and anti-cholinesterase activities. [•] The extraction solvent influences the recovery of phenolic compounds and biological activity. [Copyright &y& Elsevier]

Abstract: The importance of the complement system in Alzheimer's disease (AD) pathogenesis has been emphasized through recent genome wide association studies. However, the cellular and molecular role of these complement proteins is not fully understood. Microglia express complement receptors and the activation of specific receptors may increase Aβ clearance and reduce neurodegeneration. Here, we investigated the contribution of complement receptor 1 (CR1), the second most significant hit in GWAS studies, on microglia to neuronal damage. We show that microglia displaying an activated phenotype demonstrate an increase in CR1 expression. We also provide evidence that activation of microglial CR1 was detrimental to neurons and this correlated with an increase in microglial intracellular superoxide generation, and tumour necrosis factor-α (TNFα) and interleukin-1 β (IL-1β) secretion. Amyloid-β 42 (Aβ1–42)-treated microglia displayed an increased ability to phagocytose dextran beads following antibody blockage of CR1 but a decreased capacity to phagocytose fluorescent-tagged Aβ1–42. Together, these results indicate that microglial CR1 plays a role in the neuronal death observed in AD and investigating this further may provide a possible strategy to control neurotoxicity in the AD brain. [Copyright &y& Elsevier]

Abstract: Amyloid beta (Aβ) peptides, produced through endo-proteolytic cleavage of amyloid precursor protein, are thought to be involved in the death of neural cells in Alzheimer''s disease (AD). Although the mechanisms are not fully known, it has been suggested that disruption of cellular activity due to Aβ interactions with the cell membrane may be one of the underlying causes. Here in, we have investigated the interaction between Aβ-42 and biomimetic lipid membranes and the resulting perturbations in the lipid vesicles. We have shown that Aβ oligomeric species localized closer to the membrane surface. Localization of the fibrillar species of Aβ-42, although varied, was not as closely associated with the membrane surface. We have demonstrated that the presence of Aβ-42 leads to an increase in membrane surface area, inducing lipid temporal vesicular transformation. Furthermore, we have unequivocally shown that Aβ-peptides mediate membrane fusion. Although membrane fusion induced by Aβ has been hypothesized/proposed, this is the first time it has been visually captured. This fusion may be one of the mechanisms behind the membrane increase in surface area and the resulting vesicular transformation. We have shown that the longer ‘amyloidogenic’ isoform causes vesicular transformation more readily, and has a higher membrane fusogenic potential than Aβ-40. Although not core to this study, it is hugely interesting to observe the high agreement between membrane dynamics and the reported amyloidogenicity of the peptides and aggregation species opening up the potential role of vesicular dynamics for profiling and biosensing of Aβ-induced neuro-toxicity. [Copyright &y& Elsevier]

Abstract: Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some non-catalytic functions in the brain which are far less well characterised. AChE was shown to be secreted or shed from the neuronal cell surface like several other membrane proteins, such as the amyloid precursor protein (APP). Since AChE does not possess a transmembrane domain, its anchorage in the membrane is established via the Proline Rich Membrane Anchor (PRiMA), a transmembrane protein. Both the subunit oligomerisation and membrane anchor of AChE are shared by a related enzyme, butyrylcholinesterase (BChE), the physiological function of which in the brain is unclear. In this work, we have assayed the relative activities of AChE and BChE in membrane fractions and culture medium of three different neuronal cell lines, namely the neuroblastoma cell lines SH-SY5Y and NB7 and the mouse basal forebrain cell line SN56. In an effort to understand the shedding process of AChE, we have used several pharmacological treatments, which showed that it is likely to be mediated in part by an EDTA- and batimastat-sensitive, but GM6001-insensitive metalloprotease, with the possible additional involvement of a thiol isomerase. Cellular release of AChE by SH-SY5Y is significantly enhanced by the muscarinic acetylcholine receptor (mAChR) agonists carbachol or muscarine, with the effect of carbachol blocked by the mAChR antagonist atropine. AChE has been implicated in the pathogenesis of Alzheimer’s disease and it has been shown that it accelerates formation and increases toxicity of amyloid fibrils, which have been closely linked to the pathology of AD. In light of this, greater understanding of AChE and BChE physiology may also benefit AD research. [Copyright &y& Elsevier]

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18 F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer's disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings., Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ ( 18 F-NAV4694) and tau ( 18 F-MK6240) PET scans were included. Centiloid <25 defined negative Aβ PET (Aβ-). The presence of neocortical tau was defined quantitatively and visually., Results: Aβ- PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2 , and MAPT genes did not identify relevant functional mutations., Discussion: Discordant cases were infrequent (1.4% of all Aβ- participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present., Competing Interests: This work was supported by the National Health and Medical Research Council (NHMRC) (grant numbers APP1140853, APP1132604). Natasha Krishnadas was supported by a cofunded PhD scholarship from Australian Rotary Health and the Estate of Bartolina Peluso. Simon M. Laws has received institutionally administered grants as follows: NHMRC APP1151854, APP1161706, APP1191535, APP2001320, APP2007656; Department of Health (Government of Western Australia) ‐ Multiple Sclerosis Western Australia ‐ Australian Alzheimer's Research Foundation ‐ Edith Cowan University, Strategic Research Centre Support ‐ Florey Institute of Neuroscience and Mental Health. Simon M. Laws has participated on the Cytox Group Ltd ‐ Scientific Advisory Board (pro bono). Victor L Villemagne has received consulting fees from IXICO, Eli Lilly, Life molecular imaging, and Hospicom, and has received payment/honoraria from ACE Barcelona. Christopher C. Rowe has received grants from Cerveau Technologies (institution), Eisai (institution), and Biogen (institution). Christopher C. Rowe has received consulting fees from Nutricia (speaker fee), Prothera, and Biogen (for preparation of educational material). Christopher C. Rowe has participated on a data safety board/advisory board for Cerveau Technologies (unpaid). Vincent Doré, Tenielle Porter, Fiona Lamb, and Svetlana Bozinovski do not report any disclosures., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Abstract: Hydrogenation of oils and diary products of ruminant animals leads to an increasing amount of trans fatty acids in the human diet. Trans fatty acids are incorporated in several lipids and accumulate in the membrane of cells. Here we systematically investigate whether the regulated intramembrane proteolysis of the amyloid precursor protein (APP) is affected by trans fatty acids compared to the cis conformation. Our experiments clearly show that trans fatty acids compared to cis fatty acids increase amyloidogenic and decrease nonamyloidogenic processing of APP, resulting in an increased production of amyloid beta (Aβ) peptides, main components of senile plaques, which are a characteristic neuropathological hallmark for Alzheimer''s disease (AD). Moreover, our results show that oligomerization and aggregation of Aβ are increased by trans fatty acids. The mechanisms identified by this in vitro study suggest that the intake of trans fatty acids potentially increases the AD risk or causes an earlier onset of the disease. [Copyright &y& Elsevier]

Anomalous action of human acetylcholinesterase (hAChE) in Alzheimer's disease (AD) was restrained by various AChE inhibitors, of which the specific and potent lead candidate Donepezil is used for treating the disease AD. Besides the specificity, the observed undesirable side effects caused by Donepezil invoked the quest for new lead molecules with the increased potency and specificity for AChE. The present study elucidates the potency of six 1 N-methyl-1 S-methyl-2-nitroethylene (NMSM) derivatives to form a specific interaction with the peripheral anionic site and catalytic anionic subsite residues of hAChE. The NMSMs were prepared in good yield from 1,1-di(methylsulfanyl)-2-nitroethylene and primary amine (or) amino acid esters. In silico interaction analysis reveals specific and potent interactions between hAChE and selected ligand molecules. The site-specific interactions formed between these molecules also results in a conformational change in the orientation of active site residues of hAChE, which prevents them from being accessed by beta-amyloid protein (Aβ), which is a causative agent for amyloid plaque formation and acetylcholine (ACh). In silico interaction analysis between the ligand-bounded hAChE with Aß and ACh confirms this observation. The variation in the conformation of hAChE associated with the decreased ability of Aβ and ACh to access the respective functional residues of hAChE induced by the novel NMSMs favors their selection for in vivo analysis to present themselves as new members of hAChE inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Deposition of amyloid-β-peptide (Aβ) in the brain is considered a pathological hallmark of Alzheimer''s disease (AD). Our previous studies show that Yes-associated protein (YAP) is involved in the regulation of apoptosis induced by Aβ25–35 through YAP nuclear translocation and its pro-apoptotic function is mediated by its interaction with p73. In the present study, we first found that Low-power laser irradiation (LPLI) promoted YAP cytoplasmic translocation and inhibited Aβ25–35-induced YAP nuclear translocation. Moreover, the cytoplasmic translocation was in an Akt-dependent manner. Activated Akt by LPLI phosphorylated YAP on ser127 (S127) and resulted in decreasing the interaction between YAP and p73, and in suppressing the proapoptotic gene bax expression following Aβ25–35 treatment. Inhibition of Akt expression by siRNA significantly abolished the effect of LPLI. More importantly, LPLI could inhibit Aβ25–35-induced cell apoptosis through activation of Akt/YAP/p73 signaling pathway. Therefore, our findings first suggest that YAP may be a therapeutic target and these results directly point to a potential therapeutic strategy for the treatment of AD through Akt/YAP/p73 signaling pathway with LPLI. [Copyright &y& Elsevier]

Background: The accumulation of amyloid beta (Aβ) oligomers or fibrils is thought to be one of the main causes of synaptic and neuron loss, believed to underlie cognitive dysfunction in Alzheimer's disease (AD). Neuron loss has rarely been documented in amyloid precursor protein (APP) transgenic mouse models. We investigated whether two APP mouse models characterized by different folding states of amyloid showed different neuronal densities using an accurate method of cell counting.Findings: We examined total cell and neuronal populations in Swedish/Indiana APP mutant mice (TgCRND8) with severe Aβpathology that includes fibrils, plaques, and oligomers, and Dutch APP mutant mice with only Aβ oligomer pathology. Using the isotropic fractionator, we found no differences from control mice in regional total cell populations in either TgCRND8 or Dutch mice. However, there were 31.8% fewer hippocampal neurons in TgCRND8 compared to controls, while no such changes were observed in Dutch mice. Conclusions: We show that the isotropic fractionator is a convenient method for estimating neuronal content in milligram quantities of brain tissue and represents a useful tool to assess cell loss efficiently in transgenic models with different types of neuropathology. Our data support the hypothesis that TgCRND8 mice with a spectrum of Aβ plaque, fibril, and oligomer pathology exhibit neuronal loss whereas Dutch mice with only oligomers, showed no evidence for neuronal loss. This suggests that the combination of plaques, fibrils, and oligomers causes more damage to mouse hippocampal neurons than Aβ oligomers alone. [ABSTRACT FROM AUTHOR]

Background: The Aβ peptide that accumulates in Alzheimer's disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by β- and γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Aβ production. Results: In this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Aβ, while knockdown of LRP10 expression increases Aβ production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP β-cleavage into Aβ. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD. Conclusions: The present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: Critical events in Alzheimer’s disease (AD) involve an imbalance between the production and clearance of amyloid beta (Aβ) peptides from the brain. Current methods for Aβ quantitation rely heavily on immuno-based techniques. However, these assays require highly specific antibodies and reagents that are time-consuming and expensive to develop. Immuno-based assays are also characterized by poor dynamic ranges, cross-reactivity, matrix interferences, and dilution linearity problems. In particular, noncommercial immunoassays are especially subject to high intra- and interassay variability because they are not subject to more stringent manufacturing controls. Combinations of these factors make immunoassays more labor-intensive and often challenging to validate in support of clinical studies. Here we describe a mixed-mode solid-phase extraction method and an ultra-performance liquid chromatography tandem mass spectrometry (SPE UPLC–MS/MS) assay for the simultaneous quantitation of Aβ1–38, Aβ1–40, and Aβ1–42 from human cerebrospinal fluid (CSF). Negative ion versus positive ion species were compared using their corresponding multiple reaction monitoring (MRM) transitions, and negative ions were approximately 1.6-fold greater in intensity but lacked selectivity in matrix. The positive ion MRM assay was more than sufficient to quantify endogenous Aβ peptides. Aβ standards were prepared in artificial CSF containing 5% rat plasma, and quality control samples were prepared in three pooled CSF sources. Extraction efficiency was greater than 80% for all three peptides, and the coefficient of variation during analysis was less than 15% for all species. Mean basal levels of Aβ species from three CSF pools were 1.64, 2.17, and 1.26ng/ml for Aβ1–38; 3.24, 3.63, and 2.55ng/ml for Aβ1–40; and 0.50, 0.63, and 0.46ng/ml for Aβ1–42. [Copyright &y& Elsevier]

Abstract: Amyloid β (Aβ) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD), and nanoparticles functionalized with Aβ-specific ligands are considered promising vehicles for imaging probes and therapeutic agents. Herein, we characterized the binding properties of nanoliposomes decorated with an anti-Aβ monoclonal antibody (Aβ-MAb). The Aβ-MAb was obtained in mice by immunization with Aβ antigen followed by hybridoma fusion. Surface Plasmon Resonance (SPR) studies confirmed the very high affinity of purified Aβ-MAb for both Aβ monomers and fibrils (K D = 0.08 and 0.13 nm, respectively). The affinity of the biotinylated Aβ-MAb, used thereafter for liposome decoration, was lower although still in the low nanomolar range (K D = 2.1 and 1.6 nm, respectively). Biotin-streptavidin ligation method was used to decorate nanoliposomes with Aβ-MAb, at different densities. IgG-decorated liposomes were generated by the same methodology, as control. Vesicles were monodisperse with mean diameters 124–134 nm and demonstrated good colloidal stability and integrity when incubated with serum proteins. When studied by SPR, Aβ-MAb-liposomes, but not IgG-liposomes, markedly bound to Aβ monomers and fibrils, immobilized on the chip. KD values (calculated on Aβ-MAb content) were about 0.5 and 2 nm with liposomes at high and low Aβ-MAb density, respectively. Aβ-MAb-liposome binding to Aβ fibrils was additionally confirmed by ultracentrifugation technique, in which interactions occur in solution under physiological conditions. Moreover, Aβ-MAb-liposomes bound amyloid deposits in post-mortem AD brain samples, confirming the potential of these nanoparticles for the diagnosis and therapy of AD. [Copyright &y& Elsevier]

umulation of amyloid-β-peptide (Aβ) in the brain is considered as a pathological hallmark of Alzheimer's disease (AD). Previous studies show that p73 is vital for mediating the pathogenic process of AD. Yes-associated protein (YAP) has been shown to positively regulate p73 in promoting apoptosis induced by anti-cancer agents. However, the functional role of YAP and potential relationship between YAP and p73 in AD are unknown. In the present study, we found that YAP accelerated apoptosis in response to Aβ and the nuclear translocation of YAP was involved in cellular signals that regulated the apoptosis. Aβ induced YAP translocation from cytoplasm to nucleus accompanied with the increased phosphorylation on Y357, resulting in the enhancement of interaction between YAP and p73. Moreover, inhibition of YAP expression by small hairpin RNA (shRNA) suppressed apoptosis induced by Aβ. More importantly, p73-mediated induction of Bax expression and activation were in a YAP-dependent manner. Overexpression of YAP accelerated Bax translocation, upregulated Bax expression and promoted caspase-3 activation. Taken together, our findings first demonstrated that YAP accelerated Aβ-induced apoptosis through nucleus translocation, leading to the induction of Bax expression and activation. Our results provided a potential therapeutic strategy for the treatment of AD through inhibiting YAP/p73/Bax pathway. [ABSTRACT FROM AUTHOR]

Abstract: A systematic computational density functional theory (DFT) study was carried out in amyloid-beta (Aβ) structure to investigate the hydrogen bonding interactions (HBs) effects on Chemical shielding (CS) and electric field gradient (EFG) tensors in site of hydrogen, oxygen, nitrogen and carbon nuclei. The results indicate that these tensors are more sensitive to the HB interactions in dimer model than those of trimer model. The calculated 15N and 13C in CS tensors in trimer model are in good agreement with experimental data. Natural bonding orbital analysis, NBO, indicate a reasonable correlation between 14N quadrupole coupling constant (CQ ) and strength of Fock matrix elements (Fij ). Moreover, the quantum chemical calculations indicated that the intermolecular the HB interactions play an essential role in variation of the relative orientation of CS and EFG tensors of nitrogen, hydrogen and oxygen nuclei in the molecular frame axes. Finally, 17O CQ and ηQ show great dependency to backbone conformation, specifically dihedral angles ψ (psi). [ABSTRACT FROM AUTHOR]

Abstract: Amyloid β (Aβ) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD). It has been previously shown that curcumin targets Aβ plaques and interferes with their formation, suggesting a potential role for prevention or treatment of AD. Herein, a click chemistry method was used to generate nanoliposomes decorated with a curcumin derivative, designed to maintain the planar structure required for interaction with Aβ, as directly confirmed by Surface Plasmon Resonance experiments. Another type of liposomes was formed starting from curcumin-phospholipid conjugate, in which the planar structure of curcumin is disrupted. Both types of generated curcumin-decorated vesicles had mean diameters in the nano range (131–207 nm) and slightly negative ζ-potential values according to their lipid composition, and were stable for periods up to 20 days. They also demonstrated high integrity during incubation in presence of plasma proteins. Surface Plasmon Resonance experiments, measuring the binding of flowing liposomes to immobilized Aβ1-42, indicated that the liposomes exposing the curcumin derivative (maintaining the planarity) have extremely high affinity for Aβ1-42 fibrils (1–5 nM), likely because of the occurrence of multivalent interactions, whereas those exposing non-planar curcumin did not bind to Aβ1-42. In summary, we describe here the preparation and characterization of new nanoparticles with a very high affinity for Aβ1-42 fibrils, to be exploited as vectors for the targeted delivery of new diagnostic and therapeutic molecules for AD. [Copyright &y& Elsevier]

Abstract: Amyloid beta (Aβ) is a metabolic product of amyloid-β precursor protein (APP). Deposition of Aβ in the brain and neuronal degeneration are characteristic hallmarks of Alzheimer''s disease (AD). Aβ induces neuronal degeneration, but the mechanism of neurotoxicity remains elusive. Here we show that overexpression of APP renders hippocampal neurons vulnerable to Aβ toxicity. Deletion of the extracellular Aβ sequence of APP prevents binding of APP to Aβ, and abolishes toxicity. Aβ toxicity is also abrogated by deletion of the cytoplasmic domain of APP, or by deletions comprising the Go protein-binding sequence of APP. Treatment with Pertussis toxin (PTX) abrogates APP-dependent toxicity of Aβ. Overexpression of PTX-insensitive Gα-o subunit, but not Gα-i subunit, of G protein restores Aβ toxicity in the presence of PTX, and this requires the integrity of APP-binding site for Go protein. Altogether, these experiments indicate that interaction of APP with toxic Aβ-species promotes toxicity in hippocampal neurons by a mechanism that involves APP-mediated Go protein activation, revealing an Aβ-receptor-like function of APP directly implicated in neuronal degeneration in AD. [Copyright &y& Elsevier]

Abstract: Objective: Extremely low frequency (ELF) and radio frequency (RF) magnetic fields (MFs) pervade our environment. Whether or not these magnetic fields are associated with increased risk of serious diseases, e.g., cancers and Alzheimer''s disease, is thus important when developing a rational public policy. The Bioinitiative Report was an effort by internationally recognized scientists who have spent significant time investigating the biological consequences of exposures to these magnetic fields to address this question. Our objective was to provide an unbiased review of the current knowledge and to provide our general and specific conclusions. Results: The evidence indicates that long-term significant occupational exposure to ELF MF may certainly increase the risk of both Alzheimer''s disease and breast cancer. There is now evidence that two relevant biological processes (increased production of amyloid beta and decreased production of melatonin) are influenced by high long-term ELF MF exposure that may lead to Alzheimer''s disease. There is further evidence that one of these biological processes (decreased melatonin production) may also lead to breast cancer. Finally, there is evidence that exposures to RF MF and ELF MF have similar biological consequences. Conclusion: It is important to mitigate ELF and RF MF exposures through equipment design changes and environmental placement of electrical equipment, e.g., AC/DC transformers. Further research related to these proposed and other biological processes is required. [Copyright &y& Elsevier]

Abstract: Recent studies have reported that neuronal apoptosis is induced not only by extracellular Aβ but also by intracellular Aβ; however, the mechanism by which intracellular Aβ contributes to the regulation of cell death associated with the pathogenesis of AD remains to be elucidated. Using immunological assays and a short-lived enhanced green fluorescent protein (d2EGFP) system, we showed that intracellular Aβ and C99 form perinuclear aggregates in the cytosol, and the resulting aggregates attenuate the activity of the 26S proteasome. In addition, the immunofluorescence assays (IFA) revealed that the 20S proteasome α-subunits are recruited into perinuclear aggregates in both human embryonic kidney (HEK293) and human neuroglioma H4 (H4) cells. Interestingly, we observed an increase in the levels of Bax, cleavage of PARP-1, and mitochondrial release of proapoptotic proteins, such as cytochrome c and HtrA2, in H4 cells with intracellular Aβ or C99 aggregates, but not in HEK293 cells with those aggregates. The results of the present study indicate that intracellular Aβ and C99 aggregates induce mitochondria-dependent apoptotic cell death via elevation of Bax levels as a result of proteasome inhibition in a cell type-specific manner. [Copyright &y& Elsevier]

Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer's disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity. [ABSTRACT FROM AUTHOR]

We performed a comparative study to assess cerebral amyloid angiopathy and ApoE genotype in cases of Alzheimer’s disease (AD). Ten ApoE 3,3 and ten ApoE 4,4 AD brains, as well as ten normal control brains, were selected after matching for age, sex, and duration of disease. Sections of middle frontal and inferior parietal cortex including white matter sections were stained with an antibody against amyloid beta (Aβ), and extensive analysis of arteriolar Aβ deposition was performed using digital image analysis. Quantification of the staining revealed a larger cross-section of arteriolar walls occupied by Aβ in ApoE 4,4 and ApoE 3,3 AD subjects compared to controls. Our results show Aβ deposition in gray matter and white matter arterioles was predominantly found in ApoE 4,4 brains and, overall, Aβ deposition was greatest in these cases. This observation implies that there is greater vascular amyloid deposition (particularly in the white matter arterioles) in ApoE 4,4 AD individuals compared to ApoE 3,3 AD. These observations may give insight into the etiology behind the increased risk for AD associated with the ApoE-ε4 allele and the pathogenesis of vascular Aβ deposition. [ABSTRACT FROM AUTHOR]

Abstract: Free radical-induced aggregation of amyloid beta (Aβ) peptide is a recently proposed mechanism in which Cα-centered radicals can form on either Gly33 or Gly29 of Aβ(1-42). Limited structural data for the glycyl radical are available. In this study, the structure of N-Ac-Gly-NHMe and N-Ac-Gly -NHMe was determined using ab initio and DFT calculations. E=f(ϕ,ψ) potential energy surfaces (PES) were constructed by independently constraining the ϕ and ψ angles, 30° apart from 0 to 360°. The structure of each conformer was subsequently optimized using Hartree–Fock and DFT calculations, and the relative energy was calculated using B3LYP/6-31G(d,p). The Poisson–Boltzmann (PB) solver was used to simulate an aqueous environment. The PES of N-Ac-Gly-NHMe was flat, displaying the ability of Gly to sample conformations in both the L and D configurations. Conversely, the N-Ac-Gly -NHMe had a global minimum in the βL conformation, with a high-energy barrier preventing transitions to other minima. The restricted β conformation of N-Ac-Gly -NHMe corresponds to the anti-parallel β-sheets observed in Aβ aggregates. The β conformation permits inter-strand H-bonding that could stabilize the aggregates. [Copyright &y& Elsevier]

Abstract: Amyloid β (Aβ) is closely related to the onset of Alzheimer''s disease (AD). To construct AD animal models, a bolus administration of a large dose of toxic Aβ into the cerebral ventricles of rodents has been performed in earlier studies. In parallel, a continuous infusion system via an osmotic pump into the cerebral ventricle has been developed to make a rat AD model. In this study, we developed a mouse AD model by repetitive administration of Aβ25–35 via a cannula implanted into the cerebral ventricle. Using this administration system, we reproducibly constructed a mouse with impaired spatial working memory. In accordance with the occurrence of the abnormal mouse behavior, we found that the number of choline acetyltransferase (ChAT)-positive neurons was reduced in paraventricular regions of brains of Aβ25–35-administered mice in a dose-dependent manner. Considering that the repetitive administration of a small dose of toxic Aβ via an implanted cannula leads to a brain status more resembling that of the AD patients than a bolus injection of a large dose of Aβ, and therapeutic as well as toxic agents are able to be repeatedly and reliably administered via an implanted cannula, we concluded that the implanted cannula-bearing AD mouse model is useful for development of new AD therapy. [Copyright &y& Elsevier]

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer’s disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Aβ) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Aβ production with mitochondrial dysfunction, caspase pathway, and neuronal loss. [Copyright &y& Elsevier]

Intraneuronal inclusions containing ubiquitylated filamentous protein aggregates are a common feature of many of the major human neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Loss of function mutations in enzymes of the ubiquitin conjugation/deconjugation pathway are sufficient to cause familial forms of neurodegenerative diseases, suggesting that failure of ubiquitin-mediated proteolysis could also be central to inclusion formation in the more common sporadic cases. Examination of ubiquitin-positive inclusions at the protein level provides evidence of attempted proteasomal proteolysis, however close inspection of the temporal aspects of inclusion formation indicates that ubiquitylation is probably a late event. In this regard, the presence of ubiquitin within inclusions of idiopathic neurodegenerative disorders may indicate not a primary dysfunction of ubiquitin-mediated proteolysis, but rather a secondary, presumably protective cellular response. Within this model, other factors are likely to be initiating in inclusion biogenesis. Consistent with these proposals, non-ubiquitylated forms of the principal ubiquitylated components of Alzheimer’s disease neurofibrillary tangles and Parkinson’s disease Lewy bodies, tau and α-synuclein proteins, respectively, can be degraded by proteasomes in a pathway which does not have an absolute requirement for ubiquitylation. Inhibition of proteasome function in the pathological state, as has been reported in both Alzheimer’s and Parkinson’s disease, could therefore contribute both to accumulation of non-ubiquitylated forms of aggregation-prone neuronal proteins, as well as impaired clearance of ubiquitylated aggregates. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Pathologically, the disease is characterized by the deposition of amyloid beta (Aβ) plaques and the presence of neurofibrillary tangles. These drive microglia neuroinflammation and consequent neurodegeneration. While the means to affect Aβ plaque accumulation pharmacologically was achieved, how it affects disease outcomes remains uncertain. Cerium oxide (CeO 2 ) reduces Aβ plaques, oxidative stress, inflammation, and AD signs and symptoms. In particular, CeO 2 nanoparticles (CeO 2 NPs) induce free-radical-scavenging and cell protective intracellular signaling. This can ameliorate the pathobiology of an AD-affected brain. To investigate whether CeO 2 NPs affect microglia neurotoxic responses, a novel formulation of europium-doped CeO 2 NPs (EuCeO 2 NPs) was synthesized. We then tested EuCeO 2 NPs for its ability to generate cellular immune homeostasis in AD models. EuCeO 2 NPs attenuated microglia BV2 inflammatory activities after Aβ 1-42 exposure by increasing the cells' phagocytic and Aβ degradation activities. These were associated with increases in the expression of the CD36 scavenger receptor. EuCeO 2 NPs facilitated Aβ endolysosomal trafficking and abrogated microglial inflammatory responses. We posit that EuCeO 2 NPs may be developed as an AD immunomodulator.

Alzheimer's disease (AD) treatment is constrained due to the inability of peripherally administered therapeutic molecules to cross the blood–brain barrier. Encapsulated cell biodelivery (ECB) devices, a tissue-targeted approach for local drug release, was previously optimized for human mature nerve growth factor (hmNGF) delivery in AD patients but was found to have reduced hmNGF release over time. To understand the reason behind reduced ECB efficacy, we exposed hmNGF-releasing cells (NGC0211) in vitro to human cerebrospinal fluid (CSF) obtained from Subjective Cognitive Impairment (SCI), Lewy Body Dementia (LBD), and AD patients. Subsequently, we exposed NGC0211 cells directly to AD-related factors like amyloid-β peptides (Aβ40/42) or activated astrocyte-conditioned medium (Aβ40/42/IL-1β/TNFα-treated) and evaluated biochemical stress markers, cell death indicators, cell proliferation marker (Ki67), and hmNGF release. We found that all patients' CSF significantly reduced hmNGF release from NGC0211 cells in vitro. Aβ40/42, inflammatory molecules, and activated astrocytes significantly affected NGC0211 cell proliferation without altering hmNGF release or other parameters important for essential functions of the NGC0211 cells. Long-term constant cell proliferation within the ECB device is critically important to maintain a steady cell population needed for stable mNGF release. These data show hampered proliferation of NGC0211 cells, which may lead to a decline of the NGC0211 cell population in ECBs, thereby reducing hmNGF release. Our study highlights the need for future studies to strengthen ECB-mediated long-term drug delivery approaches. [ABSTRACT FROM AUTHOR]

• Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder and model for misfolding protein diseases. • AATD polymorphism leads to essential metal ions (iron, copper and zinc) dyshomeostasis, but there are no biochemical models of Alpha-1 antitrypsin (AAT) metal coordination and possible implications. • Metal dyshomeostasis as well as metal/peptide and metal/protein interactions are correlated with misfolding protein pathologies as Type 2 Diabetes Mellitus (T2DM) and neurodegeneration (dementia, Alzheimer's disease (AD), Parkinson's Disease (PD), prion diseases). • Conformational diseases are not distinct pathologies, but the same pathological state that is correlated with AAT polymorphism, and develop in different tissues at different stages of life. Conformational diseases are caused by the aggregation of misfolded proteins. The risk for such pathologies develops years before clinical symptoms appear, and is higher in people with alpha-1 antitrypsin (AAT) polymorphisms. Thousands of people with alpha-1 antitrypsin deficiency (AATD) are underdiagnosed. Enemy-aggregating proteins may reside in these underdiagnosed AATD patients for many years before a pathology for AATD fully develops. In this perspective review, we hypothesize that the AAT protein could exert a new and previously unconsidered biological effect as an endogenous metal ion chelator that plays a significant role in essential metal ion homeostasis. In this respect, AAT polymorphism may cause an imbalance of metal ions, which could be correlated with the aggregation of amylin, tau, amyloid beta, and alpha synuclein proteins in type 2 diabetes mellitus (T2DM), Alzheimer's and Parkinson's diseases, respectively. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found that the natural compound Nobiletin (NOB) can directly activate circadian cellular oscillators to promote metabolic health in disease models and healthy aging in naturally aged mice. In the current study, using the amyloid-β AD model APP/PS1, we investigated circadian, metabolic and amyloid characteristics of female mice and the effects of NOB. Female APP/PS1 mice showed reduced sleep bout duration, and NOB treatment exhibited a trend to improve it. While glucose tolerance was unchanged, female APP/PS1 mice displayed exaggerated oxygen consumption and CO2 production, which was mitigated by NOB. Likewise, cold tolerance in APP/PS1 was impaired relative to WT, and interestingly was markedly enhanced in NOB-treated APP/PS1 mice. Although circadian behavioral rhythms were largely unchanged, real-time qPCR analysis revealed altered expression of several core clock genes by NOB in the cerebral cortex, notably Bmal1, Npas2, and Rora. Moreover, NOB was also able to activate various clock-controlled metabolic genes involved in insulin signaling and mitochondrial function, including Igf1, Glut1, Insr, Irs1, Ucp2, and Ucp4. Finally, we observed that NOB attenuated the expression of several AD related genes including App, Bace1, and ApoE, reduced APP protein levels, and strongly ameliorated Aβ pathology in the cortex. Collectively, these results reveal novel genotype differences and importantly beneficial effects of a natural clock-enhancing compound in biological rhythms and related pathophysiology, suggesting the circadian clock as a modifiable target for AD. [ABSTRACT FROM AUTHOR]

Abstract Background Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype. Methods Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry. Results Tissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17). Conclusions Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease). Please see related article: http://www.biomedcentral.com/1741-7015/10/36

Abstract Background We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), β-amyloid precursor protein (βAPP), and fragments of the latter such as amyloid β-peptide (Aβ) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele. Methods Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1β slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1β, glutamate, Aβ, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1β, Aβ, sAPP, or glutamate. Results Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1β induces expression of βAPP, IL-1α, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1β, IL-1β-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1β also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Aβ--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1β on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK. Conclusion Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, βAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.

Cerebral amyloid angiopathy (CAA), a prevalent cerebral small vessel disease in the elderly and a common comorbidity of Alzheimer's disease, is characterized by cerebral vascular amyloid accumulation, cerebral infarction, microbleeds, and intracerebral hemorrhages and is a prominent contributor to vascular cognitive impairment and dementia. Here, we investigate proteome changes associated with specific pathological features in several brain regions of rTg-DI rats, a preclinical model of CAA. Whereas varying degrees of microvascular amyloid and associated neuroinflammation are found in several brain regions, the presence of microbleeds and occluded small vessels is largely restricted to the thalamic region of rTg-DI rats, indicating different levels of CAA and associated pathologies occur in distinct brain regions in this model. Here, using SWATHLC-MS/MS, we report specific proteomic analysis of isolated brain regions and employ pathway analysis to correlate regionally specific proteomic changes with uniquely implicated molecular pathways. Pathway analysis suggested common activation of tumor necrosis factor α (TNFα), abnormal nervous system morphology, and neutrophil degranulation in all three regions. Activation of transforming growth factor-β1 (TGF-β1) was common to the hippocampus and thalamus, which share high CAA loads, while the thalamus, which uniquely exhibits thrombotic events, additionally displayed activation of thrombin and aggregation of blood cells. Thus, we present significant and new insight into the cerebral proteome changes found in distinct brain regions with differential CAA-related pathologies of rTg-DI rats and provide new information on potential pathogenic mechanisms associated with these regional disease processes., (© 2021 International Society for Neurochemistry.)

Quantitative imaging of amyloid beta (Aβ) in brain is of great significance for pathological study and follow-up drug development of Alzheimer's disease (AD). In this work, a method using antibody-conjugated gold nanoparticles (AuNPs) was established for quantitative imaging of Aβ peptide in the brain of AD mouse by Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Aβ antibody (Anti-Aβ) was labeled with AuNPs to form the conjugate AuNPs-Anti-Aβ which was immunoreactive with Aβ in the brain slice of mouse. Quantitative imaging of Au was acquired with homogenized brain slice matrix-matched standards as external calibrants which were made by immersing in gold standard solution with different concentrations. Furthermore, the stoichiometric ratios between metal conjugates and Aβ were optimized, and the immunoreaction efficiency after labeling was also investigated. According to the molar relationship between AuNPs and Anti-Aβ (1:4.3) and the ratio of Anti-Aβ to Aβ (1:1), quantitative imaging of Aβ in brain was accomplished. The method intuitively displayed the location and concentration of Aβ aggregation, which was consistent with traditional immunohistochemical staining. Since the numerous gold atoms contained in AuNPs can enhance the signal of Aβ, the method is more intuitive and sensitive. The proposed methodology is potential in investigating the quantitative imaging of biomarker heterogeneity, and is useful to understand such complex brain mechanisms in the future. Image 1 • Quantitative imaging of Aβ in Alzheimer's disease brain by LA-ICP-MS using gold nanoparticles as labels was proposed. • Labelling conditions, immunoreaction efficiency and calibration strategy were optimized. • The proposed strategy was compared and assessed by immunohistochemistry. • Broaden the application of metal-labeling based LA-ICP-MS for pathology research and treatment of AD disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid beta (A)] and neurofibrillary tangles (aggregates of tau protein). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than A plaques. Mitochondrial damage plays an important role in AD. Mitochondrial damage has been related to amyloid-beta or tau pathology or to the presence of specific presenilin-1 mutations. Elevate reactive oxygen species/reactive nitrogen species production and defective mitochondrial dynamic balance has been suggested to be the reason as well as the consequence of AD related pathology. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagy pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between mitochondrial dysfunctioning, oxidative stress, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on mitochondrial dysfunctioning, oxidative stress, and autophagy. We also discuss the interlink mechanism of these three factors in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ1-42, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia with symptoms of deteriorating cognitive functions and memory loss, partially as a result of a decrease in cholinergic neurotransmission. The disease is incurable and treatment with cholinesterase inhibitors (ChEIs) is symptomatic. Choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (ACh), has been proven recently to be present in both cerebrospinal fluid (CSF) and plasma. As ChAT plays a role in regulating the extracellular ACh levels, it may have an impact on prognosis and cognitive performance in AD patients., Objectives: To measure ChAT activity and its protein concentration in CSF and plasma from patients with AD, mild cognitive impairment (MCI), or Subjective cognitive impairment (SCI)., Methods: Plasma and CSF samples were obtained from 21 AD, 32 MCI, and 30 SCI patients. The activity and protein levels of ChAT and acetylcholinesterase (AChE), the enzyme catalyzing the hydrolysis of ACh, were analyzed using an integrated activity and protein concentration ELISA-like assay. A Cholinergic Index was calculated as the ratio of ChAT to AChE activities in CSF. The data were analyzed in relation to dementia biomarkers and cognitive performance of the patients., Results: The CSF ChAT activity was significantly higher (55-67%) in MCI patients compared to AD and SCI cases. The CSF Cholinergic Index was 41 and 22% lower in AD patients than in MCI and SCI subjects, respectively. This index correlated positively with the Aβ 42 /p-tau ratio in CSF in SCI but negatively with that in AD and MCI. The ChAT activity and protein levels in plasma exhibited significant differences with the pattern of AD>> M C I >SCI., Conclusion: This is the first study investigating soluble levels of the key cholinergic enzyme, ChAT, in both plasma and CSF of individuals at different clinical stages of dementia. Although further validation is needed, the overall pattern of the results suggests that in the continuum of AD, the cholinergic signaling exhibits an inverse U-shape dynamic of changes in the brain that greatly differs from the changes observed in the plasma compartment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Karami, Darreh-Shori, Schultzberg and Eriksdotter.)

To date, nearly 35.6 million people world wide live with dementia, and the situation is going to get worse by 2050 with 115.4 million cases.1 In the western world, the prevalence for dementia in people over the age of 60 is greater than 5% and two thirds are due to Alzheimer disease,2-5 the most common form of dementias. Alzheimer disease (AD), first described as "presenile dementia" by the German psychiatrist and neuropathologist Alois Alzheimer in 1906,6 is a devastating disease characterized by progressive cognitive deterioration, as well as impairments in behavior, language, and visuospatial skills.7 Furthermore, Alzheimer discovered the presence of intraneuronal tangles and extracellular amyloid plaques in the diseased-damaged brain, the hallmarks of Alzheimer disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related detrimental dementia. Amyloid beta peptides (Aβ) play a crucial role in the pathology of AD. In familial AD, Aβ are generated from the full-length amyloid beta precursor protein (APP) via dysregulated proteolytic processing; however, in the case of sporadic AD, the mechanism of Aβ biogenesis remains elusive. circRNAs are a class of transcripts preferentially expressed in brain. We identified a circRNA harboring the Aβ-coding region of the APP gene termed circAβ-a. This circular RNA was detected in the brains of AD patients and non-dementia controls. With the aid of our recently established approach for analysis of circRNA functions, we demonstrated that circAβ-a is efficiently translated into a novel Aβ-containing Aβ175 polypeptide (19.2 KDa) in both cultured cells and human brain. Furthermore, Aβ175 was shown to be processed into Aβ peptides—a hallmark of AD. In summary, our analysis revealed an alternative pathway of Aβ biogenesis. Consequently, circAβ-a and its corresponding translation product could potentially represent novel therapeutic targets for AD treatment. Importantly, our data point to yet another evolutionary route for potentially increasing proteome complexity by generating additional polypeptide variants using back-splicing of primary transcripts that yield circular RNA templates. [ABSTRACT FROM AUTHOR]

Progressive mitochondrial dysfunction due to the accumulation of amyloid beta (Aβ) peptide within the mitochondrial matrix represents one of the key characteristics of Alzheimer's disease (AD) and appears already in its early stages. Inside the mitochondria, Aβ interacts with a number of biomolecules, including cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), and affects their physiological functions. However, despite intensive ongoing research, the exact mechanisms through which Aβ impairs mitochondrial functions remain to be explained. In this work, we studied the interactions of Aβ with cypD and 17β-HSD10 in vitro using the surface plasmon resonance (SPR) method and determined the kinetic parameters (association and dissociation rates) of these interactions. This is the first work which determines all these parameters under the same conditions, thus, enabling direct comparison of relative affinities of Aβ to its mitochondrial binding partners. Moreover, we used the determined characteristics of the individual interactions to simulate the concurrent interactions of Aβ with cypD and 17β-HSD10 in different model situations associated with the progression of AD. This study not only advances the understanding of Aβ-induced processes in mitochondria during AD, but it also provides a new perspective on research into complex multi-interaction biomolecular processes in general. [ABSTRACT FROM AUTHOR]

Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer's disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides' induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult. [ABSTRACT FROM AUTHOR]