Clearance Of Amyloid Beta Peptides Research Articles

SARS-CoV-2-Induced Amyloidgenesis: Not One, but Three Hypotheses for Cerebral COVID-19 Outcomes.

The main neuropathological feature of Alzheimer's disease (AD) is extracellular amyloid deposition in senile plaques, resulting from an imbalance between the production and clearance of amyloid beta peptides. Amyloid deposition is also found around cerebral blood vessels, termed cerebral amyloid angiopathy (CAA), in 90% of AD cases. Although the relationship between these two amyloid disorders is obvious, this does not make CAA a characteristic of AD, as 40% of the non-demented population presents this derangement. AD is predominantly sporadic; therefore, many factors contribute to its genesis. Herein, the starting point for discussion is the COVID-19 pandemic that we are experiencing and how SARS-CoV-2 may be able to, both directly and indirectly, contribute to CAA, with consequences for the outcome and extent of the disease. We highlight the role of astrocytes and endothelial cells in the process of amyloidgenesis, as well as the role of other amyloidgenic proteins, such as fibrinogen and serum amyloid A protein, in addition to the neuronal amyloid precursor protein. We discuss three independent hypotheses that complement each other to explain the cerebrovascular amyloidgenesis that may underlie long-term COVID-19 and new cases of dementia.

The role of circadian rhythm in choroid plexus functions.

For several years, a great effort has been devoted to understand how circadian oscillations in physiological processes are determined by the circadian clock system. This system is composed by the master clock at the suprachiasmatic nucleus which sets the pace and tunes peripheral clocks in several organs. It was recently demonstrated that the choroid plexus epithelial cells that compose the blood-cerebrospinal fluid barrier hold a circadian clock which might control their multiple functions with implications for the maintenance of brain homeostasis. However, the choroid plexus activities regulated by its inner clock are still largely unknown. In this review, we propose that several choroid plexus functions might be regulated by the circadian clock, alike in other tissues. We provide evidences that the timing of cerebrospinal fluid secretion, clearance of amyloid-beta peptides and xenobiotics, and the barrier function of the blood-cerebrospinal fluid barrier are regulated by the circadian clock. These data, highlight that the circadian regulation of the blood-cerebrospinal fluid barrier must be taken into consideration for enhancing drug delivery to central nervous system disorders.

The Role of Cathepsin B in the Degradation of Aβ and in the Production of Aβ Peptides Starting With Ala2 in Cultured Astrocytes.

Astrocytes may not only be involved in the clearance of Amyloid beta peptides (Aβ) in Alzheimer's disease (AD), but appear to produce N-terminally truncated Aβ (Aβn−x) independently of BACE1, which generates the N-Terminus of Aβ starting with Asp1 (Aβ1−x). A candidate protease for the generation of Aβn−x is cathepsin B (CatB), especially since CatB has also been reported to degrade Aβ, which could explain the opposite roles of astrocytes in AD. In this study, we investigated the influence of CatB inhibitors and the deletion of the gene encoding CatB (CTSB) using CRISPR/Cas9 technology on Aβ2−x and Aβ1−x levels in cell culture supernatants by one- and two-dimensional Urea-SDS-PAGE followed by immunoblot. While the cell-permeant inhibitors E64d and CA-074 Me did not significantly affect the Aβ1−x levels in supernatants of cultured chicken and human astrocytes, they did reduce the Aβ2−x levels. In the glioma-derived cell line H4, the Aβ2−x levels were likewise decreased in supernatants by treatment with the more specific, but cell-impermeant CatB-inhibitor CA-074, by CA-074 Me treatment, and by CTSB gene deletion. Additionally, a more than 2-fold increase in secreted Aβ1−x was observed under the latter two conditions. The CA-074 Me-mediated increase of Aβ1−x, but not the decrease of Aβ2−x, was influenced by concomitant treatment with the vacuolar H+-ATPase inhibitor Bafilomycin A1. This indicated that non-lysosomal CatB mediated the production of Aβ2−x in astrocytes, while the degradation of Aβ1−x seemed to be dependent on lysosomal CatB in H4 cells, but not in primary astrocytes. These findings highlight the importance of considering organelle targeting in drug development to promote Aβ degradation.

Effect of sacubitril/valsartan on cognitive function in patients with HFpEF: a prespecified analysis of PARAGON-HF

Abstract Background A theoretical concern has been raised about detrimental effects of sacubitril/valsartan (sac/val) on cognitive function as neprilysin is one of many pathways involved in clearance of amyloid beta peptides from brain tissue. Purpose To examine effect of sac/val, compared with valsartan, on cognitive function in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Methods In the PARAGON-HF trial, cognitive function was tested in a subgroup of patients at baseline and follow-up, using Mini-Mental State Examination [MMSE] having a maximum score of 30 (higher scores reflect better cognitive function). Change in MMSE score from baseline to 96 wks was a prespecified exploratory endpoint. Other post hoc analyses included “cognitive decline” (fall in MMSE ≥3 pts) and assessment of cognition-related adverse events (AEs). Results Among 2895 patients (60% of total) in PARAGON-HF with baseline MMSE measurement, mean (SD) score was 27.4 (3.0) in patients receiving sac/val (1453) and 27.4 (2.9) in patients receiving valsartan (1442). There was no difference between sac/val and valsartan in MMSE score change from baseline to wk 96: sac/val −0.02 (SE 0.07) and valsartan 0.00 (0.07); between-treatment difference −0.02 (95% CI: −0.22 to 0.18); p-value = 0.83. Cognitive decline at 96 weeks occurred in 115 of 1071 evaluable patients (10.7%) in sac/val group and 121 of 1053 patients (11.5%) in valsartan group; risk ratio 0.97 (0.75–1.26), p-value = 0.82. Cognition-related AEs were more frequent, than in PARADIGM-HF (likely as patients in PARAGON-HF were older) but, as in PARADIGM-HF, did not differ between sac/val and comparator treatment (Table). Conclusions Cognitive change, measured by MMSE, did not differ between treatment with sac/val & valsartan in patients with HFpEF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PARAGON-HF study was funded by Novartis Pharma.

APOE GENE POLYMORPHISM: THE IMPACT OF APOE4 ALLELE ON SYSTEMIC INFLAMMATION AND ITS ROLE IN THE PATHOGENESIS OF ALZHEIMER’S DISEASE

ApoE is a member of lipoprotein family. It is the most common lipoprotein in the central nervous system (CNS), secreted by astrocytes, microglia, neurons and immunocompetent cells, including lymphocytes, monocytes and macrophages. According to recent data, it has endotheliotropic and immunomodulatory functions, regulating inflammatory activation of mononuclear phagocytes and antigen-induced lymphocyte proliferation. APOE4 allele is a major genetic risk factor of Alzheimer’s disease, with prevalence 3-12 times higher in those who have this allele. Mechanisms that predispose carriers of the allele to earlier clinical presentation of neurodegeneration include changes in lipid metabolism in the CNS, in the buildup of neurotoxic amyloid-beta oligomers, in the clearance of amyloid-beta peptides from the CNS and in regulation of immune response. In this review the functions of ApoE protein in central nervous and immune system and changes in functional activity of the protein in APOE4 carriers are discussed. The impact of APOE4 allele on monocyte phenotype and inflammatory activation of monocytes, on specific cell-mediated immune response to amyloid-beta antigens and on effectiveness of immunomodulatory therapy in patients with Alzheimer’s disease summarized, as well as the possible role of changes in the immune response characteristic for APOE4 carriers in the increased risk of Alzheimer’s disease.

NEW INSIGHTS INTO THE ROLE OF ABC-TRANSPORTERS IN AMYLOID-BETA CLEARANCE FROM CELLS IN THE BRAIN

Accumulation of toxic amyloid-beta peptides in the brain is an established hallmark of Alzheimer's Disease. Several members of the ABC transporter family of proteins implicated in the clearance of amyloid-beta peptides across the blood brain barrier (BBB) endothelium include the drug transporter ABCB1 (or P-glycoprotein) and the lipid transporter ABCG4. However, despite years of research in this area, there are still fundamental gaps in our understanding of whether amyloid-beta peptides are direct substrates for these transporters, and how these transport processes are regulated in various cell types in the brain. We have recently published that ABCG4 is a substrate for an E3-ubiquitin ligase, NEDD4–1 (see Aleidi et al JBC 2015;290:24604), which has also been implicated in regulating ABCB1 activity. Our research aims to investigate whether these transporters may potentially have a combined function in this clearance pathway and how this may be regulated. ABC transporter expression was measured via PCR and Western Blotting in Be(2)-C neuronal and hCMEC/D3 BBB endothelial cells. Cellular ABCB1 activity was measured using Calcein-AM assays while purified recombinant ABCB1, reconstituted in vesicles, was used to measure ATP-consumption in the presence of non-aggregated amyloid-beta (1–40)-peptide. ABCB1 was expressed in BBB endothelial cells as expected but was also surprisingly highly expressed in neuronal cells, a cell type in which ABCB1 function has not been previously characterised. Cellular ABCB1 activity was in line with expression of the transporter, suggesting that ABCB1 is active in neurons. Preliminary data show that amyloid-beta (1–40)-peptide directly stimulates ATP consumption of purified reconstituted ABCB1. In addition, ABCG4 was expressed in neurons as previously described, but also in BBB endothelial cells, where its function is similarly unknown. In both cell types, ABCG4 was not regulated by Liver X receptor (LXR) ligands, as expected from previously published work on the regulation of its close family member, the lipid transporter ABCG1. ABCB1 has the potential to be of importance in the initial export of amyloid-beta peptides from neurons. We are currently investigating a potentially combined function of these two transporters in net amyloid-beta export from endothelial cells and neurons in the brain.

The Potential Roles of Aquaporin 4 in Alzheimer's Disease.

Aquaporin 4 (AQP4) is the major water channel expressed in the central nervous system (CNS), and it is primarily expressed in astrocytes. It has been studied in various brain pathological conditions. However, the potential for AQP4 to influence Alzheimer's disease (AD) is still unclear. Research regarding AQP4 functions related to AD can be traced back several years and has gradually progressed toward a better understanding of the potential mechanisms. Currently, it has been suggested that AQP4 influences synaptic plasticity, and AQP4 deficiency may impair learning and memory, in part, through glutamate transporter-1 (GLT-1). AQP4 may mediate the clearance of amyloid beta peptides (Aβ). In addition, AQP4 may influence potassium (K(+)) and calcium (Ca(2+)) ion transport, which could play decisive roles in the pathogenesis of AD. Furthermore, AQP4 knockout is involved in neuroinflammation and interferes with AD. To date, no specific therapeutic agents have been developed to inhibit or enhance AQP4. However, experimental results strongly emphasize the importance of this topic for future investigations.

Telomerase: A Target for Therapeutic Effects of Curcumin and a Curcumin Derivative in Aβ1-42 Insult In Vitro

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aβ1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aβ1–42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aβ1–42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

How Close are We to a Readily available, Clinically Reliable Blood Test for Alzheimer's disease?

Neurodegenerative Disease ManagementVol. 3, No. 5 EditorialHow close are we to a readily available, clinically reliable blood test for Alzheimer’s disease?Pedro Pesini & Manuel SarasaPedro PesiniAraclon Biotech Ltd, Vía Hispanidad 21, 50009 Zaragoza, SpainSearch for more papers by this author & Manuel Sarasa* Author for correspondenceAraclon Biotech Ltd, Vía Hispanidad 21, 50009 Zaragoza, Spain. Search for more papers by this authorEmail the corresponding author at msarasa@araclon.comPublished Online:16 Sep 2013https://doi.org/10.2217/nmt.13.48AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleReferences1 Alzheimer’s Disease International. World Alzheimer Report 2010. Alzheimer’s Disease International, London, UK (2010).Google Scholar2 Jack CR Jr, Knopman DS, Jagust WJ et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol.9(1),119–128 (2010).Crossref, Medline, CAS, Google Scholar3 Villemagne VL, Burnham S, Bourgeat P et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol.12,357–367 (2013).Crossref, Medline, CAS, Google Scholar4 Sperling RA, Aisen PS, Beckett LA et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers Dement.7(3),280–292 (2011).Crossref, Medline, Google Scholar5 Jack CR Jr, Knopman DS, Weigand SD et al. An operational approach to National Institute on Aging – Alzheimer’s Association criteria for preclinical Alzheimer disease. Ann. Neurol.71(6),765–775 (2012).Crossref, Medline, Google Scholar6 Petersen RC, Aisen P, Boeve BF et al. Criteria for mild cognitive impairment due to alzheimer’s disease in the community. Ann. 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Peripheral clearance of amyloid beta peptide by complement C3-dependent adherence to erythrocytes. Neurobiol. Aging27(12),1733–1739 (2006).Crossref, Medline, CAS, Google Scholar16 Becan-McBride K. Laboratory sampling. Does the process affect the outcome? J. Intraven. Nurs.22(3),137–142 (1999).Medline, CAS, Google Scholar17 DeMeyer G, Shapiro F, Vanderstichele H et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch. Neurol.67(8),949–956 (2010).Crossref, Medline, Google Scholar18 Foster N, King R, Wang A et al. Diagnostic classification with amyloid PET and FDG-PET among clinically diagnosed Alzheimer’s disease patients in the Alzheimer’s disease neuroimaging initiative. Hum. Amyloid Imaging Abstract (2012).Google Scholar19 Cummings JL, Dubois B, Molinuevo JL, Scheltens P. International Work Group criteria for the diagnosis of Alzheimer disease. Med. Clin. North Am.97(3),363–368 (2013).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 3, No. 5 Follow us on social media for the latest updates Metrics Downloaded 17 times History Published online 16 September 2013 Published in print October 2013 Information© Future Medicine LtdFinancial & competing interests disclosureM Sarasa is the scientific founder of Araclon Biotech Ltd and its current President, CEO and CSO, and P Pesini is its research and development director. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Vitamin D-Mentia: Randomized Clinical Trials Should Be the Next Step

Hypovitaminosis D is highly prevalent in the elderly. Its possible role in the pathogenesis of Alzheimer’s disease (AD) is particularly important, as AD remains a public health concern with no current efficient treatment. Vitamin D administration could be a multitarget stabilizing treatment for AD since vitamin D simultaneously targets several factors leading to neurodegeneration through immunoregulatory, antioxidant and anti-ischemic actions, as well as the regulation of neurotrophic factors, acetylcholine neurotransmitter and clearance of amyloid beta peptide, and the avoidance of hyperparathyroidism. By preventing neuronal loss, the question is whether correcting hypovitaminosis D among older adults could also prevent AD-related cognitive decline. The cross-sectional associations between the vitamin D intakes – whether from diet, sun exposure or drug supplements – and cognition strengthened this hypothesis, but prevented the finding of a cause and effect link. Pre-post studies showed an improvement of cognition concomitant with the increase in 25-hydroxyvitamin D concentrations. One randomized trial found that supraphysiological doses of vitamin D were not better than physiological doses at improving cognition in AD. At this stage, only clinical trials testing vitamin D supplements versus placebo can further determine the impact of vitamin D administration on cognition and AD with higher levels of evidence.

Novel resveratrol analogues as activators of AMPK signaling and amyloid-beta peptide clearance

Novel resveratrol analogues as activators of AMPK signaling and amyloid-beta peptide clearance

O2-05-02: Inhibition of amyloid precursor protein processing by beta-secretase via site directed antibodies

clearance of amyloid beta peptides by immunological or chemical means as a method of treatment for Alzheimer’s disease (AD). One of the new findings that immerged from these immunological studies was that passive immunization with amyloid beta peptide antibodies resulted in an efflux of amyloid beta peptide from the brain into the plasma (DeMattos et al., Proc Natl Acad Sci USA 98:8850-8855, 2001; DeMattos et al., Science 295: 2264-2267, 2002.) producing what was termed a peripheral “sink effect”. An elegant extension of this “sink effect” concept was described by Matsuoka et al., (J Neurosci. 23:29-33, 2003) who used two amyloid beta peptide-binding compounds, ganglioside GM1 and gelsolin, to bind plasma amyloid beta peptide in hAPP transgenic mice, resulting in a lowering of brain amyloid beta peptide levels by 50% or more. Objective: We have tested the peripheral sink effect using an amyloid peptide degrading enzyme. Methods: We have expressed the amyloid peptide degrading peptidase neprilysin, or an inactive form of neprilysin, on leukocytes in hAPP transgenic mice. Results and Conclusions: Expression of neprilysin activity on leukocytes declined over a four-month period. Mice expressing active neprilysin at two months of age and sacrificed at 7 months of age showed a dramatic decrease in diffuse amyloid deposits in their brain relative to mice expressing inactive neprilysin. These studies demonstrate the use of peripheral neprilysin as a way to prevent amyloid deposition in brain. This work was supported in part by grant AG024899 from the National Institute on Aging.

Susceptibility of Amyloid β Peptide Degrading Enzymes to Oxidative Damage: A Potential Alzheimer's Disease Spiral

Insulysin (IDE) and neprilysin (NEP) were found to be inactivated by oxidation with hydrogen peroxide, an iron-ascorbate oxidation system, and by treatment with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). In each case reaction led to the introduction of protein carbonyl groups as judged by reaction with 2,4-dintrophenylhydrazine. IDE was inactivated by reaction with 4-hydroxy-2-nonenal (HNE) with the concomitant formation of protein adducts. NEP was not inactivated to a significant extent by HNE, but some HNE-adduct formation did occur. Prior reaction with hydrogen peroxide or AAPH led to enhanced formation of HNE adducts. Treatment of IDE with AAHP or hydrogen peroxide increased its susceptibility to proteolysis, while treatment of NEP with iron/ascorbate or hydrogen peroxide increased its susceptibility to proteolysis. Since IDE and NEP play a prominent role in the clearance of amyloid beta peptides, their oxidative inactivation and enhanced proteolysis can contribute to the onset and/or progression of Alzheimer's disease.

Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries.

In Alzheimer's disease, the neuritic or senile amyloid plaques in hippocampus and association cortex, the diffuse plaques in brain areas such as the cerebellum and sensorimotor cortex, and the amyloid deposits in the walls of pial and parenchymal blood vessels are mainly composed of amyloid beta-peptides. In the present study, either soluble 40-residue amyloid beta-peptide radiolabeled with 125I (I-sAbeta) or [14C]polyethylene glycol ([14C]PEG, a reference material) was briefly infused into one lateral ventricle of normal rats. By 3.5 min, 30% of the I-sAbeta was cleared from ventricular CSF into blood; another 30% was removed over the next 6.5 min. No [14C]PEG was lost from the CSF-brain system during the first 5 min, and only 20% was cleared by 10 min. Much of the I-sAbeta that reached the subarachnoid space was retained by pial arteries and arterioles. Virtually no I-sAbeta was found in brain. The clearance of amyloid beta-peptides from the CSF-brain system, reported herein for normal rats, may be reduced in Alzheimer's disease, thus contributing to amyloid deposition in cerebral tissue and blood vessels.