Unhealthy Diets Determine Benign or Toxic Amyloid Beta States and Promote Brain Amyloid Beta Aggregation

Review Article

Austin J Clin Neurol 2015;2(7): 1060.

Unhealthy Diets Determine Benign or Toxic Amyloid Beta States and Promote Brain Amyloid Beta Aggregation

Martins IJ1,2,3*

¹Centre of Excellence in Alzheimer’s disease Research and Care, Edith Cowan University, Australia

²School of Psychiatry and Clinical Neurosciences, University of Western Australia, Australia

³McCusker Alzheimer’s Research Foundation, Hollywood Medical Centre, Australia

*Corresponding author: Ian Martins, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Western Australia 6027, Australia

Received: April 21, 2015; Accepted: June 26, 2015; Published: June 29, 2015


Interests in amyloid beta oligomers and their relevance to mechanisms for toxic amyloid beta species has accelerated with effects on neuronal apoptosis in Alzheimer’s disease. Unhealthy diets that accelerate amyloidogenic pathways may involve lipids such as palmitic acid and cholesterol that promote hydrophobic self association reactions with amyloid beta aggregation in the brain. These diets corrupt membrane amyloid beta homeostasis and determine neuron senescence and the aging process. Amyloid beta oligomers generated by cell membrane cholesterol and phospholipids interact with acute phase reactants that determine the benign or toxic amyloid beta conformational states. In yeast amyloid beta oligomers have different toxicities and are relevant to human amyloid beta oligomers in the brain. In mammalian cells the dynamic nature of the amyloid beta oligomer states may be altered by bacterial lipopolysaccharides that involve membrane amphiphilic and charge polarization. Lipopolysaccarides partition in cell membranes and its interaction with apolipoprotein E corrupts the peripheral amyloid beta metabolism with effects on toxic amyloid beta generation in the brain with relevance to neurodegeneration and Alzheimer’s disease. The role of atherogenic diets involve dysregulation of peripheral lipopolysaccharide metabolism with effects on apolipoprotein E/amyloid beta and albumin/amyloid beta interactions associated with increased lipopolysaccharides in brain cells that determine neuroinflammation with relevance to toxic amyloid beta behaviour and memory disorders.

Keywords: Diet; Amyloid beta; Lipopolysaccharides; Cholesterol; Neurodegeneration; NAFLD


HDL: High Density Lipoprotein; LDL: Low Density Lipoprotein; LPS: Lipopolysaccharide; NAFLD: Non Alcoholic Fatty Liver Disease; AD: Alzheimer’s Disease; apo E: Apolipoprotein E; Aβ: Amyloid beta; APP: Acute Phase Proteins; PLTP: Phospholipid Transfer Protein; LBP: LPS Binding Protein; ABCA1: ATP Binding Cassette Transporter 1; EGCG: (-)-epigallactocatechin-3-gallate; LRP-1: Low Density Lipoprotein Receptor Related Protein 1; Sirt 1: Sirtuin 1; LDLr: Low Density Lipoprotein Receptor; BBB: Blood Brain Barrier; CD14: Cluster Of Differentiation 14; TLR-4: Toll-like Receptor 4


Healthy diets such as low fat and high fibre diets [1] that prevent metabolic diseases and neurodegeneration and have become of critical interest to the prevention of Alzheimer’s disease (AD) a neurodegenerative condition that involves disturbances in multiple higher brain functions that include cognition and memory. The main constituent of senile plaques associated with AD is amyloid beta (Aβ) [2] that is a proteolytic product of the larger amyloid precursor protein (APP). APP is cleaved by three proteases classified as α, β and γ secretases in neurons with formation of Aβ by a two step process that involves the β-site cleaving enzyme (BACE) and the γ secretases. Intracellular cholesterol levels determine the increased production of Aβ 40 and Aβ 42 species [3,4] from APP with early stages of cholesterol involved in the altered apolipoprotein E (apo E) and Aβ interaction with the acceleration of amyloidogenesis [5]. Most proteins fold into their native structure with few intermediate structures that become toxic to cells. The understanding of Aβ and protein folding has increased with the ability of the peptide to self associate and determine the benign or toxic Aβ states that promote brain Aβ aggregation [6]. The Aβ self association properties in mouse and man differ [5] and similarities between yeast and mammalian cells in toxic Aβ oligomer species have been shown [7,8]. The aggregation of Aβ involves the electrostatic nature of oligomeric amyloid assemblies that leads to Aβ plaque with extensive brain pathology. In man unhealthy diets have attracted interest and determine the benign or toxic amyloid beta oligomers that involve abnormal apoE cell membrane interactions with neuronal death.

Healthy diets that contain unsaturated fat, fruit and fish (omega-3) are associated with the reversal of non alcoholic liver disease (NAFLD) with the prevention of accelerated brain ageing [9-13]. High fibre diets that contain phytosterols are important to lower brain membrane cholesterol [1] and promote Aβ metabolism by the liver with the prevention of oligomeric Aβ species generation in the brain. In aging and neurodegeneration healthy diets that protect neurons early in life have become important with the regulation of neuronal cholesterol by phytosterols that reduce increased Aβ production and its ability to self-associate with Aβ aggregation [1]. Low carbohydrate diets and diets without xenobiotics [14] improve the rapid transport of Aβ from the brain to the liver with the prevention of early neurodegeneration. Healthy diets further improve drug therapy (statins) by the up regulation of the low density lipoprotein (LDL) receptor that lower brain cholesterol and oligomers with effects on the reverse transport of Aβ across the blood brain barrier to the periphery (peripheral sink abeta hypothesis).

Unhealthy diets that include high protein intake, high fat and high sugar diets have been associated with circadian imbalances and AD [11,15]. Low fat diets improve the circadian rhythm and also lower the absorption of lipophilic xenobiotics that may enter the CNS and promote circadian disturbances and neurodegeneration [14]. Interest in low calorie diets have increased in the developing and developed world with activation of the calorie sensitive anti-aging gene Sirtuin 1 (Sirt 1), a nicotinamide dependent protein deacetylase that is involved in brain neuron proliferation [16], circadian rhythm and Aβ metabolism [11]. Unhealthy diets that contain excess fatty acids (palmitic acid) and glucose down regulate Sirt 1 with the development of NAFLD and AD. The role of nutrigenomics and metabolic health have become central to the treatment of AD with nutritional therapy involved in the activation of genes such as Sirt 1[12] involved in brain neuron cholesterol and the early stages of amyloidogenesis. Reduction in food intake and increased consumption of Sirt 1 activators such as leucine and pyruvic acid reverse the effects of unhealthy diets associated with toxic Aβ states and Aβ aggregation [11].

Neuroinflammation has now become closely linked to AD with unhealthy diets associated with an increase in acute phase reactants and cytokines in the blood plasma [5,17]. The links between acute phase proteins (APP) that prevent toxic Aβ generation are now linked to abnormalities in various cholesterol containing lipoproteins such as LDL and high density lipoproteins (HDL). Interests in food restriction and fasting that leads to the reduced transport of fat from the intestine to the plasma and liver has increased with relevance to reducing the detrimental effects of bacterial lipopolysacchardies (LPS) that are endotoxins released from the outer layer of gram negative bacteria in the gut [17,18] that are responsible for cholesterol dyshomeostasis and inflammatory acute phase reactants associated with α-synuclein and Aβ aggregation [17,18]. Diets and foods (high fat, dairy, meat) that contain gram negative bacteria produce LPS have now become of critical importance to organ disease in global communities [19] with connections between nutrient metabolism, dyslipidemia and amyloidosis. Diets that contain high fat, protein and carbohydrates delay the clearance of plasma LPS and the Aβ peptide with the possible induction of NAFLD and AD [20,21]. NAFLD in obese and diabetic individuals delays LPS clearance that provokes a strong inflammatory immune response with risk for endotoxemia with altered apo E regulated amyloidosis. Therefore the amount and nature of food eaten is connected to plasma LPS levels with relevance to the accelerated aging process that is linked to defective HDL cholesterol metabolism and toxic Aβ oligomer generation involved with memory disorders and brain amyloidosis.

LPS effects on apo E and albumin levels are associated with amyloid beta oligomer metabolism

The understanding of the role of the peripheral sink Aβ hypothesis in AD implicates LPS of central importance in the determination of lipoprotein metabolism, phospholipid transfer protein (PLTP) activity that involve lipoprotein/membrane cholesterol efflux and the role of various APP involved in Aβ aggregation (Figure 1). LPS are endotoxins and essential components of the outer membrane of gram negative bacteria and consist of covalently linked segments, surface carbohydrate polymer, core oligosaccharide and acylated glycolipid that can bind to cell membranes to alter membrane interactions [17]. Experiments in yeast that involve endocytic Aβ trafficking with toxic Aβ oligomer species generation [7,8,22] are different to Aβ metabolism in mammalian cells with the recent involvement of bacterial LPS that regulates mammalian cell membrane cholesterol and Aβ oligomer metabolism [17]. In obese and diabetic individuals the increased LPS levels are involved in the neutralization of apo E mediated hepatic clearance of abeta [5,17,19].

Citation: Martins IJ. Unhealthy Diets Determine Benign or Toxic Amyloid Beta States and Promote Brain Amyloid Beta Aggregation. Austin J Clin Neurol 2015;2(7): 1060. ISSN : 2381-9154