Your search for: 'author:("Martins, R.N.")' has returned 7 results. (0.01s) Save search

Authors: Ling, Xie | Martins, R.N. | Racchi, M. | Craft, S. | Helmerhorst, E.

Article Type: Research Article

Abstract: Amyloid β (Aβ) peptides are direct competitive inhibitors of insulin binding and action [25]. We demonstrate that Aβ peptides can inhibit the effect of insulin on the metabolic processing of the amyloid β protein precursor (AβPP). As evidence emerges concerning the role of insulin and insulin like growth factors (IGFs) in learning and memory, recent findings have suggested that insulin may have a significant role in the pathogenetic pathways leading to Alzheimer's disease (AD). As an example several investigators have demonstrated upregulation of insulin receptors and defective insulin receptor signal transduction in AD brains. Moreover insulin has been shown to …positively modulate AβPP proteolytic processing. The fact that insulin and Aβ appear to share a common system for degradation and disposal as they are both substrates of the insulin degrading enzyme (IDE) suggested the possibility of a reciprocal interference. Here we report that Aβ can directly interfere with insulin receptor signalling inhibiting the autophosphorylation of partially purified insulin receptors. As a consequence of such interaction we also demonstrate that Aβ blocks the effect of insulin on the release of sAβPPα in chinese hamster ovaries (CHO) cells transfected with insulin receptors. Show more

Keywords: Insulin, Insulin receptor autophosphorylation, amyloid β, amyloid β-protein precursor protein, Alzheimer's disease

DOI: 10.3233/JAD-2002-4504

Citation: Journal of Alzheimer's Disease, vol. 4, no. 5, pp. 369-374, 2002

Authors: Hone, E. | Martins, I.J. | Fonte, J. | Martins, R.N.

Article Type: Research Article

Abstract: The relationship between amyloid-β protein (Aβ) metabolism and Alzheimer's disease is currently poorly understood. While it is well known that the generation of Aβ results from enzymatic cleavage of its parent molecule, the amyloid β protein precursor (AβPP), there is little information available regarding its in vivo clearance. The E4 isoform of apolipoprotein E (apoE) has been associated with poor clearance of Aβ under in vitro conditions. This is thought to be due to its poor ability to bind Aβ compared with the other common isoforms, apoE2 and apoE3. Although cell culture studies support the notion that Aβ clearance depends …upon apoE isoform, validation of these findings requires Aβ clearance studies in vivo. In this study, we examined the clearance of Aβ in vivo from the periphery in mice that expressed apoE (C57BL/6J) or lacked apoE (APOE knockout). We measured the clearance of peripherally injected Aβ over time and additionally, the quantities sequestered by peripheral organs. Western blot analysis of the murine plasma indicated that the half-life of Aβ in the periphery was approximately 15 minutes. The livers of the C57BL/6J mice were found to have sequestered approximately 40% of the total injected Aβ at 90 minutes post-injection, whilst their kidneys contained 5% of the total injected Aβ. In contrast, the livers and kidneys of the APOE knockout animals were found to contain no detectable Aβ. These findings indicate that Aβ is rapidly removed from the plasma by murine peripheral tissues and the rate of its clearance is affected by apoE. Show more

Keywords: Amyloid-β protein, mouse, clearance, Alzheimer's disease, periphery, apolipoprotein E

DOI: 10.3233/JAD-2003-5101

Citation: Journal of Alzheimer's Disease, vol. 5, no. 1, pp. 1-8, 2003

Authors: Hone, E. | Martins, I.J. | Jeoung, M. | Ji, T.H. | Gandy, S.E. | Martins, R.N.

Article Type: Research Article

Abstract: The major protein component of the extracellular deposits in Alzheimer's disease (AD) is a 4 kDa peptide termed amyloid-β (Aβ). This peptide is known to bind apolipoprotein E (apoE), a key mediator of lipoprotein transport, in an isoform specific manner. Whilst these isoform specific effects on apoE are well recognized, the functional significance of this interaction is poorly understood. Here, we investigated the influence of Aβ on apoE-mediated lipoprotein binding to cells using fluorescently tagged lipoprotein-like emulsions. Using this approach, we demonstrate that Aβ enhanced the normally poor binding of apoE2 lipoprotein-like particles to fibroblasts in culture, whilst markedly reducing …the binding of apoE3 and apoE4. This suggests that the action of apoE isoforms on cellular lipoprotein or cholesterol metabolism is differentially modulated by Aβ. This also suggests that Aβ may also compromise apoE function in the Alzheimer disease affected brain. Show more

Keywords: Amyloid-β, Alzheimer's disease, apolipoprotein E, periphery, cholesterol, lipoproteins

DOI: 10.3233/JAD-2005-7406

Citation: Journal of Alzheimer's Disease, vol. 7, no. 4, pp. 303-314, 2005

Authors: Flicker, L. | Martins, R.N. | Thomas, J. | Acres, J. | Taddei, K. | Norman, P. | Jamrozik, K. | Almeida, O.P.

Article Type: Research Article

Abstract: The ε4 allele of apolipoprotein E (APOE), and the plasma levels of APOE, amyloid β-protein precursor, amyloid β1-40 (Aβ40) and homocysteine (Hcy) have all been correlated with the presence of dementia. Mutations in the methylnetetrahydrofolate reductase enzyme (MTHFR) have been associated with elevated levels of Hcy. This study explored the association of these factors with cognition and depression in community dwelling older men. Two hundred and ninety-nine men, mean age 78.9 years (SD 2.8), were studied in this cross-sectional survey. Mean plasma Hcy was 13.5 (SD 5.3) μmol/L. The MTHFR genotype had no obvious impact on Hcy levels. Ln Hcy …and Ln Aβ40 were both inversely correlated with calculated glomerular filtration rate (cGFR), r = -0.41 (p < 0.001) and r = -0.28 (p < 0.001), respectively. There was a positive correlation between Ln Hcy and Ln Aβ40, r = 0.19 (p < 0.001), which remained significant after adjusting for cGFR, with a doubling of Hcy associated with a 24% increase of Aβ40. The e4 allele was associated with increased depressive symptoms as measured by the Geriatric Depression Scale-15, Odds ratio (OR) = 2.59 (95%CI 1.06–6.34) and poorer performance on the Clock Drawing Test, OR = 2.32 (95% CI: 1.25–4.29). There was a positive association between Aβ40 and Hcy, even after adjustment for cGFR in this sample of well, community dwelling older men. This association may help elucidate the link between elevated levels of Hcy and Alzheimer's disease. Show more

Keywords: dementia, amyloid protein, Apolipoprotein E, cognition, depression, homocysteine, methylnetetrahydrofolate reductase, geriatric

DOI: 10.3233/JAD-2004-6313

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 329-336, 2004

Authors: Gillett, M.J. | Martins, R.N. | Clarnette, R.M. | Chubb, S.A.P. | Bruce, D.G. | Yeap, B.B.

Article Type: Research Article

Abstract: In a group of 28 older men with either subjective memory loss or dementia, serum total testosterone and sex hormone binding globulin (SHBG) correlated inversely with plasma levels of amyloid beta peptide 40 (Aβ40, r=-0.5, P=0.01 and r=-0.4, P=0.04, respectively). Calculated free testosterone was also inversely correlated (r=-0.4, P=0.03), and all three relationships remained statistically significant after allowing for age. A similar but non-significant trend was seen with dehydroepiandrosterone sulphate (DHEAS), and neither luteinising hormone (LH) nor estradiol correlated with Aβ40. These data demonstrate that lower androgen levels are associated with increased plasma Aβ40 in older men with memory loss …or dementia, suggesting that subclinical androgen deficiency enhances the expression of Alzheimer's disease-related peptides in vivo. An inverse correlation exists between SHBG and Aβ40, warranting further investigation. Show more

Keywords: testosterone, sex hormone binding globulin, amyloid beta peptide 40, memory loss, dementia, men

DOI: 10.3233/JAD-2003-5401

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 267-269, 2003

Authors: Lautenschlager, N.T. | Wu, Jing-Shan | Laws, S.M. | Almeida, O.P. | Clarnette, R.M. | Joesbury, K. | Wagenpfeil, S. | Martins, G. | Paton, A. | Gandy, S.E. | Förstl, H. | Martins, R.N.

Article Type: Research Article

Abstract: Neurodegeneration is associated with increased frequency of neurological soft signs (NSS). We designed the present study to investigate the association between NSS and subjective memory complaints, cognitive function and apolipoprotein E genotype in a community-dwelling sample of volunteers participating in an ongoing longitudinal program investigating predictors of cognitive decline. NSS were found to be associated with apolipoprotein E (APOE) ε4 genotype (p = 0.015), age (p = 0.012) and poor cognitive performance, as assessed by the Mini Mental State Examination (p = 0.053). There was no significant difference between subjects with and without memory complaints in relation to the frequency …of NSS (p = 0.130). The association with age and the APOE ε4 genotype suggests that the systematic investigation of NSS may contribute to identify subjects at risk of clinically significant cognitive decline in later life. Show more

Keywords: Apolipoprotein E, neurological soft signs, memory impairment, apoE promoter polymorphisms, cognitive decline

DOI: 10.3233/JAD-2005-7409

Citation: Journal of Alzheimer's Disease, vol. 7, no. 4, pp. 325-330, 2005

Authors: Burkhardt, M.S. | Foster, J.K. | Laws, S.M. | Baker, L.D. | Craft, S. | Gandy, S.E. | Stuckey, B.G.A. | Clarnette, R. | Nolan, D. | Hewson-Bower, B. | Martins, R.N.

Article Type: Research Article

Abstract: There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an ε4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents …a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 ± 6.34); ERT non-users (n = 80, mean age 67.03 ± 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2–5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE ε4 allele. APOEε4 carriers receiving ERT performed no better on episodic memory testing than APOE ε4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE ε4 allele. Show more

Keywords: oestrogen supplementation, post-menopausal women, cognition, apolipoprotein E genotype, Alzheimer's disease

DOI: 10.3233/JAD-2004-6302

Citation: Journal of Alzheimer's Disease, vol. 6, no. 3, pp. 221-228, 2004