Amla Therapy as a Potential Modulator of Alzheimer’s Disease Risk Factors and Physiological Change
Authors: Teimouri, Elham | Rainey-Smith, Stephanie R. | Bharadwaj, Prashant | Verdile, Giuseppe | Martins, Ralph N.
Article Type: Review Article
Abstract: There is currently no effective treatment for Alzheimer’s disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some …clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD. Show more
Keywords: Amla, Alzheimer’s disease, anti-inflammatory, antioxidant, cardiovascular disease, type 2 diabetes
DOI: 10.3233/JAD-191033
Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 713-733, 2020
The Effects of Latrepirdine on Amyloid-β Aggregation and Toxicity
Authors: Porter, Tenielle | Bharadwaj, Prashant | Groth, David | Paxman, Adrian | Laws, Simon M. | Martins, Ralph N. | Verdile, Giuseppe
Article Type: Research Article
Abstract: Latrepirdine (Dimebon™) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer’s disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was …assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties. Show more
Keywords: Alzheimer’s disease, amyloid-beta, latrepirdine, neurotoxicity, Thiofavin T
DOI: 10.3233/JAD-150790
Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 895-905, 2016
The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins
Authors: Bharadwaj, Prashant | Wijesekara, Nadeeja | Liyanapathirana, Milindu | Newsholme, Philip | Ittner, Lars | Fraser, Paul | Verdile, Giuseppe
Article Type: Review Article
Abstract: A wealth of evidence indicates a strong link between type 2 diabetes (T2D) and neurodegenerative diseases such as Alzheimer’s disease (AD). Although the precise mechanism remains unclear, T2D can exacerbate neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism, and central nervous system insulin resistance are features of both AD and T2D. The T2D phenotype (glucose dyshomeostasis, insulin resistance, impaired insulin signaling) also promotes AD pathology, namely accumulation of amyloid-β (Aβ) and hyperphosphorylated tau and can induce other aspects of neuronal degeneration including inflammatory and oxidative processes. Aβ and hyperphosphorylated tau may also have roles in pancreatic β-cell dysfunction and in …reducing insulin sensitivity and glucose uptake by peripheral tissues such as liver, skeletal muscle, and adipose tissue. This suggests a role for these AD-related proteins in promoting T2D. The accumulation of the islet amyloid polypeptide (IAPP, or amylin) within islet β-cells is a major pathological feature of the pancreas in patients with chronic T2D. Co-secreted with insulin, amylin accumulates over time and contributes to β-cell toxicity, ultimately leading to reduced insulin secretion and onset of overt (insulin dependent) diabetes. Recent evidence also suggests that this protein accumulates in the brain of AD patients and may interact with Aβ to exacerbate the neurodegenerative process. In this review, we highlight evidence indicating T2D in promoting Aβ and tau mediated neurodegeneration and the potential contributions of Aβ and tau in promoting a diabetic phenotype that could further exacerbate neurodegeneration. We also discuss underlying mechanisms by which amylin can contribute to the neurodegenerative processes. Show more
Keywords: Alzheimer’s disease, amylin, amyloid-β protein, insulin, tau, type 2 diabetes
DOI: 10.3233/JAD-161192
Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 421-432, 2017
Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer’s Disease
Authors: Jayne, Tanya | Newman, Morgan | Verdile, Giuseppe | Sutherland, Greg | Münch, Gerald | Musgrave, Ian | Moussavi Nik, Seyyed Hani | Lardelli, Michael
Article Type: Review Article
Abstract: The majority of mutations causing familial Alzheimer’s disease (fAD) have been found in the gene PRESENILIN1 (PSEN1 ) with additional mutations in the related gene PRESENILIN2 (PSEN2 ). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A βPP/APP ) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on …γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the “fAD mutation reading frame preservation rule” that applies to PSEN1 and PSEN2 (and A βPP ) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a “PSEN holoprotein multimer hypothesis” where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs’ γ-secretase activity. Show more
Keywords: Amyloid precursor protein secretases, familial Alzheimer’s disease, gamma-secretase, human APP protein, human PSEN1 protein, human PSEN2 protein
DOI: 10.3233/JAD-151186
Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 781-799, 2016
The Dynamics of CD147 in Alzheimer's Disease Development and Pathology
Authors: Kanyenda, Limbikani J. | Verdile, Giuseppe | Boulos, Sherif | Krishnaswamy, Sudarsan | Taddei, Kevin | Meloni, Bruno P. | Mastaglia, Frank L. | Martins, Ralph N.
Article Type: Review Article
Abstract: CD147, also known as basigin, EMMPRIN, neurothelin, TCSF, M6, HT7, OX47, or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues including the hippocampus, pre-frontal cortex thyroid, heart, early erythroid, amygdala, and placenta. This protein is involved in various cellular and biological functions, such as lymphocyte migration and maturation, tissue repair cancer progression, T and B lymphocyte activation, and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with other proteins such as cyclophilin A (CyPA), Cyclophilin B (CyPB), sterol carrier protein (SCP), caveolin-1 and integrins, and can influence amyloid-β (Aβ) …peptide levels, a protein that is central to Alzheimer's disease (AD) pathogenesis. Mechanisms by which CD147 regulate Aβ levels remain unclear, thus in this review we discuss its involvement in Aβ production and clearance and potential mechanisms by which controlling CD147 levels could impact on Aβ accumulation and AD pathogenesis. Show more
Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, CD147, cholesterol, EMMPRIN, γ-secretase, immunoglobulin superfamily, sterol carrier protein-2
DOI: 10.3233/JAD-2011-110584
Citation: Journal of Alzheimer's Disease, vol. 26, no. 4, pp. 593-605, 2011
Targeting Mitophagy in Alzheimer’s Disease
Authors: Jayatunga, Dona P.W. | Hone, Eugene | Bharadwaj, Prashant | Garg, Manohar | Verdile, Giuseppe | Guillemin, Gilles J. | Martins, Ralph N.
Article Type: Review Article
Abstract: Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer’s disease (AD). Targeting mitophagy pathways has been suggested …to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD. Show more
Keywords: Alzheimer’s disease, mitophagy, neuroprotection, nutraceuticals
DOI: 10.3233/JAD-191258
Citation: Journal of Alzheimer's Disease, vol. 78, no. 4, pp. 1273-1297, 2020
Plasma Aβ42 correlates positively with increased body fat in healthy individuals
Authors: Balakrishnan, Kelvin | Verdile, Giuseppe | Mehta, Pankaj D. | Beilby, John | Nolan, David | Galvão, Daniel A. | Newton, Robert | Gandy, Samuel E. | Martins, Ralph N.
Article Type: Research Article
Abstract: Obesity and overweight, well known risk factors for cardiovascular disease and type 2 diabetes, are now associated with Alzheimer's disease (AD). It remains to be determined if obesity and overweight contribute to the risk of developing AD through modulating levels of amyloid-beta (Aβ), a key molecule in AD pathogenesis. Thus, we investigated whether there were any associations between plasma Aβ levels and body mass index (BMI) or fat mass (FM) in a group of 18 healthy adults. A statistically significant correlation was found between BMI, FM, and plasma levels of Aβ42 (BMI r= 0.602, P=0.008; FM r= 0.547, P=0.019), the …longer, more pathogenic form of Aβ, but not with plasma levels of the shorter, less pathogenic Aβ40. Although not significant, positive correlations between plasma levels of Aβ42 and levels of insulin and the inflammatory marker C-reactive protein (CRP), along with an inverse trend between plasma Aβ42 levels and levels of high density lipoprotein (HDL) were answered. These results suggest that proteins implicated in inflammation, cardiovascular disease and type 2 diabetes, which in turn are risk factors for AD, may contribute to the associations between BMI/FM and plasma Aβ42 levels. Longitudinal studies involving larger cohorts are required to determine if elevated body fat may predispose individuals to AD through increasing Aβ42 levels throughout early to late adulthood. Show more
DOI: 10.3233/JAD-2005-8305
Citation: Journal of Alzheimer's Disease, vol. 8, no. 3, pp. 269-282, 2005
Multiple Mechanisms Linking Type 2 Diabetes and Alzheimer’s Disease: Testosterone as a Modifier
Authors: Asih, Prita R. | Tegg, Michelle L. | Sohrabi, Hamid | Carruthers, Malcolm | Gandy, Samuel E. | Saad, Farid | Verdile, Giuseppe | Ittner, Lars M. | Martins, Ralph N.
Article Type: Review Article
Abstract: Evidence in support of links between type-2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) has increased considerably in recent years. AD pathological hallmarks include the accumulation of extracellular amyloid-β (Aβ) and intracellular hyperphosphorylated tau in the brain, which are hypothesized to promote inflammation, oxidative stress, and neuronal loss. T2DM exhibits many AD pathological features, including reduced brain insulin uptake, lipid dysregulation, inflammation, oxidative stress, and depression; T2DM has also been shown to increase AD risk, and with increasing age, the prevalence of both conditions increases. In addition, amylin deposition in the pancreas is more common in AD than in normal …aging, and although there is no significant increase in cerebral Aβ deposition in T2DM, the extent of Aβ accumulation in AD correlates with T2DM duration. Given these similarities and correlations, there may be common underlying mechanism(s) that predispose to both T2DM and AD. In other studies, an age-related gradual loss of testosterone and an increase in testosterone resistance has been shown in men; low testosterone levels can also occur in women. In this review, we focus on the evidence for low testosterone levels contributing to an increased risk of T2DM and AD, and the potential of testosterone treatment in reducing this risk in both men and women. However, such testosterone treatment may need to be long-term, and would need regular monitoring to maintain testosterone at physiological levels. It is possible that a combination of testosterone therapy together with a healthy lifestyle approach, including improved diet and exercise, may significantly reduce AD risk. Show more
Keywords: Alzheimer’s disease, men, testosterone, type-2 diabetes, women
DOI: 10.3233/JAD-161259
Citation: Journal of Alzheimer's Disease, vol. 59, no. 2, pp. 445-466, 2017
Distinct Effects of Testosterone on Plasma and Cerebrospinal Fluid Amyloid-β Levels
Authors: Wahjoepramono, Eka J. | Wijaya, Linda K. | Taddei, Kevin | Martins, Georgia | Howard, Matthew | de Ruyck, Karl | Bates, Kristyn | Dhaliwal, Satvinder S. | Verdile, Giuseppe | Carruthers, Malcolm | Martins, Ralph N.
Article Type: Research Article
Abstract: The effect of testosterone on the levels of the Alzheimer's disease amyloid-β peptide (Aβ) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Aβ40 levels were measured. Plasma Aβ40 levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Aβ40 levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Aβ40 levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Aβ40 levels significantly increased over …time in these animals. These results indicate that the extent of testosterone-induced changes to Aβ40 levels and their response rates depend on both the tissue examined and testosterone dosage. Show more
Keywords: Aging, Alzheimer's disease, amyloid-β, castration, cerebrospinal fluid, guinea pig, testosterone
DOI: 10.3233/JAD-2008-15111
Citation: Journal of Alzheimer's Disease, vol. 15, no. 1, pp. 129-137, 2008
Evaluation of Color Preference in Zebrafish for Learning and Memory
Authors: Avdesh, Avdesh | Martin-Iverson, Mathew T. | Mondal, Alinda | Chen, Mengqi | Askraba, Sreten | Morgan, Newman | Lardelli, Michael | Groth, David M. | Verdile, Giuseppe | Martins, Ralph N.
Article Type: Research Article
Abstract: There is growing interest in using zebrafish (Danio rerio) as a model of neurodegenerative disorders such as Alzheimer's disease. A zebrafish model of tauopathies has recently been developed and characterized in terms of presence of the pathological hallmarks (i.e., neurofibrillary tangles and cell death). However, it is also necessary to validate these models for function by assessing learning and memory. The majority of tools to assess memory and learning in animal models involve visual stimuli, including color preference. The color preference of zebrafish has received little attention. To validate zebrafish as a model for color-associated-learning and memory, it is necessary …to evaluate its natural preferences or any pre-existing biases towards specific colors. In the present study, we have used four different colors (red, yellow, green, and blue) to test natural color preferences of the zebrafish using two procedures: Place preference and T-maze. Results from both experiments indicate a strong aversion toward blue color relative to all other colors (red, yellow, and green) when tested in combinations. No preferences or biases were found among reds, yellows, and greens in the place preference procedure. However, red and green were equally preferred and both were preferred over yellow by zebrafish in the T-maze procedure. The results from the present study show a strong aversion towards blue color compared to red, green, and yellow, with yellow being less preferred relative to red and green. The findings from this study may underpin any further designing of color-based learning and memory paradigms or experiments involving aversion, anxiety, or fear in the zebrafish. Show more
Keywords: Alzheimer's disease, color preference, learning and memory, place preference, T-maze, zebrafish
DOI: 10.3233/JAD-2011-110704
Citation: Journal of Alzheimer's Disease, vol. 28, no. 2, pp. 459-469, 2012